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Emerging data help inform immunotherapy for urothelial cancer
SAN FRANCISCO – Emerging data from phase 3 clinical trials are better clarifying the efficacy and safety of immunotherapy in advanced urothelial cancer and helping identify patients most likely to benefit.
An updated analysis of the KEYNOTE-045 trial showed that, compared with chemotherapy, pembrolizumab (Keytruda), an antibody to programmed death-1 (PD-1), almost doubled the 2-year survival rate in patients with recurrent or advanced urothelial cancer. No cumulative toxicity was seen.
Biomarker analyses from the IMvigor 211 trial showed that, compared with chemotherapy, atezolizumab (Tecentriq), an antibody to programmed cell death ligand 1 (PD-L1), prolonged survival by more than 7 months in patients with platinum-treated locally advanced or metastatic disease whose tumors were positive for this ligand and had a high mutational burden. The difference translated to a halving of the risk of death.
Results of both trials were reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
“It is clear that PD-1 and PD-L1 targeted immunotherapy now has a role in most patients with advanced urothelial cancer,” Robert J. Jones, MBChB, PhD, professor of clinical cancer research, University of Glasgow, Beatson West of Scotland Cancer Centre, commented in an invited discussion. “It is also true that cytotoxic chemotherapy maintains a role for many, and that both modalities are often ineffective and may be toxic.”
KEYNOTE-045 trial update
Initial results of KEYNOTE-045, at a median follow-up of 14.1 months, provided level I evidence for the safety and efficacy of pembrolizumab over chemotherapy as second-line therapy for recurrent, advanced urothelial cancer (N Engl J Med. 2017;376:1015-26), leading to approval for that indication. (Pembrolizumab is also approved as first-line therapy for cisplatin-ineligible patients).
Lead investigator Joaquim Bellmunt, MD, PhD, an associate professor of medicine at Harvard Medical School and director of the Bladder Cancer Center, Dana-Farber Cancer Institute, both in Boston, reported a trial update, now at a median follow-up of 27.7 months.
Results among 542 patients showed that the initial overall survival benefit of pembrolizumab over chemotherapy (vinflunine, paclitaxel, or docetaxel) (hazard ratio, 0.73; P = .0022) was sustained and in fact now somewhat greater with longer follow-up (HR, 0.70; P = .00017).
Median overall survival was 10.3 months and 7.3 months, respectively. Corresponding 1-year survival rates were 44.4% and 29.8%, and corresponding 2-year survival rates, 27.0% and 14.3%.
At 24 months, 60.6% of patients in the chemotherapy arm had received an immunotherapy agent, including some who had received pembrolizumab as part of crossover, Dr. Bellmunt noted.
Overall survival benefit was generally similar across subgroups, including patients with PD-L1–positive tumors (defined as a combined positive score of 10% or higher) (HR, 0.56; P = .00153) and patients with PD-L1–negative tumors (HR, 0.75; P = .00859).
The lack of a progression-free survival benefit of pembrolizumab over chemotherapy in the initial analysis (HR, 0.98; P = .420) persisted in the updated analysis (HR, 0.96; P = .317).
The overall response rate now was 21.1% with pembrolizumab and 11.0% with chemotherapy. In the former group, the rate of complete response had increased from 7.0% to 9.3% with the longer follow-up. Median time to response was identical, at 2.1 months, but duration of response was longer with pembrolizumab (not reached vs. 4.4 months).
“We haven’t seen any signals of cumulative toxicity with subsequent follow-up,” Dr. Bellmunt reported. Similar to findings of the initial analysis, the most common grade 3-5 treatment-related adverse events were pruritus, fatigue, and diarrhea with pembrolizumab, and neutropenia, anemia, and fatigue with chemotherapy. As expected, the pembrolizumab group had higher rates of hypothyroidism, pneumonitis, hyperthyroidism, and colitis.
“The overall survival benefit and superior safety of pembrolizumab versus chemotherapy in this second-line patient population is maintained after 2 years of follow-up. At 24 months, 27% of patients are alive, and this is similar to what we are seeing with other immune-sensitive diseases like melanoma,” he concluded. “Results in patients with PD-L1–positive or –negative tumors were consistent with the intent-to-treat population. We have seen some hints with this biomarker, but they are not very striking.”
IMvigor 211 trial biomarker analyses
The IMvigor 211 trial enrolled 931 patients with locally advanced or metastatic urothelial carcinoma who had experienced progression during or after platinum-based chemotherapy and had received at most two prior lines of therapy.
At a median follow-up of 17.3 months, the trial did not meet its primary endpoint of significantly better overall survival with atezolizumab versus chemotherapy (vinflunine, docetaxel, or paclitaxel) in patients having PD-L1–positive tumors, defined as immunohistochemical staining of 2 or 3 (HR, 0.87; 95% confidence interval, 0.63-1.21; P = .41) (Lancet. 2018;391:748-57).
Findings were similar in the entire intention-to-treat population (HR, 0.85; 95% CI, 0.73-0.99) and in the subset with tumors having PD-L1–negative tumors, defined as immunohistochemical staining of 0 or 1 (HR, 0.84; 0.71-1.00). In an unexpected finding, PD-L1 positivity was associated with better outcome in both treatment arms.
“So PD-L1 is a classic prognostic, not predictive, biomarker,” commented lead investigator Thomas Powles, MBBS, MRCP, MD, a clinical professor of genitourinary oncology with Barts Health NHS Trust, St. Bartholomew’s Hospital, London. The investigators therefore conducted a series of analyses in the intent-to-treat population to identify predictive biomarkers.
Results were essentially the same with the tumor gene expression 3 (tGE3) signature, an RNA signature that captures expression of the genes encoding interferon gamma, a chemokine ligand, and PD-L1, and that is a marker for preexisting T-cell immunity. And they were also similar with the DNA damage response (DDR) biomarker.
However, a different pattern was seen with tumor mutational burden (TMB), a FoundationOne panel. Patients with TMB-high tumors had a substantial gain in overall survival from atezolizumab versus chemotherapy (HR, 0.68; 95% CI, 0.51-0.90), whereas those with TMB-low tumors did not (HR, 1.00; 95% CI, 0.75-1.32).
“TMB appears to be a predictive but not a prognostic biomarker,” Dr. Powles said. “It’s not perfect. Complete and partial responses and long overall survival were seen in both arms. Nevertheless, it seems like a step in the right direction.”
Finally, with insight on the nature and relationships of the various biomarkers, the investigators assessed the combination of TMB with PD-L1, finding that atezolizumab had a marked overall survival benefit in patients with TMB-high and PD-L1–positive tumors (17.8 vs. 10.6 months; HR, 0.50; 95% CI, 0.29-0.86).
“I think by using combinations of biomarkers, first-generation and second-generation, we may actually be able to better select patients for treatment in the future,” Dr. Powles concluded.
New data, new insights
“We already know the KEYNOTE-045 trial is positive,” commented the invited discussant, Dr. Jones. “This longer follow-up data is important because we need to better describe the magnitude of benefit.”
The updated survival findings are exciting because they resemble those seen with ipilimumab in melanoma, with about a fifth of patients still alive several years out, he said. Longer follow-up is needed, but “the data we see today are in keeping with the possibility that we might be seeing a similar long-term tail – the so-called immuno-oncology tail – of survival for patients with urothelial cancer as well.”
Although not statistically significant, the difference in progression-free survival is clinically important, according to Dr. Jones. This benefit is driven by both higher response rate and longer duration of response with pembrolizumab.
Long-term toxicity, especially immune-related toxicity, is also a consideration. “There is a small increment in the number of some of these toxicities, but essentially it hasn’t changed. So it would appear that there is certainly not an unexpected peak of latent immunotoxicity with this treatment,” he noted.
“Our confidence in the data for second-line pembrolizumab, if it needed to be further increased, is increased. This does help our patients make an informed decision about whether or not to accept this treatment,” he summarized.
Turning to the IMvigor 211 biomarker study, Dr. Jones said, “I would argue that the choice of second-line therapy in advanced urothelial cancer is not a clinically important decision. The reason for saying that is the case for second-line chemotherapy is poor. We’ve all used it, but we’ve never had high level evidence of benefit. … But it’s important because when we consider moving into the first-line setting, where there are active alternatives, or maybe even more into the perioperative setting, it actually could be vitally important.”
Studies of immunotherapies and targeted therapies in other cancers suggest that a clinically useful predictive biomarker will identify patients who will derive at least a doubling of favorable outcome or a halving of unfavorable outcome when given the drug as compared with a control. “So it appears that the bar has been set quite high,” Dr. Jones said.
“These IMvigor 211 data are exploratory, and they would need further independent validation, in my view,” he said. Nevertheless, “this may provide us the opportunity to use combinations of biomarkers where now we are seeing a hazard ratio of 0.50 [for risk of death] combining PD-L1 with high tumor mutational burden (TMB). That hazard ratio is bringing it into the area where it may be of a magnitude big enough to use in clinical practice, if this could be validated.”
“I would say that none of these data support a role for second-line cytotoxics after failure of platinum, at least not in preference to a checkpoint inhibitor,” Dr. Jones concluded. “There is still no biomarker to inform a choice in second-line treatment. However, TMB, either alone or in combination with other markers, shows promise, which we need to validate in future randomized trials.”
SOURCE: Bellmunt J et al. GUC 2018 Abstract 410; Powles T et al. GUC 2018, Abstract 409.
SAN FRANCISCO – Emerging data from phase 3 clinical trials are better clarifying the efficacy and safety of immunotherapy in advanced urothelial cancer and helping identify patients most likely to benefit.
An updated analysis of the KEYNOTE-045 trial showed that, compared with chemotherapy, pembrolizumab (Keytruda), an antibody to programmed death-1 (PD-1), almost doubled the 2-year survival rate in patients with recurrent or advanced urothelial cancer. No cumulative toxicity was seen.
Biomarker analyses from the IMvigor 211 trial showed that, compared with chemotherapy, atezolizumab (Tecentriq), an antibody to programmed cell death ligand 1 (PD-L1), prolonged survival by more than 7 months in patients with platinum-treated locally advanced or metastatic disease whose tumors were positive for this ligand and had a high mutational burden. The difference translated to a halving of the risk of death.
Results of both trials were reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
“It is clear that PD-1 and PD-L1 targeted immunotherapy now has a role in most patients with advanced urothelial cancer,” Robert J. Jones, MBChB, PhD, professor of clinical cancer research, University of Glasgow, Beatson West of Scotland Cancer Centre, commented in an invited discussion. “It is also true that cytotoxic chemotherapy maintains a role for many, and that both modalities are often ineffective and may be toxic.”
KEYNOTE-045 trial update
Initial results of KEYNOTE-045, at a median follow-up of 14.1 months, provided level I evidence for the safety and efficacy of pembrolizumab over chemotherapy as second-line therapy for recurrent, advanced urothelial cancer (N Engl J Med. 2017;376:1015-26), leading to approval for that indication. (Pembrolizumab is also approved as first-line therapy for cisplatin-ineligible patients).
Lead investigator Joaquim Bellmunt, MD, PhD, an associate professor of medicine at Harvard Medical School and director of the Bladder Cancer Center, Dana-Farber Cancer Institute, both in Boston, reported a trial update, now at a median follow-up of 27.7 months.
Results among 542 patients showed that the initial overall survival benefit of pembrolizumab over chemotherapy (vinflunine, paclitaxel, or docetaxel) (hazard ratio, 0.73; P = .0022) was sustained and in fact now somewhat greater with longer follow-up (HR, 0.70; P = .00017).
Median overall survival was 10.3 months and 7.3 months, respectively. Corresponding 1-year survival rates were 44.4% and 29.8%, and corresponding 2-year survival rates, 27.0% and 14.3%.
At 24 months, 60.6% of patients in the chemotherapy arm had received an immunotherapy agent, including some who had received pembrolizumab as part of crossover, Dr. Bellmunt noted.
Overall survival benefit was generally similar across subgroups, including patients with PD-L1–positive tumors (defined as a combined positive score of 10% or higher) (HR, 0.56; P = .00153) and patients with PD-L1–negative tumors (HR, 0.75; P = .00859).
The lack of a progression-free survival benefit of pembrolizumab over chemotherapy in the initial analysis (HR, 0.98; P = .420) persisted in the updated analysis (HR, 0.96; P = .317).
The overall response rate now was 21.1% with pembrolizumab and 11.0% with chemotherapy. In the former group, the rate of complete response had increased from 7.0% to 9.3% with the longer follow-up. Median time to response was identical, at 2.1 months, but duration of response was longer with pembrolizumab (not reached vs. 4.4 months).
“We haven’t seen any signals of cumulative toxicity with subsequent follow-up,” Dr. Bellmunt reported. Similar to findings of the initial analysis, the most common grade 3-5 treatment-related adverse events were pruritus, fatigue, and diarrhea with pembrolizumab, and neutropenia, anemia, and fatigue with chemotherapy. As expected, the pembrolizumab group had higher rates of hypothyroidism, pneumonitis, hyperthyroidism, and colitis.
“The overall survival benefit and superior safety of pembrolizumab versus chemotherapy in this second-line patient population is maintained after 2 years of follow-up. At 24 months, 27% of patients are alive, and this is similar to what we are seeing with other immune-sensitive diseases like melanoma,” he concluded. “Results in patients with PD-L1–positive or –negative tumors were consistent with the intent-to-treat population. We have seen some hints with this biomarker, but they are not very striking.”
IMvigor 211 trial biomarker analyses
The IMvigor 211 trial enrolled 931 patients with locally advanced or metastatic urothelial carcinoma who had experienced progression during or after platinum-based chemotherapy and had received at most two prior lines of therapy.
At a median follow-up of 17.3 months, the trial did not meet its primary endpoint of significantly better overall survival with atezolizumab versus chemotherapy (vinflunine, docetaxel, or paclitaxel) in patients having PD-L1–positive tumors, defined as immunohistochemical staining of 2 or 3 (HR, 0.87; 95% confidence interval, 0.63-1.21; P = .41) (Lancet. 2018;391:748-57).
Findings were similar in the entire intention-to-treat population (HR, 0.85; 95% CI, 0.73-0.99) and in the subset with tumors having PD-L1–negative tumors, defined as immunohistochemical staining of 0 or 1 (HR, 0.84; 0.71-1.00). In an unexpected finding, PD-L1 positivity was associated with better outcome in both treatment arms.
“So PD-L1 is a classic prognostic, not predictive, biomarker,” commented lead investigator Thomas Powles, MBBS, MRCP, MD, a clinical professor of genitourinary oncology with Barts Health NHS Trust, St. Bartholomew’s Hospital, London. The investigators therefore conducted a series of analyses in the intent-to-treat population to identify predictive biomarkers.
Results were essentially the same with the tumor gene expression 3 (tGE3) signature, an RNA signature that captures expression of the genes encoding interferon gamma, a chemokine ligand, and PD-L1, and that is a marker for preexisting T-cell immunity. And they were also similar with the DNA damage response (DDR) biomarker.
However, a different pattern was seen with tumor mutational burden (TMB), a FoundationOne panel. Patients with TMB-high tumors had a substantial gain in overall survival from atezolizumab versus chemotherapy (HR, 0.68; 95% CI, 0.51-0.90), whereas those with TMB-low tumors did not (HR, 1.00; 95% CI, 0.75-1.32).
“TMB appears to be a predictive but not a prognostic biomarker,” Dr. Powles said. “It’s not perfect. Complete and partial responses and long overall survival were seen in both arms. Nevertheless, it seems like a step in the right direction.”
Finally, with insight on the nature and relationships of the various biomarkers, the investigators assessed the combination of TMB with PD-L1, finding that atezolizumab had a marked overall survival benefit in patients with TMB-high and PD-L1–positive tumors (17.8 vs. 10.6 months; HR, 0.50; 95% CI, 0.29-0.86).
“I think by using combinations of biomarkers, first-generation and second-generation, we may actually be able to better select patients for treatment in the future,” Dr. Powles concluded.
New data, new insights
“We already know the KEYNOTE-045 trial is positive,” commented the invited discussant, Dr. Jones. “This longer follow-up data is important because we need to better describe the magnitude of benefit.”
The updated survival findings are exciting because they resemble those seen with ipilimumab in melanoma, with about a fifth of patients still alive several years out, he said. Longer follow-up is needed, but “the data we see today are in keeping with the possibility that we might be seeing a similar long-term tail – the so-called immuno-oncology tail – of survival for patients with urothelial cancer as well.”
Although not statistically significant, the difference in progression-free survival is clinically important, according to Dr. Jones. This benefit is driven by both higher response rate and longer duration of response with pembrolizumab.
Long-term toxicity, especially immune-related toxicity, is also a consideration. “There is a small increment in the number of some of these toxicities, but essentially it hasn’t changed. So it would appear that there is certainly not an unexpected peak of latent immunotoxicity with this treatment,” he noted.
“Our confidence in the data for second-line pembrolizumab, if it needed to be further increased, is increased. This does help our patients make an informed decision about whether or not to accept this treatment,” he summarized.
Turning to the IMvigor 211 biomarker study, Dr. Jones said, “I would argue that the choice of second-line therapy in advanced urothelial cancer is not a clinically important decision. The reason for saying that is the case for second-line chemotherapy is poor. We’ve all used it, but we’ve never had high level evidence of benefit. … But it’s important because when we consider moving into the first-line setting, where there are active alternatives, or maybe even more into the perioperative setting, it actually could be vitally important.”
Studies of immunotherapies and targeted therapies in other cancers suggest that a clinically useful predictive biomarker will identify patients who will derive at least a doubling of favorable outcome or a halving of unfavorable outcome when given the drug as compared with a control. “So it appears that the bar has been set quite high,” Dr. Jones said.
“These IMvigor 211 data are exploratory, and they would need further independent validation, in my view,” he said. Nevertheless, “this may provide us the opportunity to use combinations of biomarkers where now we are seeing a hazard ratio of 0.50 [for risk of death] combining PD-L1 with high tumor mutational burden (TMB). That hazard ratio is bringing it into the area where it may be of a magnitude big enough to use in clinical practice, if this could be validated.”
“I would say that none of these data support a role for second-line cytotoxics after failure of platinum, at least not in preference to a checkpoint inhibitor,” Dr. Jones concluded. “There is still no biomarker to inform a choice in second-line treatment. However, TMB, either alone or in combination with other markers, shows promise, which we need to validate in future randomized trials.”
SOURCE: Bellmunt J et al. GUC 2018 Abstract 410; Powles T et al. GUC 2018, Abstract 409.
SAN FRANCISCO – Emerging data from phase 3 clinical trials are better clarifying the efficacy and safety of immunotherapy in advanced urothelial cancer and helping identify patients most likely to benefit.
An updated analysis of the KEYNOTE-045 trial showed that, compared with chemotherapy, pembrolizumab (Keytruda), an antibody to programmed death-1 (PD-1), almost doubled the 2-year survival rate in patients with recurrent or advanced urothelial cancer. No cumulative toxicity was seen.
Biomarker analyses from the IMvigor 211 trial showed that, compared with chemotherapy, atezolizumab (Tecentriq), an antibody to programmed cell death ligand 1 (PD-L1), prolonged survival by more than 7 months in patients with platinum-treated locally advanced or metastatic disease whose tumors were positive for this ligand and had a high mutational burden. The difference translated to a halving of the risk of death.
Results of both trials were reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
“It is clear that PD-1 and PD-L1 targeted immunotherapy now has a role in most patients with advanced urothelial cancer,” Robert J. Jones, MBChB, PhD, professor of clinical cancer research, University of Glasgow, Beatson West of Scotland Cancer Centre, commented in an invited discussion. “It is also true that cytotoxic chemotherapy maintains a role for many, and that both modalities are often ineffective and may be toxic.”
KEYNOTE-045 trial update
Initial results of KEYNOTE-045, at a median follow-up of 14.1 months, provided level I evidence for the safety and efficacy of pembrolizumab over chemotherapy as second-line therapy for recurrent, advanced urothelial cancer (N Engl J Med. 2017;376:1015-26), leading to approval for that indication. (Pembrolizumab is also approved as first-line therapy for cisplatin-ineligible patients).
Lead investigator Joaquim Bellmunt, MD, PhD, an associate professor of medicine at Harvard Medical School and director of the Bladder Cancer Center, Dana-Farber Cancer Institute, both in Boston, reported a trial update, now at a median follow-up of 27.7 months.
Results among 542 patients showed that the initial overall survival benefit of pembrolizumab over chemotherapy (vinflunine, paclitaxel, or docetaxel) (hazard ratio, 0.73; P = .0022) was sustained and in fact now somewhat greater with longer follow-up (HR, 0.70; P = .00017).
Median overall survival was 10.3 months and 7.3 months, respectively. Corresponding 1-year survival rates were 44.4% and 29.8%, and corresponding 2-year survival rates, 27.0% and 14.3%.
At 24 months, 60.6% of patients in the chemotherapy arm had received an immunotherapy agent, including some who had received pembrolizumab as part of crossover, Dr. Bellmunt noted.
Overall survival benefit was generally similar across subgroups, including patients with PD-L1–positive tumors (defined as a combined positive score of 10% or higher) (HR, 0.56; P = .00153) and patients with PD-L1–negative tumors (HR, 0.75; P = .00859).
The lack of a progression-free survival benefit of pembrolizumab over chemotherapy in the initial analysis (HR, 0.98; P = .420) persisted in the updated analysis (HR, 0.96; P = .317).
The overall response rate now was 21.1% with pembrolizumab and 11.0% with chemotherapy. In the former group, the rate of complete response had increased from 7.0% to 9.3% with the longer follow-up. Median time to response was identical, at 2.1 months, but duration of response was longer with pembrolizumab (not reached vs. 4.4 months).
“We haven’t seen any signals of cumulative toxicity with subsequent follow-up,” Dr. Bellmunt reported. Similar to findings of the initial analysis, the most common grade 3-5 treatment-related adverse events were pruritus, fatigue, and diarrhea with pembrolizumab, and neutropenia, anemia, and fatigue with chemotherapy. As expected, the pembrolizumab group had higher rates of hypothyroidism, pneumonitis, hyperthyroidism, and colitis.
“The overall survival benefit and superior safety of pembrolizumab versus chemotherapy in this second-line patient population is maintained after 2 years of follow-up. At 24 months, 27% of patients are alive, and this is similar to what we are seeing with other immune-sensitive diseases like melanoma,” he concluded. “Results in patients with PD-L1–positive or –negative tumors were consistent with the intent-to-treat population. We have seen some hints with this biomarker, but they are not very striking.”
IMvigor 211 trial biomarker analyses
The IMvigor 211 trial enrolled 931 patients with locally advanced or metastatic urothelial carcinoma who had experienced progression during or after platinum-based chemotherapy and had received at most two prior lines of therapy.
At a median follow-up of 17.3 months, the trial did not meet its primary endpoint of significantly better overall survival with atezolizumab versus chemotherapy (vinflunine, docetaxel, or paclitaxel) in patients having PD-L1–positive tumors, defined as immunohistochemical staining of 2 or 3 (HR, 0.87; 95% confidence interval, 0.63-1.21; P = .41) (Lancet. 2018;391:748-57).
Findings were similar in the entire intention-to-treat population (HR, 0.85; 95% CI, 0.73-0.99) and in the subset with tumors having PD-L1–negative tumors, defined as immunohistochemical staining of 0 or 1 (HR, 0.84; 0.71-1.00). In an unexpected finding, PD-L1 positivity was associated with better outcome in both treatment arms.
“So PD-L1 is a classic prognostic, not predictive, biomarker,” commented lead investigator Thomas Powles, MBBS, MRCP, MD, a clinical professor of genitourinary oncology with Barts Health NHS Trust, St. Bartholomew’s Hospital, London. The investigators therefore conducted a series of analyses in the intent-to-treat population to identify predictive biomarkers.
Results were essentially the same with the tumor gene expression 3 (tGE3) signature, an RNA signature that captures expression of the genes encoding interferon gamma, a chemokine ligand, and PD-L1, and that is a marker for preexisting T-cell immunity. And they were also similar with the DNA damage response (DDR) biomarker.
However, a different pattern was seen with tumor mutational burden (TMB), a FoundationOne panel. Patients with TMB-high tumors had a substantial gain in overall survival from atezolizumab versus chemotherapy (HR, 0.68; 95% CI, 0.51-0.90), whereas those with TMB-low tumors did not (HR, 1.00; 95% CI, 0.75-1.32).
“TMB appears to be a predictive but not a prognostic biomarker,” Dr. Powles said. “It’s not perfect. Complete and partial responses and long overall survival were seen in both arms. Nevertheless, it seems like a step in the right direction.”
Finally, with insight on the nature and relationships of the various biomarkers, the investigators assessed the combination of TMB with PD-L1, finding that atezolizumab had a marked overall survival benefit in patients with TMB-high and PD-L1–positive tumors (17.8 vs. 10.6 months; HR, 0.50; 95% CI, 0.29-0.86).
“I think by using combinations of biomarkers, first-generation and second-generation, we may actually be able to better select patients for treatment in the future,” Dr. Powles concluded.
New data, new insights
“We already know the KEYNOTE-045 trial is positive,” commented the invited discussant, Dr. Jones. “This longer follow-up data is important because we need to better describe the magnitude of benefit.”
The updated survival findings are exciting because they resemble those seen with ipilimumab in melanoma, with about a fifth of patients still alive several years out, he said. Longer follow-up is needed, but “the data we see today are in keeping with the possibility that we might be seeing a similar long-term tail – the so-called immuno-oncology tail – of survival for patients with urothelial cancer as well.”
Although not statistically significant, the difference in progression-free survival is clinically important, according to Dr. Jones. This benefit is driven by both higher response rate and longer duration of response with pembrolizumab.
Long-term toxicity, especially immune-related toxicity, is also a consideration. “There is a small increment in the number of some of these toxicities, but essentially it hasn’t changed. So it would appear that there is certainly not an unexpected peak of latent immunotoxicity with this treatment,” he noted.
“Our confidence in the data for second-line pembrolizumab, if it needed to be further increased, is increased. This does help our patients make an informed decision about whether or not to accept this treatment,” he summarized.
Turning to the IMvigor 211 biomarker study, Dr. Jones said, “I would argue that the choice of second-line therapy in advanced urothelial cancer is not a clinically important decision. The reason for saying that is the case for second-line chemotherapy is poor. We’ve all used it, but we’ve never had high level evidence of benefit. … But it’s important because when we consider moving into the first-line setting, where there are active alternatives, or maybe even more into the perioperative setting, it actually could be vitally important.”
Studies of immunotherapies and targeted therapies in other cancers suggest that a clinically useful predictive biomarker will identify patients who will derive at least a doubling of favorable outcome or a halving of unfavorable outcome when given the drug as compared with a control. “So it appears that the bar has been set quite high,” Dr. Jones said.
“These IMvigor 211 data are exploratory, and they would need further independent validation, in my view,” he said. Nevertheless, “this may provide us the opportunity to use combinations of biomarkers where now we are seeing a hazard ratio of 0.50 [for risk of death] combining PD-L1 with high tumor mutational burden (TMB). That hazard ratio is bringing it into the area where it may be of a magnitude big enough to use in clinical practice, if this could be validated.”
“I would say that none of these data support a role for second-line cytotoxics after failure of platinum, at least not in preference to a checkpoint inhibitor,” Dr. Jones concluded. “There is still no biomarker to inform a choice in second-line treatment. However, TMB, either alone or in combination with other markers, shows promise, which we need to validate in future randomized trials.”
SOURCE: Bellmunt J et al. GUC 2018 Abstract 410; Powles T et al. GUC 2018, Abstract 409.
REPORTING FROM GUCS 2018
Key clinical point:
Major finding: Pembrolizumab yielded a higher 2-year rate of survival vs. chemotherapy (27.0% vs. 14.3%). Atezolizumab had a marked survival benefit vs. chemotherapy in patients with TMB-high, PD-L1–positive tumors (17.8 vs. 10.6 months; HR, 0.50).
Data source: Two-year follow-up of a phase 3 randomized trial among 542 patients with recurrent, advanced urothelial cancer (KEYNOTE-045 trial). Biomarker analyses of a phase 3 randomized trial among 931 patients with platinum-treated locally advanced or metastatic urothelial cancer (IMvigor 211 trial).
Disclosures: Dr. Bellmunt disclosed that he has a consulting or advisory role with Astellas Pharma, AstraZeneca/MedImmune, Bristol-Myers Squibb, Genentech, Merck, Novartis, Pfizer, and Pierre Fabre; that his institution receives research funding from Millennium and Sanofi; and that he receives travel, accommodations, and/or expenses from MSD Oncology and Pfizer. KEYNOTE-045 was funded by Merck & Co. Dr. Powles disclosed that he receives honoraria from Bristol-Myers Squibb, Merck, and Roche/Genentech; has a consulting or advisory role with AstraZeneca; Bristol-Myers Squibb, Roche/Genentech, Merck, and Novartis; receives research funding from AstraZeneca/MedImmune and Roche/Genentech; and has another relationship with Bristol-Myers Squibb and Ipsen. IMvigor 211 was sponsored by Hoffmann-La Roche.
Sources: Bellmunt J et al. GUC 2018 Abstract 410; Powles T et al. GUC 2018, Abstract 409.
Enzalutamide shines in nonmetastatic castration-resistant prostate cancer
SAN FRANCISCO – The androgen receptor inhibitor enzalutamide is efficacious for treating nonmetastatic castration-resistant prostate cancer accompanied by a rapidly rising prostate-specific antigen (PSA) level, according to results of the phase 3 PROSPER trial.
“Nonmetastatic castration-resistant prostate cancer is an area of unmet need with no currently approved therapies. The development of metastases is predictable in this group of patients and is associated with increasing baseline PSA and a PSA doubling time of less than 10 months,” said lead author Maha Hussain, MBChB, deputy director at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago. “Delaying time to all metastases, which is a very clinically relevant endpoint because that is the terminal phase of the disease, is important, with the potential to delay cancer-related morbidity and also prolong overall survival.”
The PROSPER investigators enrolled 1,401 men with nonmetastatic castration-resistant prostate cancer and a PSA doubling time of 10 months or less despite castrate levels of testosterone. They were randomized 2:1 to enzalutamide (Xtandi) or placebo, with continuation of androgen deprivation therapy in both groups. (At present, enzalutamide is approved by the Food and Drug Administration for untreated and docetaxel-treated metastatic castration-resistant prostate cancer).
With a median follow-up of 22 months, median metastasis-free survival (based on radiographic progression or death) was about 22 months longer with enzalutamide versus placebo, according to results reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. The difference translated to a 71% reduction in risk of events.
Relative to peers in the placebo group, patients in the enzalutamide group also had dramatically longer time to PSA progression (93% risk reduction) and time to first use of new antineoplastic therapy (79% risk reduction). An interim analysis showed a trend toward better overall survival with the drug as well, and it was well tolerated.
Although progression on PROSPER was ascertained by conventional imaging, advent of new, more sensitive imaging modalities, such as fluciclovine and prostate-specific membrane antigen PET, are unlikely to change the calculus, according to Dr. Hussain. “These patients have micrometastatic disease. The fact that we have imaging criteria right now that are not very sensitive does not mean we don’t think the patients have micromets. With the newer technologies, certainly, a good chunk of these patients could have physical metastatic disease,” she elaborated. And cancer treatments often achieve greater benefits when moved earlier in the disease course.
Approved indications aside, oncologists will likely take a tailored approach when deciding to treat nonmetastatic castration-resistant prostate cancer with enzalutamide or a similar agent, Dr. Hussain said. “Like anything else, the issue is going to boil down to a shared decision with the patient, pros and cons, and then making a decision together.”
The findings with enzalutamide in the PROSPER trial are also noteworthy in that they largely mirror those obtained with apalutamide in the SPARTAN trial, which were reported in the same session at the symposium.
Weighing the evidence
The 2-year prolongation of metastasis-free survival with apalutamide and enzalutamide is “very impressive,” said invited discussant Philip Kantoff, MD, a medical oncologist and chair of the department of medicine, Memorial Sloan Kettering Cancer Center in New York. “These drugs are very biologically active. This potentially gives us options for men with M0 castration-resistant prostate cancer. It’s something I would like to see as a clinician, but we have to be a little bit cautious. Treating asymptomatic patients carries a certain burden of proof wherein benefit must clearly outweigh risk.”
Clinical benefit of a drug in this patient population could be shown in three ways, he said: curing disease (which is unlikely), prolonging survival (which is as yet unproven), and improving quality of life by, for example, reducing anxiety over rising PSA levels and preventing skeletal-related adverse events (which is hinted at by SPARTAN data showing that enzalutamide delayed time to symptomatic progression).
“Clinical benefit, to me, is not fully demonstrated in these two studies, and there are some untoward effects that need to be better defined,” Dr. Kantoff maintained. In particular, apalutamide was associated with higher (albeit still low) rates of grade 3 or worse falls, fractures, and rash, and enzalutamide with more deaths in the absence of radiographic progression, for unclear reasons.
“My confidence in declaring victory would be greater with further scrutiny of the toxicities and understanding how the care patterns in these studies compare with actual practice, specifically, the timing of initiation of alternative therapies in these trials as opposed to what’s going on in the community,” he said.
It is too early to determine whether one drug is superior, according to Dr. Kantoff. “These were not comparative trials, so we don’t have enough information to say one versus the other. There’s a hint of different toxicity profiles. It isn’t clear that the efficacy is different.” And when it comes to adoption by community oncology, the FDA will have a role, sifting through the data for both drugs and rendering decisions, he said.
Study details
Median metastasis-free survival in PROSPER was 36.6 months with enzalutamide and 14.7 months with placebo (hazard ratio, 0.29; P less than .0001), Dr. Hussain reported. Benefit was similar across a range of patient subgroups, including patients with PSA doubling times of less than and greater than 6 months.
Patients in the enzalutamide group had half the rate of progression events when compared with peers in the placebo group (23% vs. 49%). Among those with a metastasis-free survival event, the rate of deaths without documented radiographic progression after stopping study treatment was higher with enzalutamide (15% vs. 2%); there were somewhat more cardiovascular deaths with the drug within this subset, but no single cause was clearly predominant, she said.
Median time to PSA progression was 37.2 months with enzalutamide and merely 3.9 months with placebo (HR, 0.07; P less than .0001). Median time to first use of new antineoplastic therapy was 39.6 months and 17.7 months, respectively (HR, 0.21; P less than .0001).
Median overall survival was not yet reached in either group, but tended to be longer with enzalutamide (HR, 0.80).
“Therapy overall was well tolerated. Adverse events were generally consistent with those reported in prior clinical trials in men with castration-resistant disease,” Dr. Hussain said. The rate of grade 3 or worse events was 31% with enzalutamide and 23% with placebo. The enzalutamide group more commonly experienced grade 3 or worse hypertension (5% vs. 2%) and fatigue (3% vs. 1%).
The rate of adverse events leading to study discontinuation was 9% with enzalutamide and 6% with placebo, and that of death due to adverse events was 3% and 1%, respectively.
Dr. Hussain disclosed that she receives honoraria from OncLive; has a consulting or advisory role with Abbvie, Bayer, and Genentech/Roche; has patents, royalties, or other intellectual property pertaining to dual inhibition of MET and VEGF for the treatment of castration-resistant prostate cancer; and receives travel, accommodations, or expenses from Abbvie, Bayer, and Genentech. In addition, her institution receives research funding from AstraZeneca, Genentech, PCCTC, and Pfizer. The trial was sponsored by Pfizer, with collaboration of Astellas Pharma Inc. and Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
SOURCE: Hussain M et al. Abstract 3.
SAN FRANCISCO – The androgen receptor inhibitor enzalutamide is efficacious for treating nonmetastatic castration-resistant prostate cancer accompanied by a rapidly rising prostate-specific antigen (PSA) level, according to results of the phase 3 PROSPER trial.
“Nonmetastatic castration-resistant prostate cancer is an area of unmet need with no currently approved therapies. The development of metastases is predictable in this group of patients and is associated with increasing baseline PSA and a PSA doubling time of less than 10 months,” said lead author Maha Hussain, MBChB, deputy director at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago. “Delaying time to all metastases, which is a very clinically relevant endpoint because that is the terminal phase of the disease, is important, with the potential to delay cancer-related morbidity and also prolong overall survival.”
The PROSPER investigators enrolled 1,401 men with nonmetastatic castration-resistant prostate cancer and a PSA doubling time of 10 months or less despite castrate levels of testosterone. They were randomized 2:1 to enzalutamide (Xtandi) or placebo, with continuation of androgen deprivation therapy in both groups. (At present, enzalutamide is approved by the Food and Drug Administration for untreated and docetaxel-treated metastatic castration-resistant prostate cancer).
With a median follow-up of 22 months, median metastasis-free survival (based on radiographic progression or death) was about 22 months longer with enzalutamide versus placebo, according to results reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. The difference translated to a 71% reduction in risk of events.
Relative to peers in the placebo group, patients in the enzalutamide group also had dramatically longer time to PSA progression (93% risk reduction) and time to first use of new antineoplastic therapy (79% risk reduction). An interim analysis showed a trend toward better overall survival with the drug as well, and it was well tolerated.
Although progression on PROSPER was ascertained by conventional imaging, advent of new, more sensitive imaging modalities, such as fluciclovine and prostate-specific membrane antigen PET, are unlikely to change the calculus, according to Dr. Hussain. “These patients have micrometastatic disease. The fact that we have imaging criteria right now that are not very sensitive does not mean we don’t think the patients have micromets. With the newer technologies, certainly, a good chunk of these patients could have physical metastatic disease,” she elaborated. And cancer treatments often achieve greater benefits when moved earlier in the disease course.
Approved indications aside, oncologists will likely take a tailored approach when deciding to treat nonmetastatic castration-resistant prostate cancer with enzalutamide or a similar agent, Dr. Hussain said. “Like anything else, the issue is going to boil down to a shared decision with the patient, pros and cons, and then making a decision together.”
The findings with enzalutamide in the PROSPER trial are also noteworthy in that they largely mirror those obtained with apalutamide in the SPARTAN trial, which were reported in the same session at the symposium.
Weighing the evidence
The 2-year prolongation of metastasis-free survival with apalutamide and enzalutamide is “very impressive,” said invited discussant Philip Kantoff, MD, a medical oncologist and chair of the department of medicine, Memorial Sloan Kettering Cancer Center in New York. “These drugs are very biologically active. This potentially gives us options for men with M0 castration-resistant prostate cancer. It’s something I would like to see as a clinician, but we have to be a little bit cautious. Treating asymptomatic patients carries a certain burden of proof wherein benefit must clearly outweigh risk.”
Clinical benefit of a drug in this patient population could be shown in three ways, he said: curing disease (which is unlikely), prolonging survival (which is as yet unproven), and improving quality of life by, for example, reducing anxiety over rising PSA levels and preventing skeletal-related adverse events (which is hinted at by SPARTAN data showing that enzalutamide delayed time to symptomatic progression).
“Clinical benefit, to me, is not fully demonstrated in these two studies, and there are some untoward effects that need to be better defined,” Dr. Kantoff maintained. In particular, apalutamide was associated with higher (albeit still low) rates of grade 3 or worse falls, fractures, and rash, and enzalutamide with more deaths in the absence of radiographic progression, for unclear reasons.
“My confidence in declaring victory would be greater with further scrutiny of the toxicities and understanding how the care patterns in these studies compare with actual practice, specifically, the timing of initiation of alternative therapies in these trials as opposed to what’s going on in the community,” he said.
It is too early to determine whether one drug is superior, according to Dr. Kantoff. “These were not comparative trials, so we don’t have enough information to say one versus the other. There’s a hint of different toxicity profiles. It isn’t clear that the efficacy is different.” And when it comes to adoption by community oncology, the FDA will have a role, sifting through the data for both drugs and rendering decisions, he said.
Study details
Median metastasis-free survival in PROSPER was 36.6 months with enzalutamide and 14.7 months with placebo (hazard ratio, 0.29; P less than .0001), Dr. Hussain reported. Benefit was similar across a range of patient subgroups, including patients with PSA doubling times of less than and greater than 6 months.
Patients in the enzalutamide group had half the rate of progression events when compared with peers in the placebo group (23% vs. 49%). Among those with a metastasis-free survival event, the rate of deaths without documented radiographic progression after stopping study treatment was higher with enzalutamide (15% vs. 2%); there were somewhat more cardiovascular deaths with the drug within this subset, but no single cause was clearly predominant, she said.
Median time to PSA progression was 37.2 months with enzalutamide and merely 3.9 months with placebo (HR, 0.07; P less than .0001). Median time to first use of new antineoplastic therapy was 39.6 months and 17.7 months, respectively (HR, 0.21; P less than .0001).
Median overall survival was not yet reached in either group, but tended to be longer with enzalutamide (HR, 0.80).
“Therapy overall was well tolerated. Adverse events were generally consistent with those reported in prior clinical trials in men with castration-resistant disease,” Dr. Hussain said. The rate of grade 3 or worse events was 31% with enzalutamide and 23% with placebo. The enzalutamide group more commonly experienced grade 3 or worse hypertension (5% vs. 2%) and fatigue (3% vs. 1%).
The rate of adverse events leading to study discontinuation was 9% with enzalutamide and 6% with placebo, and that of death due to adverse events was 3% and 1%, respectively.
Dr. Hussain disclosed that she receives honoraria from OncLive; has a consulting or advisory role with Abbvie, Bayer, and Genentech/Roche; has patents, royalties, or other intellectual property pertaining to dual inhibition of MET and VEGF for the treatment of castration-resistant prostate cancer; and receives travel, accommodations, or expenses from Abbvie, Bayer, and Genentech. In addition, her institution receives research funding from AstraZeneca, Genentech, PCCTC, and Pfizer. The trial was sponsored by Pfizer, with collaboration of Astellas Pharma Inc. and Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
SOURCE: Hussain M et al. Abstract 3.
SAN FRANCISCO – The androgen receptor inhibitor enzalutamide is efficacious for treating nonmetastatic castration-resistant prostate cancer accompanied by a rapidly rising prostate-specific antigen (PSA) level, according to results of the phase 3 PROSPER trial.
“Nonmetastatic castration-resistant prostate cancer is an area of unmet need with no currently approved therapies. The development of metastases is predictable in this group of patients and is associated with increasing baseline PSA and a PSA doubling time of less than 10 months,” said lead author Maha Hussain, MBChB, deputy director at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago. “Delaying time to all metastases, which is a very clinically relevant endpoint because that is the terminal phase of the disease, is important, with the potential to delay cancer-related morbidity and also prolong overall survival.”
The PROSPER investigators enrolled 1,401 men with nonmetastatic castration-resistant prostate cancer and a PSA doubling time of 10 months or less despite castrate levels of testosterone. They were randomized 2:1 to enzalutamide (Xtandi) or placebo, with continuation of androgen deprivation therapy in both groups. (At present, enzalutamide is approved by the Food and Drug Administration for untreated and docetaxel-treated metastatic castration-resistant prostate cancer).
With a median follow-up of 22 months, median metastasis-free survival (based on radiographic progression or death) was about 22 months longer with enzalutamide versus placebo, according to results reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. The difference translated to a 71% reduction in risk of events.
Relative to peers in the placebo group, patients in the enzalutamide group also had dramatically longer time to PSA progression (93% risk reduction) and time to first use of new antineoplastic therapy (79% risk reduction). An interim analysis showed a trend toward better overall survival with the drug as well, and it was well tolerated.
Although progression on PROSPER was ascertained by conventional imaging, advent of new, more sensitive imaging modalities, such as fluciclovine and prostate-specific membrane antigen PET, are unlikely to change the calculus, according to Dr. Hussain. “These patients have micrometastatic disease. The fact that we have imaging criteria right now that are not very sensitive does not mean we don’t think the patients have micromets. With the newer technologies, certainly, a good chunk of these patients could have physical metastatic disease,” she elaborated. And cancer treatments often achieve greater benefits when moved earlier in the disease course.
Approved indications aside, oncologists will likely take a tailored approach when deciding to treat nonmetastatic castration-resistant prostate cancer with enzalutamide or a similar agent, Dr. Hussain said. “Like anything else, the issue is going to boil down to a shared decision with the patient, pros and cons, and then making a decision together.”
The findings with enzalutamide in the PROSPER trial are also noteworthy in that they largely mirror those obtained with apalutamide in the SPARTAN trial, which were reported in the same session at the symposium.
Weighing the evidence
The 2-year prolongation of metastasis-free survival with apalutamide and enzalutamide is “very impressive,” said invited discussant Philip Kantoff, MD, a medical oncologist and chair of the department of medicine, Memorial Sloan Kettering Cancer Center in New York. “These drugs are very biologically active. This potentially gives us options for men with M0 castration-resistant prostate cancer. It’s something I would like to see as a clinician, but we have to be a little bit cautious. Treating asymptomatic patients carries a certain burden of proof wherein benefit must clearly outweigh risk.”
Clinical benefit of a drug in this patient population could be shown in three ways, he said: curing disease (which is unlikely), prolonging survival (which is as yet unproven), and improving quality of life by, for example, reducing anxiety over rising PSA levels and preventing skeletal-related adverse events (which is hinted at by SPARTAN data showing that enzalutamide delayed time to symptomatic progression).
“Clinical benefit, to me, is not fully demonstrated in these two studies, and there are some untoward effects that need to be better defined,” Dr. Kantoff maintained. In particular, apalutamide was associated with higher (albeit still low) rates of grade 3 or worse falls, fractures, and rash, and enzalutamide with more deaths in the absence of radiographic progression, for unclear reasons.
“My confidence in declaring victory would be greater with further scrutiny of the toxicities and understanding how the care patterns in these studies compare with actual practice, specifically, the timing of initiation of alternative therapies in these trials as opposed to what’s going on in the community,” he said.
It is too early to determine whether one drug is superior, according to Dr. Kantoff. “These were not comparative trials, so we don’t have enough information to say one versus the other. There’s a hint of different toxicity profiles. It isn’t clear that the efficacy is different.” And when it comes to adoption by community oncology, the FDA will have a role, sifting through the data for both drugs and rendering decisions, he said.
Study details
Median metastasis-free survival in PROSPER was 36.6 months with enzalutamide and 14.7 months with placebo (hazard ratio, 0.29; P less than .0001), Dr. Hussain reported. Benefit was similar across a range of patient subgroups, including patients with PSA doubling times of less than and greater than 6 months.
Patients in the enzalutamide group had half the rate of progression events when compared with peers in the placebo group (23% vs. 49%). Among those with a metastasis-free survival event, the rate of deaths without documented radiographic progression after stopping study treatment was higher with enzalutamide (15% vs. 2%); there were somewhat more cardiovascular deaths with the drug within this subset, but no single cause was clearly predominant, she said.
Median time to PSA progression was 37.2 months with enzalutamide and merely 3.9 months with placebo (HR, 0.07; P less than .0001). Median time to first use of new antineoplastic therapy was 39.6 months and 17.7 months, respectively (HR, 0.21; P less than .0001).
Median overall survival was not yet reached in either group, but tended to be longer with enzalutamide (HR, 0.80).
“Therapy overall was well tolerated. Adverse events were generally consistent with those reported in prior clinical trials in men with castration-resistant disease,” Dr. Hussain said. The rate of grade 3 or worse events was 31% with enzalutamide and 23% with placebo. The enzalutamide group more commonly experienced grade 3 or worse hypertension (5% vs. 2%) and fatigue (3% vs. 1%).
The rate of adverse events leading to study discontinuation was 9% with enzalutamide and 6% with placebo, and that of death due to adverse events was 3% and 1%, respectively.
Dr. Hussain disclosed that she receives honoraria from OncLive; has a consulting or advisory role with Abbvie, Bayer, and Genentech/Roche; has patents, royalties, or other intellectual property pertaining to dual inhibition of MET and VEGF for the treatment of castration-resistant prostate cancer; and receives travel, accommodations, or expenses from Abbvie, Bayer, and Genentech. In addition, her institution receives research funding from AstraZeneca, Genentech, PCCTC, and Pfizer. The trial was sponsored by Pfizer, with collaboration of Astellas Pharma Inc. and Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
SOURCE: Hussain M et al. Abstract 3.
REPORTING FROM GUCS 2018
Key clinical point:
Major finding: Metastasis-free survival was 36.6 months with enzalutamide and 14.7 months with placebo (hazard ratio, 0.29; P less than .0001).
Data source: A phase 3 randomized trial among 1,401 men with nonmetastatic castration-resistant prostate cancer and rapidly rising PSA level (PROSPER trial).
Disclosures: Dr. Hussain disclosed that she receives honoraria from OncLive; has a consulting or advisory role with Abbvie, Bayer, and Genentech/Roche; has patents, royalties, or other intellectual property pertaining to dual inhibition of MET and VEGF for the treatment of castration-resistant prostate cancer; and receives travel, accommodations, or expenses from Abbvie, Bayer, and Genentech. In addition, her institution receives research funding from AstraZeneca, Genentech, PCCTC, and Pfizer. The trial was sponsored by Pfizer, with collaboration of Astellas Pharma Inc. and Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
Source: Hussain M et al. Abstract 3.
Bladder cancer: Two chemoradiation therapy regimens on par for muscle-invasive disease
SAN FRANCISCO – Two concurrent chemoradiation induction regimens had similar safety and efficacy when used as part of a bladder-sparing strategy in patients with muscle-invasive bladder cancer, suggest primary results of the NRG/RTOG 0712 trial. But one offers better patient convenience.
The selective bladder-preservation paradigm entails maximal transurethral resection of the bladder tumor (TURBT) followed by induction radiation and concomitant chemotherapy, lead author John J. Coen, MD, a radiation oncologist with 21st Century Oncology, Providence, Rhode Island, noted at the 2018 Genitourinary Cancers Symposium. Patients then undergo cystoscopy to assess their response.
“A key component of this therapy is close urologic surveillance,” he noted. “This is trimodality therapy with close urologic surveillance, and cystectomy is prompted at the earliest time it’s indicated.”
The 70 patients enrolled in the multicenter randomized phase 2 trial had undergone TURBT and were randomized evenly to twice-daily radiation plus 5-flourouracil-cisplatin (the RTOG standard at the time of trial planning) or to daily radiation plus gemcitabine (a modification of a successful regimen developed at the University of Michigan). All were offered adjuvant chemotherapy regardless of whether they responded and whether they underwent consolidation therapy or cystectomy.
At a median follow-up of 5.1 years among the 52 evaluable patients, the 3-year rate of freedom from distant metastasis, the trial’s primary endpoint, was 78% with twice-daily radiation plus 5-flourouracil-cisplatin and 84% with daily radiation plus gemcitabine, according to results reported at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Both values were higher than the trial’s predefined benchmark of 75% for defining the regimen as promising. “This trial wasn’t necessarily powered to compare arms, so the conclusion would be that both arms exceeded the benchmark and it would be appropriate to evaluate both arms further in subsequent trials,” Dr. Coen commented.
In each trial arm, more than three-fourths of patients had a complete response, and about two-thirds of patients were alive and free of distant metastasis with their bladder intact at 3 years.
Toxicity, which was supposed to be the tie-breaker if efficacy was similar, was also essentially the same for the two regimens. Both were fairly well tolerated in the acute period; the primary grade 3 and 4 toxicities were hematologic ones.
“So where do we go from here? I think this trial does demonstrate concurrent gemcitabine is a reasonable alternative to cisplatin for patients undergoing selective bladder preservation,” Dr. Coen summarized. “This is especially important in patients with poor renal function or hearing loss. And bladder cancer is often a disease in the elderly, so tolerance of various regimens is a very important aspect to planning further trials.”
“This trial also demonstrates that daily radiation is a reasonable alternative to twice-a-day radiation, which had become the standard through the RTOG on more contemporary trials,” he added. “Daily radiation would allow wider adoption of selective bladder preservation by trimodality therapy.”
Clinical implications
“I would have to see more details about the toxicity data for the chemotherapy, the radiosensitizers,” session co-chair Yair Lotan, MD, a professor of urology at the UT Southwestern Medical Center, Dallas, Texas, commented in an interview. “But in general, if you have two equivalent protocols in terms of effectiveness, and one is less toxic or more convenient, that’s always preferable. From the standpoint of coming once a day rather than twice a day to get radiation, if I were a patient, I would prefer that regimen”
Current practice in this patient population likely hinges on where a patient is treated, he said. “Based on the new nonmetastatic muscle-invasive guidelines, many of them would be recommended surgery or possibly chemoradiation protocols, and then there are a lot of factors such as patient preference and outcomes that would probably impact the decision making.”
“Certainly, this study won’t prove standard of care because standard of care in the global picture for a patient with muscle-invasive disease really will depend on a randomized trial of surgery versus radiation or chemoradiation, multimodal therapies,” Dr. Lotan maintained. “Not every patient is even eligible; some patients with hydronephrosis or unresectable disease may not be the best candidates for multimodal therapy. But more information from these types of trials may help clinicians decide which multimodal therapy approach to use.”
Study details
Patients enrolled in NRG/RTOG 0712, a multicenter randomized phase 2 trial supported by the National Cancer Institute, had clinical T2 or T3-4a bladder cancer. Hydronephrosis and obvious lymph node involvement were exclusion criteria.
Like the rate of freedom from metastasis, the rate of complete response after induction therapy was similar for the two arms: 87.9% with twice-daily radiation plus 5-flourouracil-cisplatin and 75.8% with daily radiation plus gemcitabine.
“These rates exceed historical complete response rates, and this is likely a result of improved selection over time and more thorough TURBTs performed over time,” Dr. Coen proposed. “Over the course of multiple successive RTOG trials, our selection criteria have been refined. One excellent example would be that hydronephrosis has been excluded on more contemporary trials, but if you look at older trials, those patients were included.”
The 3-year rate of bladder-intact distant metastasis–free survival was 66.7% and 69%, respectively. “This is a very important endpoint. These results are excellent,” he commented. “And there is really no appreciable difference between the two arms on the actuarial analysis.”
As far as specific treatment failure events in the trial overall, three patients died, eight underwent cystectomy, and eight developed distant metastases. Although numbers were small, these events appeared fairly evenly distributed across arms.
The rate of grade 3 or 4 acute toxicity was 57.6% with twice-daily radiation plus 5-flourouracil-cisplatin and 54.6% with daily radiation plus gemcitabine. The large majority of events were blood and bone marrow toxicity. “It’s quite notable that the rates of GU and GI toxicity were very low,” commented Dr. Coen, who disclosed that he had no relevant conflicts of interest.
SOURCE: Coen, J. et al, 2018 Genitourinary Cancers Symposium, Abstract 408
SAN FRANCISCO – Two concurrent chemoradiation induction regimens had similar safety and efficacy when used as part of a bladder-sparing strategy in patients with muscle-invasive bladder cancer, suggest primary results of the NRG/RTOG 0712 trial. But one offers better patient convenience.
The selective bladder-preservation paradigm entails maximal transurethral resection of the bladder tumor (TURBT) followed by induction radiation and concomitant chemotherapy, lead author John J. Coen, MD, a radiation oncologist with 21st Century Oncology, Providence, Rhode Island, noted at the 2018 Genitourinary Cancers Symposium. Patients then undergo cystoscopy to assess their response.
“A key component of this therapy is close urologic surveillance,” he noted. “This is trimodality therapy with close urologic surveillance, and cystectomy is prompted at the earliest time it’s indicated.”
The 70 patients enrolled in the multicenter randomized phase 2 trial had undergone TURBT and were randomized evenly to twice-daily radiation plus 5-flourouracil-cisplatin (the RTOG standard at the time of trial planning) or to daily radiation plus gemcitabine (a modification of a successful regimen developed at the University of Michigan). All were offered adjuvant chemotherapy regardless of whether they responded and whether they underwent consolidation therapy or cystectomy.
At a median follow-up of 5.1 years among the 52 evaluable patients, the 3-year rate of freedom from distant metastasis, the trial’s primary endpoint, was 78% with twice-daily radiation plus 5-flourouracil-cisplatin and 84% with daily radiation plus gemcitabine, according to results reported at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Both values were higher than the trial’s predefined benchmark of 75% for defining the regimen as promising. “This trial wasn’t necessarily powered to compare arms, so the conclusion would be that both arms exceeded the benchmark and it would be appropriate to evaluate both arms further in subsequent trials,” Dr. Coen commented.
In each trial arm, more than three-fourths of patients had a complete response, and about two-thirds of patients were alive and free of distant metastasis with their bladder intact at 3 years.
Toxicity, which was supposed to be the tie-breaker if efficacy was similar, was also essentially the same for the two regimens. Both were fairly well tolerated in the acute period; the primary grade 3 and 4 toxicities were hematologic ones.
“So where do we go from here? I think this trial does demonstrate concurrent gemcitabine is a reasonable alternative to cisplatin for patients undergoing selective bladder preservation,” Dr. Coen summarized. “This is especially important in patients with poor renal function or hearing loss. And bladder cancer is often a disease in the elderly, so tolerance of various regimens is a very important aspect to planning further trials.”
“This trial also demonstrates that daily radiation is a reasonable alternative to twice-a-day radiation, which had become the standard through the RTOG on more contemporary trials,” he added. “Daily radiation would allow wider adoption of selective bladder preservation by trimodality therapy.”
Clinical implications
“I would have to see more details about the toxicity data for the chemotherapy, the radiosensitizers,” session co-chair Yair Lotan, MD, a professor of urology at the UT Southwestern Medical Center, Dallas, Texas, commented in an interview. “But in general, if you have two equivalent protocols in terms of effectiveness, and one is less toxic or more convenient, that’s always preferable. From the standpoint of coming once a day rather than twice a day to get radiation, if I were a patient, I would prefer that regimen”
Current practice in this patient population likely hinges on where a patient is treated, he said. “Based on the new nonmetastatic muscle-invasive guidelines, many of them would be recommended surgery or possibly chemoradiation protocols, and then there are a lot of factors such as patient preference and outcomes that would probably impact the decision making.”
“Certainly, this study won’t prove standard of care because standard of care in the global picture for a patient with muscle-invasive disease really will depend on a randomized trial of surgery versus radiation or chemoradiation, multimodal therapies,” Dr. Lotan maintained. “Not every patient is even eligible; some patients with hydronephrosis or unresectable disease may not be the best candidates for multimodal therapy. But more information from these types of trials may help clinicians decide which multimodal therapy approach to use.”
Study details
Patients enrolled in NRG/RTOG 0712, a multicenter randomized phase 2 trial supported by the National Cancer Institute, had clinical T2 or T3-4a bladder cancer. Hydronephrosis and obvious lymph node involvement were exclusion criteria.
Like the rate of freedom from metastasis, the rate of complete response after induction therapy was similar for the two arms: 87.9% with twice-daily radiation plus 5-flourouracil-cisplatin and 75.8% with daily radiation plus gemcitabine.
“These rates exceed historical complete response rates, and this is likely a result of improved selection over time and more thorough TURBTs performed over time,” Dr. Coen proposed. “Over the course of multiple successive RTOG trials, our selection criteria have been refined. One excellent example would be that hydronephrosis has been excluded on more contemporary trials, but if you look at older trials, those patients were included.”
The 3-year rate of bladder-intact distant metastasis–free survival was 66.7% and 69%, respectively. “This is a very important endpoint. These results are excellent,” he commented. “And there is really no appreciable difference between the two arms on the actuarial analysis.”
As far as specific treatment failure events in the trial overall, three patients died, eight underwent cystectomy, and eight developed distant metastases. Although numbers were small, these events appeared fairly evenly distributed across arms.
The rate of grade 3 or 4 acute toxicity was 57.6% with twice-daily radiation plus 5-flourouracil-cisplatin and 54.6% with daily radiation plus gemcitabine. The large majority of events were blood and bone marrow toxicity. “It’s quite notable that the rates of GU and GI toxicity were very low,” commented Dr. Coen, who disclosed that he had no relevant conflicts of interest.
SOURCE: Coen, J. et al, 2018 Genitourinary Cancers Symposium, Abstract 408
SAN FRANCISCO – Two concurrent chemoradiation induction regimens had similar safety and efficacy when used as part of a bladder-sparing strategy in patients with muscle-invasive bladder cancer, suggest primary results of the NRG/RTOG 0712 trial. But one offers better patient convenience.
The selective bladder-preservation paradigm entails maximal transurethral resection of the bladder tumor (TURBT) followed by induction radiation and concomitant chemotherapy, lead author John J. Coen, MD, a radiation oncologist with 21st Century Oncology, Providence, Rhode Island, noted at the 2018 Genitourinary Cancers Symposium. Patients then undergo cystoscopy to assess their response.
“A key component of this therapy is close urologic surveillance,” he noted. “This is trimodality therapy with close urologic surveillance, and cystectomy is prompted at the earliest time it’s indicated.”
The 70 patients enrolled in the multicenter randomized phase 2 trial had undergone TURBT and were randomized evenly to twice-daily radiation plus 5-flourouracil-cisplatin (the RTOG standard at the time of trial planning) or to daily radiation plus gemcitabine (a modification of a successful regimen developed at the University of Michigan). All were offered adjuvant chemotherapy regardless of whether they responded and whether they underwent consolidation therapy or cystectomy.
At a median follow-up of 5.1 years among the 52 evaluable patients, the 3-year rate of freedom from distant metastasis, the trial’s primary endpoint, was 78% with twice-daily radiation plus 5-flourouracil-cisplatin and 84% with daily radiation plus gemcitabine, according to results reported at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Both values were higher than the trial’s predefined benchmark of 75% for defining the regimen as promising. “This trial wasn’t necessarily powered to compare arms, so the conclusion would be that both arms exceeded the benchmark and it would be appropriate to evaluate both arms further in subsequent trials,” Dr. Coen commented.
In each trial arm, more than three-fourths of patients had a complete response, and about two-thirds of patients were alive and free of distant metastasis with their bladder intact at 3 years.
Toxicity, which was supposed to be the tie-breaker if efficacy was similar, was also essentially the same for the two regimens. Both were fairly well tolerated in the acute period; the primary grade 3 and 4 toxicities were hematologic ones.
“So where do we go from here? I think this trial does demonstrate concurrent gemcitabine is a reasonable alternative to cisplatin for patients undergoing selective bladder preservation,” Dr. Coen summarized. “This is especially important in patients with poor renal function or hearing loss. And bladder cancer is often a disease in the elderly, so tolerance of various regimens is a very important aspect to planning further trials.”
“This trial also demonstrates that daily radiation is a reasonable alternative to twice-a-day radiation, which had become the standard through the RTOG on more contemporary trials,” he added. “Daily radiation would allow wider adoption of selective bladder preservation by trimodality therapy.”
Clinical implications
“I would have to see more details about the toxicity data for the chemotherapy, the radiosensitizers,” session co-chair Yair Lotan, MD, a professor of urology at the UT Southwestern Medical Center, Dallas, Texas, commented in an interview. “But in general, if you have two equivalent protocols in terms of effectiveness, and one is less toxic or more convenient, that’s always preferable. From the standpoint of coming once a day rather than twice a day to get radiation, if I were a patient, I would prefer that regimen”
Current practice in this patient population likely hinges on where a patient is treated, he said. “Based on the new nonmetastatic muscle-invasive guidelines, many of them would be recommended surgery or possibly chemoradiation protocols, and then there are a lot of factors such as patient preference and outcomes that would probably impact the decision making.”
“Certainly, this study won’t prove standard of care because standard of care in the global picture for a patient with muscle-invasive disease really will depend on a randomized trial of surgery versus radiation or chemoradiation, multimodal therapies,” Dr. Lotan maintained. “Not every patient is even eligible; some patients with hydronephrosis or unresectable disease may not be the best candidates for multimodal therapy. But more information from these types of trials may help clinicians decide which multimodal therapy approach to use.”
Study details
Patients enrolled in NRG/RTOG 0712, a multicenter randomized phase 2 trial supported by the National Cancer Institute, had clinical T2 or T3-4a bladder cancer. Hydronephrosis and obvious lymph node involvement were exclusion criteria.
Like the rate of freedom from metastasis, the rate of complete response after induction therapy was similar for the two arms: 87.9% with twice-daily radiation plus 5-flourouracil-cisplatin and 75.8% with daily radiation plus gemcitabine.
“These rates exceed historical complete response rates, and this is likely a result of improved selection over time and more thorough TURBTs performed over time,” Dr. Coen proposed. “Over the course of multiple successive RTOG trials, our selection criteria have been refined. One excellent example would be that hydronephrosis has been excluded on more contemporary trials, but if you look at older trials, those patients were included.”
The 3-year rate of bladder-intact distant metastasis–free survival was 66.7% and 69%, respectively. “This is a very important endpoint. These results are excellent,” he commented. “And there is really no appreciable difference between the two arms on the actuarial analysis.”
As far as specific treatment failure events in the trial overall, three patients died, eight underwent cystectomy, and eight developed distant metastases. Although numbers were small, these events appeared fairly evenly distributed across arms.
The rate of grade 3 or 4 acute toxicity was 57.6% with twice-daily radiation plus 5-flourouracil-cisplatin and 54.6% with daily radiation plus gemcitabine. The large majority of events were blood and bone marrow toxicity. “It’s quite notable that the rates of GU and GI toxicity were very low,” commented Dr. Coen, who disclosed that he had no relevant conflicts of interest.
SOURCE: Coen, J. et al, 2018 Genitourinary Cancers Symposium, Abstract 408
AT THE GENITOURINARY CANCERS SYMPOSIUM
Key clinical point:
Major finding: The rate of freedom from distant metastasis at 3 years was 77.8% with twice-daily radiation plus 5-flourouracil-cisplatin and 84.0% with daily radiation plus gemcitabine.
Data source: A multicenter randomized phase 2 trial among 70 patients with muscle-invasive (cT2-4a) bladder cancer who had undergone TURBT (NRG/RTOG 0712 trial).
Disclosures: Dr. Coen disclosed that he had no relevant conflicts of interest. The trial was supported by the National Cancer Institute.
Source: Coen, J. et al, 2018 Genitourinary Cancers Symposium, Abstract 408.
Adjuvant chemo halves DFS events in upper-tract urothelial cancer
SAN FRANCISCO – Patients who have undergone nephro-ureterectomy for upper-tract urothelial cancer (UTUC) fare much better if they are given adjuvant chemotherapy, according to the first results of the POUT trial reported at the 2018 Genitourinary Cancers Symposium.
Standard treatment for this rare cancer is radical nephro-ureterectomy followed by surveillance, noted lead author Alison Jane Birtle, MD, MRCP, FRCR, a consultant clinical oncologist at the Rosemere Cancer Centre, Royal Preston Hospital, Preston, United Kingdom. Evidence has been insufficient to recommend adjuvant therapy.
“We know that UTUC shares a similar etiology with bladder cancer, where there is strong evidence for chemotherapy,” she said. “Trials of adjuvant chemotherapy in bladder cancer have been challenging because of cystectomy being a much more morbid operation. So adjuvant chemotherapy after nephro-ureterectomy should be much easier to give because of the less morbid procedure.”
The POUT (Peri-Operative Chemotherapy Versus sUrveillance in Upper Tract Urothelial Cancer, NCT0199397) investigators enrolled in the trial 261 patients from 57 UK centers who had undergone radical nephro-ureterectomy for urothelial cancer of the renal pelvis or ureter. Patients were randomized evenly to receive surveillance or adjuvant platinum-based combination chemotherapy, with specific platinum (cisplatin or carboplatin) based on glomerular filtration rate (GFR).
Trial enrollment was stopped early, after a median follow-up of 19.3 months, because of efficacy of chemotherapy, Dr. Birtle reported at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Main results showed that risks of both disease-free survival events and metastasis-free survival events were 51% lower for the chemotherapy group as compared with the surveillance group. Overall survival showed a trend toward benefit as well.
Not surprisingly, grade 3 or worse adverse events during treatment were about four times more common with chemotherapy, but the treatment was overall feasible and safe, even though the majority of patients were older than 60 years.
“Based on these results, adjuvant platinum-based chemotherapy should be considered a new standard of care in these patients,” Dr. Birtle maintained. “The next thing is how are we going to move this data forward? We are looking at the successor study at the moment, which is currently in development…[POUT] has been a triumph of UK urologists really getting behind it, but to do a further study, it would be great to look at international collaboration.”
Optimal timing of chemotherapy, before or after surgery, remains an open question, according session co-chair Jeanny B. Aragon-Ching, MD, a medical oncologist with the Inova Medical Group, Fairfax, Virginia.
“This trial offers high-level evidence for consideration of adjuvant chemotherapy in those who are unable to receive neoadjuvant chemotherapy in UTUC, although it is still important to evaluate what the prospective neoadjuvant chemotherapy data in UTUC would show,” she said in an interview. “Ongoing studies include the ECOG 8141 study (clinicaltrials.gov NCT02412670), but certainly, several retrospective trials showed benefit of neoadjuvant chemotherapy in UTUC.”
Other viewpoints
“It’s fantastic that we finally have data in upper-tract cancer. However, I worry about how this data is going to be interpreted, and I argue that it should not be considered the standard of care,” session attendee Matthew Campbell, MD, of the MD Anderson Cancer Center, Houston, commented during a question and answer period.
“I believe that this is showing that chemotherapy is very important in this disease, and if anything, it should be moved into the neoadjuvant setting, where more patients will be cisplatin candidates. Though there is challenge with staging upper-tract disease, at MD Anderson, we consider patients with high-grade disease or hydronephrosis to be at high enough risk to consider for neoadjuvant chemotherapy, and that’s been our approach.”
“When we looked at developing POUT, there was a big debate about whether it should be a neoadjuvant or adjuvant study,” Dr. Birtle replied. UK oncologists expressed concern that not all patients have histologic confirmation of UTUC preoperatively; therefore, chemotherapy could lead to overtreatment for some.
“We plan to go back and look at the CT urograms and the diagnostic imaging done prior to surgery just to see if we can be 100% confident in our diagnostic accuracy preoperatively, to see if we would be more confident with a neoadjuvant study,” she added. The investigators have also reviewed data from the British Association of Urological Surgeons on the postoperative dip in GFR. “It didn’t really seem from that 2015 data that there was a huge unmet need for patients postoperatively, where we would have missed them had we not treated them preoperatively,” she said.
On a related note, session attendee Surena Matin, MD, also of MD Anderson, asked “How many patients were potentially precluded because of their GFR, and do you have any data regarding response rates in the carboplatin arm?”
The main reason for exclusion was ineligible pathology and not GFR, according to Dr. Birtle. “This goes back to the previous question of can you be certain that a patient has locally advanced disease prior to nephro-ureterectomy? About 60% of patients who were thought to have muscle-invasive disease ultimately on nephro-ureterectomy didn’t.”
Confidence intervals for chemotherapy benefit in the subgroup given carboplatin were wide and overlapped unity, but still favoring benefit and falling within the overall treatment effect, she said.
Session attendee Joaquim Bellmunt, MD, Dana-Farber Cancer Institute, Boston, noted that the chemotherapy benefit was not significant in that subgroup and also in the subgroups with lymph node–positive disease and with positive margins. “I think that saying … chemotherapy is for everybody based on this trial” is incorrect, he asserted. “It may be good just to tone down the message that this is the new standard of care.” He further questioned the trial’s early stopping, noting that continuing would have provided more information in these patients.
Those subgroups were small, so analyses were underpowered to definitively rule out chemotherapy benefit, according to Dr. Birtle. The investigators had intensive discussion about the recommendation to stop early, because of a goal to determine overall survival impact. Ultimately, “when we saw the data in terms of disease-free survival and metastasis-free survival, the magnitude of the effect was so big that we felt it was uncomfortable and unethical not to offer patients treatment,” she said.
Study details
Patients in POUT’s chemotherapy arm received four cycles of chemotherapy—gemcitabine-cisplatin if their GFR was 50 mL/min or higher, or gemcitabine-carboplatin if their GFR was 30-49 mL/min—starting within 90 days of nephro-ureterectomy.
Of note, approximately 40% of all patients in the trial were aged 70 years or older, including the 5% who were aged 80 years or older. “This is very reassuring for a study of adjuvant platinum-based chemotherapy,” Dr. Birtle commented. Fully 71.2% of the chemotherapy patients received all four planned cycles.
In an intention-to-treat analysis, risk of disease-free survival events (death from any cause, metastasis, or any ureteric or renal bed recurrence) was sharply reduced with chemotherapy versus surveillance (hazard ratio, 0.49; P=.001). The proportion of patients event free at 2 years was 71% in the chemotherapy group and 54% in the surveillance group. Benefit was generally similar across subgroups, and findings were much the same after adjustment for nodal involvement, microscopic margin status, and planned chemotherapy regimen (hazard ratio, 0.47; P=.001).
Risk of metastasis-free survival events was also sharply lower with chemotherapy (hazard ratio, 0.49; P=.002), with a proportion event free at 2 years of 74% in the chemotherapy group and 60% in the surveillance group. These findings were also much the same after adjustment for the above factors (hazard ratio, 0.47; P=.002).
Overall survival tended to be better with chemotherapy than with surveillance (hazard ratio, 0.55), but data are still immature for this endpoint.
The rate of grade 3 or worse adverse events during the treatment period was 53.2% with chemotherapy and 13.5% with surveillance; events with chemotherapy were as expected, with neutropenia, thrombocytopenia, and gastrointestinal events predominating. The rate of febrile neutropenia was 5.7% with gemcitabine-cisplatin and 7.8% with gemcitabine-carboplatin, but there were no neutropenic deaths.
The rate of grade 3 or worse adverse events for the entire trial period was 62.1% with chemotherapy and 24.8% with surveillance.
Data on nephrotoxicity are still being evaluated, according to Dr. Birtle. Only seven patients who started on gemcitabine-cisplatin had to switch to gemcitabine-carboplatin because their GFR fell.
In a related translational study, the investigators are evaluating both the baseline CT urograms and the resected tumors to identify prognostic and predictive markers, she said.
Dr. Birtle disclosed that she receives honoraria from Roche, Janssen, Astellas, and Bayer, and is a consultant to Sanofi-Aventis. The trial was funded by the UK Clinical Trials Awards and Advisory Committee.
SOURCE: Birtle A et al. Genitourinary Cancers Symposium. Abstract 407
SAN FRANCISCO – Patients who have undergone nephro-ureterectomy for upper-tract urothelial cancer (UTUC) fare much better if they are given adjuvant chemotherapy, according to the first results of the POUT trial reported at the 2018 Genitourinary Cancers Symposium.
Standard treatment for this rare cancer is radical nephro-ureterectomy followed by surveillance, noted lead author Alison Jane Birtle, MD, MRCP, FRCR, a consultant clinical oncologist at the Rosemere Cancer Centre, Royal Preston Hospital, Preston, United Kingdom. Evidence has been insufficient to recommend adjuvant therapy.
“We know that UTUC shares a similar etiology with bladder cancer, where there is strong evidence for chemotherapy,” she said. “Trials of adjuvant chemotherapy in bladder cancer have been challenging because of cystectomy being a much more morbid operation. So adjuvant chemotherapy after nephro-ureterectomy should be much easier to give because of the less morbid procedure.”
The POUT (Peri-Operative Chemotherapy Versus sUrveillance in Upper Tract Urothelial Cancer, NCT0199397) investigators enrolled in the trial 261 patients from 57 UK centers who had undergone radical nephro-ureterectomy for urothelial cancer of the renal pelvis or ureter. Patients were randomized evenly to receive surveillance or adjuvant platinum-based combination chemotherapy, with specific platinum (cisplatin or carboplatin) based on glomerular filtration rate (GFR).
Trial enrollment was stopped early, after a median follow-up of 19.3 months, because of efficacy of chemotherapy, Dr. Birtle reported at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Main results showed that risks of both disease-free survival events and metastasis-free survival events were 51% lower for the chemotherapy group as compared with the surveillance group. Overall survival showed a trend toward benefit as well.
Not surprisingly, grade 3 or worse adverse events during treatment were about four times more common with chemotherapy, but the treatment was overall feasible and safe, even though the majority of patients were older than 60 years.
“Based on these results, adjuvant platinum-based chemotherapy should be considered a new standard of care in these patients,” Dr. Birtle maintained. “The next thing is how are we going to move this data forward? We are looking at the successor study at the moment, which is currently in development…[POUT] has been a triumph of UK urologists really getting behind it, but to do a further study, it would be great to look at international collaboration.”
Optimal timing of chemotherapy, before or after surgery, remains an open question, according session co-chair Jeanny B. Aragon-Ching, MD, a medical oncologist with the Inova Medical Group, Fairfax, Virginia.
“This trial offers high-level evidence for consideration of adjuvant chemotherapy in those who are unable to receive neoadjuvant chemotherapy in UTUC, although it is still important to evaluate what the prospective neoadjuvant chemotherapy data in UTUC would show,” she said in an interview. “Ongoing studies include the ECOG 8141 study (clinicaltrials.gov NCT02412670), but certainly, several retrospective trials showed benefit of neoadjuvant chemotherapy in UTUC.”
Other viewpoints
“It’s fantastic that we finally have data in upper-tract cancer. However, I worry about how this data is going to be interpreted, and I argue that it should not be considered the standard of care,” session attendee Matthew Campbell, MD, of the MD Anderson Cancer Center, Houston, commented during a question and answer period.
“I believe that this is showing that chemotherapy is very important in this disease, and if anything, it should be moved into the neoadjuvant setting, where more patients will be cisplatin candidates. Though there is challenge with staging upper-tract disease, at MD Anderson, we consider patients with high-grade disease or hydronephrosis to be at high enough risk to consider for neoadjuvant chemotherapy, and that’s been our approach.”
“When we looked at developing POUT, there was a big debate about whether it should be a neoadjuvant or adjuvant study,” Dr. Birtle replied. UK oncologists expressed concern that not all patients have histologic confirmation of UTUC preoperatively; therefore, chemotherapy could lead to overtreatment for some.
“We plan to go back and look at the CT urograms and the diagnostic imaging done prior to surgery just to see if we can be 100% confident in our diagnostic accuracy preoperatively, to see if we would be more confident with a neoadjuvant study,” she added. The investigators have also reviewed data from the British Association of Urological Surgeons on the postoperative dip in GFR. “It didn’t really seem from that 2015 data that there was a huge unmet need for patients postoperatively, where we would have missed them had we not treated them preoperatively,” she said.
On a related note, session attendee Surena Matin, MD, also of MD Anderson, asked “How many patients were potentially precluded because of their GFR, and do you have any data regarding response rates in the carboplatin arm?”
The main reason for exclusion was ineligible pathology and not GFR, according to Dr. Birtle. “This goes back to the previous question of can you be certain that a patient has locally advanced disease prior to nephro-ureterectomy? About 60% of patients who were thought to have muscle-invasive disease ultimately on nephro-ureterectomy didn’t.”
Confidence intervals for chemotherapy benefit in the subgroup given carboplatin were wide and overlapped unity, but still favoring benefit and falling within the overall treatment effect, she said.
Session attendee Joaquim Bellmunt, MD, Dana-Farber Cancer Institute, Boston, noted that the chemotherapy benefit was not significant in that subgroup and also in the subgroups with lymph node–positive disease and with positive margins. “I think that saying … chemotherapy is for everybody based on this trial” is incorrect, he asserted. “It may be good just to tone down the message that this is the new standard of care.” He further questioned the trial’s early stopping, noting that continuing would have provided more information in these patients.
Those subgroups were small, so analyses were underpowered to definitively rule out chemotherapy benefit, according to Dr. Birtle. The investigators had intensive discussion about the recommendation to stop early, because of a goal to determine overall survival impact. Ultimately, “when we saw the data in terms of disease-free survival and metastasis-free survival, the magnitude of the effect was so big that we felt it was uncomfortable and unethical not to offer patients treatment,” she said.
Study details
Patients in POUT’s chemotherapy arm received four cycles of chemotherapy—gemcitabine-cisplatin if their GFR was 50 mL/min or higher, or gemcitabine-carboplatin if their GFR was 30-49 mL/min—starting within 90 days of nephro-ureterectomy.
Of note, approximately 40% of all patients in the trial were aged 70 years or older, including the 5% who were aged 80 years or older. “This is very reassuring for a study of adjuvant platinum-based chemotherapy,” Dr. Birtle commented. Fully 71.2% of the chemotherapy patients received all four planned cycles.
In an intention-to-treat analysis, risk of disease-free survival events (death from any cause, metastasis, or any ureteric or renal bed recurrence) was sharply reduced with chemotherapy versus surveillance (hazard ratio, 0.49; P=.001). The proportion of patients event free at 2 years was 71% in the chemotherapy group and 54% in the surveillance group. Benefit was generally similar across subgroups, and findings were much the same after adjustment for nodal involvement, microscopic margin status, and planned chemotherapy regimen (hazard ratio, 0.47; P=.001).
Risk of metastasis-free survival events was also sharply lower with chemotherapy (hazard ratio, 0.49; P=.002), with a proportion event free at 2 years of 74% in the chemotherapy group and 60% in the surveillance group. These findings were also much the same after adjustment for the above factors (hazard ratio, 0.47; P=.002).
Overall survival tended to be better with chemotherapy than with surveillance (hazard ratio, 0.55), but data are still immature for this endpoint.
The rate of grade 3 or worse adverse events during the treatment period was 53.2% with chemotherapy and 13.5% with surveillance; events with chemotherapy were as expected, with neutropenia, thrombocytopenia, and gastrointestinal events predominating. The rate of febrile neutropenia was 5.7% with gemcitabine-cisplatin and 7.8% with gemcitabine-carboplatin, but there were no neutropenic deaths.
The rate of grade 3 or worse adverse events for the entire trial period was 62.1% with chemotherapy and 24.8% with surveillance.
Data on nephrotoxicity are still being evaluated, according to Dr. Birtle. Only seven patients who started on gemcitabine-cisplatin had to switch to gemcitabine-carboplatin because their GFR fell.
In a related translational study, the investigators are evaluating both the baseline CT urograms and the resected tumors to identify prognostic and predictive markers, she said.
Dr. Birtle disclosed that she receives honoraria from Roche, Janssen, Astellas, and Bayer, and is a consultant to Sanofi-Aventis. The trial was funded by the UK Clinical Trials Awards and Advisory Committee.
SOURCE: Birtle A et al. Genitourinary Cancers Symposium. Abstract 407
SAN FRANCISCO – Patients who have undergone nephro-ureterectomy for upper-tract urothelial cancer (UTUC) fare much better if they are given adjuvant chemotherapy, according to the first results of the POUT trial reported at the 2018 Genitourinary Cancers Symposium.
Standard treatment for this rare cancer is radical nephro-ureterectomy followed by surveillance, noted lead author Alison Jane Birtle, MD, MRCP, FRCR, a consultant clinical oncologist at the Rosemere Cancer Centre, Royal Preston Hospital, Preston, United Kingdom. Evidence has been insufficient to recommend adjuvant therapy.
“We know that UTUC shares a similar etiology with bladder cancer, where there is strong evidence for chemotherapy,” she said. “Trials of adjuvant chemotherapy in bladder cancer have been challenging because of cystectomy being a much more morbid operation. So adjuvant chemotherapy after nephro-ureterectomy should be much easier to give because of the less morbid procedure.”
The POUT (Peri-Operative Chemotherapy Versus sUrveillance in Upper Tract Urothelial Cancer, NCT0199397) investigators enrolled in the trial 261 patients from 57 UK centers who had undergone radical nephro-ureterectomy for urothelial cancer of the renal pelvis or ureter. Patients were randomized evenly to receive surveillance or adjuvant platinum-based combination chemotherapy, with specific platinum (cisplatin or carboplatin) based on glomerular filtration rate (GFR).
Trial enrollment was stopped early, after a median follow-up of 19.3 months, because of efficacy of chemotherapy, Dr. Birtle reported at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Main results showed that risks of both disease-free survival events and metastasis-free survival events were 51% lower for the chemotherapy group as compared with the surveillance group. Overall survival showed a trend toward benefit as well.
Not surprisingly, grade 3 or worse adverse events during treatment were about four times more common with chemotherapy, but the treatment was overall feasible and safe, even though the majority of patients were older than 60 years.
“Based on these results, adjuvant platinum-based chemotherapy should be considered a new standard of care in these patients,” Dr. Birtle maintained. “The next thing is how are we going to move this data forward? We are looking at the successor study at the moment, which is currently in development…[POUT] has been a triumph of UK urologists really getting behind it, but to do a further study, it would be great to look at international collaboration.”
Optimal timing of chemotherapy, before or after surgery, remains an open question, according session co-chair Jeanny B. Aragon-Ching, MD, a medical oncologist with the Inova Medical Group, Fairfax, Virginia.
“This trial offers high-level evidence for consideration of adjuvant chemotherapy in those who are unable to receive neoadjuvant chemotherapy in UTUC, although it is still important to evaluate what the prospective neoadjuvant chemotherapy data in UTUC would show,” she said in an interview. “Ongoing studies include the ECOG 8141 study (clinicaltrials.gov NCT02412670), but certainly, several retrospective trials showed benefit of neoadjuvant chemotherapy in UTUC.”
Other viewpoints
“It’s fantastic that we finally have data in upper-tract cancer. However, I worry about how this data is going to be interpreted, and I argue that it should not be considered the standard of care,” session attendee Matthew Campbell, MD, of the MD Anderson Cancer Center, Houston, commented during a question and answer period.
“I believe that this is showing that chemotherapy is very important in this disease, and if anything, it should be moved into the neoadjuvant setting, where more patients will be cisplatin candidates. Though there is challenge with staging upper-tract disease, at MD Anderson, we consider patients with high-grade disease or hydronephrosis to be at high enough risk to consider for neoadjuvant chemotherapy, and that’s been our approach.”
“When we looked at developing POUT, there was a big debate about whether it should be a neoadjuvant or adjuvant study,” Dr. Birtle replied. UK oncologists expressed concern that not all patients have histologic confirmation of UTUC preoperatively; therefore, chemotherapy could lead to overtreatment for some.
“We plan to go back and look at the CT urograms and the diagnostic imaging done prior to surgery just to see if we can be 100% confident in our diagnostic accuracy preoperatively, to see if we would be more confident with a neoadjuvant study,” she added. The investigators have also reviewed data from the British Association of Urological Surgeons on the postoperative dip in GFR. “It didn’t really seem from that 2015 data that there was a huge unmet need for patients postoperatively, where we would have missed them had we not treated them preoperatively,” she said.
On a related note, session attendee Surena Matin, MD, also of MD Anderson, asked “How many patients were potentially precluded because of their GFR, and do you have any data regarding response rates in the carboplatin arm?”
The main reason for exclusion was ineligible pathology and not GFR, according to Dr. Birtle. “This goes back to the previous question of can you be certain that a patient has locally advanced disease prior to nephro-ureterectomy? About 60% of patients who were thought to have muscle-invasive disease ultimately on nephro-ureterectomy didn’t.”
Confidence intervals for chemotherapy benefit in the subgroup given carboplatin were wide and overlapped unity, but still favoring benefit and falling within the overall treatment effect, she said.
Session attendee Joaquim Bellmunt, MD, Dana-Farber Cancer Institute, Boston, noted that the chemotherapy benefit was not significant in that subgroup and also in the subgroups with lymph node–positive disease and with positive margins. “I think that saying … chemotherapy is for everybody based on this trial” is incorrect, he asserted. “It may be good just to tone down the message that this is the new standard of care.” He further questioned the trial’s early stopping, noting that continuing would have provided more information in these patients.
Those subgroups were small, so analyses were underpowered to definitively rule out chemotherapy benefit, according to Dr. Birtle. The investigators had intensive discussion about the recommendation to stop early, because of a goal to determine overall survival impact. Ultimately, “when we saw the data in terms of disease-free survival and metastasis-free survival, the magnitude of the effect was so big that we felt it was uncomfortable and unethical not to offer patients treatment,” she said.
Study details
Patients in POUT’s chemotherapy arm received four cycles of chemotherapy—gemcitabine-cisplatin if their GFR was 50 mL/min or higher, or gemcitabine-carboplatin if their GFR was 30-49 mL/min—starting within 90 days of nephro-ureterectomy.
Of note, approximately 40% of all patients in the trial were aged 70 years or older, including the 5% who were aged 80 years or older. “This is very reassuring for a study of adjuvant platinum-based chemotherapy,” Dr. Birtle commented. Fully 71.2% of the chemotherapy patients received all four planned cycles.
In an intention-to-treat analysis, risk of disease-free survival events (death from any cause, metastasis, or any ureteric or renal bed recurrence) was sharply reduced with chemotherapy versus surveillance (hazard ratio, 0.49; P=.001). The proportion of patients event free at 2 years was 71% in the chemotherapy group and 54% in the surveillance group. Benefit was generally similar across subgroups, and findings were much the same after adjustment for nodal involvement, microscopic margin status, and planned chemotherapy regimen (hazard ratio, 0.47; P=.001).
Risk of metastasis-free survival events was also sharply lower with chemotherapy (hazard ratio, 0.49; P=.002), with a proportion event free at 2 years of 74% in the chemotherapy group and 60% in the surveillance group. These findings were also much the same after adjustment for the above factors (hazard ratio, 0.47; P=.002).
Overall survival tended to be better with chemotherapy than with surveillance (hazard ratio, 0.55), but data are still immature for this endpoint.
The rate of grade 3 or worse adverse events during the treatment period was 53.2% with chemotherapy and 13.5% with surveillance; events with chemotherapy were as expected, with neutropenia, thrombocytopenia, and gastrointestinal events predominating. The rate of febrile neutropenia was 5.7% with gemcitabine-cisplatin and 7.8% with gemcitabine-carboplatin, but there were no neutropenic deaths.
The rate of grade 3 or worse adverse events for the entire trial period was 62.1% with chemotherapy and 24.8% with surveillance.
Data on nephrotoxicity are still being evaluated, according to Dr. Birtle. Only seven patients who started on gemcitabine-cisplatin had to switch to gemcitabine-carboplatin because their GFR fell.
In a related translational study, the investigators are evaluating both the baseline CT urograms and the resected tumors to identify prognostic and predictive markers, she said.
Dr. Birtle disclosed that she receives honoraria from Roche, Janssen, Astellas, and Bayer, and is a consultant to Sanofi-Aventis. The trial was funded by the UK Clinical Trials Awards and Advisory Committee.
SOURCE: Birtle A et al. Genitourinary Cancers Symposium. Abstract 407
AT THE GENITOURINARY CANCERS SYMPOSIUM
Key clinical point:
Major finding: Compared with surveillance, adjuvant chemotherapy halved risk of disease-free survival events (hazard ratio, 0.49; P=.001).
Data source: A phase 3 randomized trial of adjuvant platinum-based chemotherapy versus surveillance in 261 patients with upper-tract urothelial cancer (POUT trial).
Disclosures: Dr. Birtle disclosed that she receives honoraria from Roche, Janssen, Astellas, and Bayer, and is a consultant to Sanofi-Aventis. The trial was funded by the UK Clinical Trials Awards and Advisory Committee.
Source: Birtle A et al. Genitourinary Cancers Symposium. Abstract 407.
Adding docetaxel to hormone therapy for advanced prostate cancer nets QOL benefit
SAN FRANCISCO – Adding docetaxel to first-line long-term hormone therapy for advanced prostate cancer, whether metastatic or not, improves quality of life, reduces need for subsequent therapy, and is cost effective, suggests a new analysis of data from the STAMPEDE trial.
Hormone therapy alone has historically been standard of care for this disease, lead study author Nicholas D. James, MD, PhD, a professor of clinical oncology at the University of Birmingham, England, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.
The new analysis focused on health economic and quality of life outcomes. Results of a model based largely on STAMPEDE data showed that adding docetaxel to first-line hormone therapy yielded an increase of about 0.4 quality-adjusted life-years among men with nonmetastatic disease and about 0.5 quality-adjusted life-years among men with metastatic disease.
Adding docetaxel actually led to a small reduction in total lifetime costs, on the order of several hundred pounds sterling, for patients with nonmetastatic disease, because the drug costs were more than offset by reductions in costs associated with adverse outcomes. On the other hand, adding docetaxel increased total costs by a fairly modest amount, roughly 3,000 pounds sterling, for patients with metastatic disease, but that increase was due in large part to costs associated with prolonged survival.
“Upfront docetaxel gives you a gain in quality-adjusted life-years in all subgroups,” Dr. James said. “Analysis suggests a high degree of certainty relating to the quality-adjusted life-year gain associated with docetaxel.”
“The results therefore support the existing health care policy in the U.K. and elsewhere across the world in newly diagnosed metastatic patients. You’ve got a pretty modest cost for a survival gain and a quality gain,” he maintained. “But very importantly, we think these results extend the applicability to nonmetastatic patients because at the patient level there is very clear evidence of a quality-adjusted life-year gain, and the modeling also predicts an eventual survival gain. And at the provider level, it’s a very cost-effective use of resources. For a very modest upfront docetaxel cost, it actually is cost saving in the nonmetastatic patient because of the subsequent downstream [averted events], things like spinal cord compression.”
Full results of the analysis, including model-predicted overall survival, will be reported at the symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Clinical implications
“In this analysis of data from the STAMPEDE trial, we see that docetaxel, a chemotherapy drug that has been in our armamentarium for prostate cancer for over a decade, may be applied in earlier and earlier settings in the disease,” commented ASCO expert and moderator of the press briefing, Sumanta K. Pal, MD. “Dr. James has previously reported the survival gains associated with this drug, but today adds the dimension of demonstrating improved quality of life and potentially cost-effectiveness as well.”
Results can be compared against those seen with abiraterone (Zytiga), an oral hormonal therapy that has shown similar benefit in these same patient populations, he said. “Abiraterone may offer the benefit of improved tolerability over a short course versus chemotherapy, but does require a much more extensive duration of use and further mandates concomitant use of prednisone.”
“Understanding the cost and quality of life associated with abiraterone in this setting may help adjudicate between giving this drug or docetaxel for the patients that Dr. James describes,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.
Study details
The ongoing multi-arm STAMPEDE randomized trial has thus far enrolled more than 9,000 men with advanced (nonmetastatic and metastatic) prostate cancer and evaluated 10 treatments for the disease. About 60% of enrolled men have metastases.
Dr. James and colleagues developed a state transition model to reflect the natural history of patients entering the trial. Rate of progression and quality of life data (assessed with the EuroQol EQ-5D tool) were ascertained from the trial; costs came from both the trial and the literature.
Results indicated that, despite the adverse quality of life impacts of receiving chemotherapy and of living longer with metastatic disease, adding docetaxel to hormone therapy ultimately increased quality-adjusted life-years, with similar benefit seen in both nonmetastatic and metastatic disease.
“It was very interesting to us that, in the nonmetastatic patients, the quality-adjusted life-year gain was almost of the same magnitude, despite there being no evidence yet in STAMPEDE follow-up of a definite survival benefit in this group,” Dr. James noted. In these patients, chemotherapy has an upfront “quality of life penalty,” but that is offset by the later quality of life gains from delaying relapses (and thus time to further treatment) and, when nonmetastatic disease becomes metastatic, reducing events such as fractures and spinal cord compression.
“These later gains essentially wipe out the quality of life cost, if you like, from docetaxel, giving you a net gain almost as big in magnitude as the gain in metastatic patients,” he summarized. “We think this is a really important new finding.”
In a cost breakdown, adding docetaxel to hormone therapy increased drug costs in patients with both nonmetastatic and metastatic disease. Costs for end of life care, adverse events, and monitoring changed little in either group
Adding docetaxel increased costs for management by about 1,000 pounds sterling in patients with nonmetastatic disease (likely related to the chemotherapy administration) and about 2,000 pounds sterling in patients with metastatic disease (likely related to chemotherapy administration and longer survival).
Of special note, with addition of docetaxel, costs for other life-prolonging therapies – abiraterone, enzalutamide (Xtandi), radium (Xofigo), and similar treatments – fell by about 2,500 pounds sterling in nonmetastatic disease and 1,000 pounds sterling in metastatic disease. These savings are attributable to a shorter period of time spent in the relapsed state for patients who receive docetaxel, Dr. James explained. And savings are much greater for patients with nonmetastatic disease because they spend a much shorter time post relapse, given that the extended failure-free survival with docetaxel does not fully translate to extended overall survival.
When it comes to total lifetime costs, “basically, your downstream savings almost completely wipe out, even in the metastatic patients, the upfront costs,” he summarized.
Dr. James disclosed that he receives honoraria from Sanofi/Aventis, Janssen, Astellas Medivation, Bayer Health, and Merck Sharp & Dohme; has a consulting or advisory role with Janssen, Sanofi/Aventis, Merck Sharp & Dohme, Roche, Astellas Medivation, and Bayer; and is on the speakers’ bureau for Bayer, Janssen, Roche, and Ipsen; in addition, his institution receives research funding from Janssen, Astellas Medivation, Bayer, Sanofi/Aventis, and Roche. The study was funded by Cancer Research UK and the Medical Research Council, United Kingdom.
SOURCE: James ND et al. GUCS Abstract 162.
SAN FRANCISCO – Adding docetaxel to first-line long-term hormone therapy for advanced prostate cancer, whether metastatic or not, improves quality of life, reduces need for subsequent therapy, and is cost effective, suggests a new analysis of data from the STAMPEDE trial.
Hormone therapy alone has historically been standard of care for this disease, lead study author Nicholas D. James, MD, PhD, a professor of clinical oncology at the University of Birmingham, England, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.
The new analysis focused on health economic and quality of life outcomes. Results of a model based largely on STAMPEDE data showed that adding docetaxel to first-line hormone therapy yielded an increase of about 0.4 quality-adjusted life-years among men with nonmetastatic disease and about 0.5 quality-adjusted life-years among men with metastatic disease.
Adding docetaxel actually led to a small reduction in total lifetime costs, on the order of several hundred pounds sterling, for patients with nonmetastatic disease, because the drug costs were more than offset by reductions in costs associated with adverse outcomes. On the other hand, adding docetaxel increased total costs by a fairly modest amount, roughly 3,000 pounds sterling, for patients with metastatic disease, but that increase was due in large part to costs associated with prolonged survival.
“Upfront docetaxel gives you a gain in quality-adjusted life-years in all subgroups,” Dr. James said. “Analysis suggests a high degree of certainty relating to the quality-adjusted life-year gain associated with docetaxel.”
“The results therefore support the existing health care policy in the U.K. and elsewhere across the world in newly diagnosed metastatic patients. You’ve got a pretty modest cost for a survival gain and a quality gain,” he maintained. “But very importantly, we think these results extend the applicability to nonmetastatic patients because at the patient level there is very clear evidence of a quality-adjusted life-year gain, and the modeling also predicts an eventual survival gain. And at the provider level, it’s a very cost-effective use of resources. For a very modest upfront docetaxel cost, it actually is cost saving in the nonmetastatic patient because of the subsequent downstream [averted events], things like spinal cord compression.”
Full results of the analysis, including model-predicted overall survival, will be reported at the symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Clinical implications
“In this analysis of data from the STAMPEDE trial, we see that docetaxel, a chemotherapy drug that has been in our armamentarium for prostate cancer for over a decade, may be applied in earlier and earlier settings in the disease,” commented ASCO expert and moderator of the press briefing, Sumanta K. Pal, MD. “Dr. James has previously reported the survival gains associated with this drug, but today adds the dimension of demonstrating improved quality of life and potentially cost-effectiveness as well.”
Results can be compared against those seen with abiraterone (Zytiga), an oral hormonal therapy that has shown similar benefit in these same patient populations, he said. “Abiraterone may offer the benefit of improved tolerability over a short course versus chemotherapy, but does require a much more extensive duration of use and further mandates concomitant use of prednisone.”
“Understanding the cost and quality of life associated with abiraterone in this setting may help adjudicate between giving this drug or docetaxel for the patients that Dr. James describes,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.
Study details
The ongoing multi-arm STAMPEDE randomized trial has thus far enrolled more than 9,000 men with advanced (nonmetastatic and metastatic) prostate cancer and evaluated 10 treatments for the disease. About 60% of enrolled men have metastases.
Dr. James and colleagues developed a state transition model to reflect the natural history of patients entering the trial. Rate of progression and quality of life data (assessed with the EuroQol EQ-5D tool) were ascertained from the trial; costs came from both the trial and the literature.
Results indicated that, despite the adverse quality of life impacts of receiving chemotherapy and of living longer with metastatic disease, adding docetaxel to hormone therapy ultimately increased quality-adjusted life-years, with similar benefit seen in both nonmetastatic and metastatic disease.
“It was very interesting to us that, in the nonmetastatic patients, the quality-adjusted life-year gain was almost of the same magnitude, despite there being no evidence yet in STAMPEDE follow-up of a definite survival benefit in this group,” Dr. James noted. In these patients, chemotherapy has an upfront “quality of life penalty,” but that is offset by the later quality of life gains from delaying relapses (and thus time to further treatment) and, when nonmetastatic disease becomes metastatic, reducing events such as fractures and spinal cord compression.
“These later gains essentially wipe out the quality of life cost, if you like, from docetaxel, giving you a net gain almost as big in magnitude as the gain in metastatic patients,” he summarized. “We think this is a really important new finding.”
In a cost breakdown, adding docetaxel to hormone therapy increased drug costs in patients with both nonmetastatic and metastatic disease. Costs for end of life care, adverse events, and monitoring changed little in either group
Adding docetaxel increased costs for management by about 1,000 pounds sterling in patients with nonmetastatic disease (likely related to the chemotherapy administration) and about 2,000 pounds sterling in patients with metastatic disease (likely related to chemotherapy administration and longer survival).
Of special note, with addition of docetaxel, costs for other life-prolonging therapies – abiraterone, enzalutamide (Xtandi), radium (Xofigo), and similar treatments – fell by about 2,500 pounds sterling in nonmetastatic disease and 1,000 pounds sterling in metastatic disease. These savings are attributable to a shorter period of time spent in the relapsed state for patients who receive docetaxel, Dr. James explained. And savings are much greater for patients with nonmetastatic disease because they spend a much shorter time post relapse, given that the extended failure-free survival with docetaxel does not fully translate to extended overall survival.
When it comes to total lifetime costs, “basically, your downstream savings almost completely wipe out, even in the metastatic patients, the upfront costs,” he summarized.
Dr. James disclosed that he receives honoraria from Sanofi/Aventis, Janssen, Astellas Medivation, Bayer Health, and Merck Sharp & Dohme; has a consulting or advisory role with Janssen, Sanofi/Aventis, Merck Sharp & Dohme, Roche, Astellas Medivation, and Bayer; and is on the speakers’ bureau for Bayer, Janssen, Roche, and Ipsen; in addition, his institution receives research funding from Janssen, Astellas Medivation, Bayer, Sanofi/Aventis, and Roche. The study was funded by Cancer Research UK and the Medical Research Council, United Kingdom.
SOURCE: James ND et al. GUCS Abstract 162.
SAN FRANCISCO – Adding docetaxel to first-line long-term hormone therapy for advanced prostate cancer, whether metastatic or not, improves quality of life, reduces need for subsequent therapy, and is cost effective, suggests a new analysis of data from the STAMPEDE trial.
Hormone therapy alone has historically been standard of care for this disease, lead study author Nicholas D. James, MD, PhD, a professor of clinical oncology at the University of Birmingham, England, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.
The new analysis focused on health economic and quality of life outcomes. Results of a model based largely on STAMPEDE data showed that adding docetaxel to first-line hormone therapy yielded an increase of about 0.4 quality-adjusted life-years among men with nonmetastatic disease and about 0.5 quality-adjusted life-years among men with metastatic disease.
Adding docetaxel actually led to a small reduction in total lifetime costs, on the order of several hundred pounds sterling, for patients with nonmetastatic disease, because the drug costs were more than offset by reductions in costs associated with adverse outcomes. On the other hand, adding docetaxel increased total costs by a fairly modest amount, roughly 3,000 pounds sterling, for patients with metastatic disease, but that increase was due in large part to costs associated with prolonged survival.
“Upfront docetaxel gives you a gain in quality-adjusted life-years in all subgroups,” Dr. James said. “Analysis suggests a high degree of certainty relating to the quality-adjusted life-year gain associated with docetaxel.”
“The results therefore support the existing health care policy in the U.K. and elsewhere across the world in newly diagnosed metastatic patients. You’ve got a pretty modest cost for a survival gain and a quality gain,” he maintained. “But very importantly, we think these results extend the applicability to nonmetastatic patients because at the patient level there is very clear evidence of a quality-adjusted life-year gain, and the modeling also predicts an eventual survival gain. And at the provider level, it’s a very cost-effective use of resources. For a very modest upfront docetaxel cost, it actually is cost saving in the nonmetastatic patient because of the subsequent downstream [averted events], things like spinal cord compression.”
Full results of the analysis, including model-predicted overall survival, will be reported at the symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Clinical implications
“In this analysis of data from the STAMPEDE trial, we see that docetaxel, a chemotherapy drug that has been in our armamentarium for prostate cancer for over a decade, may be applied in earlier and earlier settings in the disease,” commented ASCO expert and moderator of the press briefing, Sumanta K. Pal, MD. “Dr. James has previously reported the survival gains associated with this drug, but today adds the dimension of demonstrating improved quality of life and potentially cost-effectiveness as well.”
Results can be compared against those seen with abiraterone (Zytiga), an oral hormonal therapy that has shown similar benefit in these same patient populations, he said. “Abiraterone may offer the benefit of improved tolerability over a short course versus chemotherapy, but does require a much more extensive duration of use and further mandates concomitant use of prednisone.”
“Understanding the cost and quality of life associated with abiraterone in this setting may help adjudicate between giving this drug or docetaxel for the patients that Dr. James describes,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.
Study details
The ongoing multi-arm STAMPEDE randomized trial has thus far enrolled more than 9,000 men with advanced (nonmetastatic and metastatic) prostate cancer and evaluated 10 treatments for the disease. About 60% of enrolled men have metastases.
Dr. James and colleagues developed a state transition model to reflect the natural history of patients entering the trial. Rate of progression and quality of life data (assessed with the EuroQol EQ-5D tool) were ascertained from the trial; costs came from both the trial and the literature.
Results indicated that, despite the adverse quality of life impacts of receiving chemotherapy and of living longer with metastatic disease, adding docetaxel to hormone therapy ultimately increased quality-adjusted life-years, with similar benefit seen in both nonmetastatic and metastatic disease.
“It was very interesting to us that, in the nonmetastatic patients, the quality-adjusted life-year gain was almost of the same magnitude, despite there being no evidence yet in STAMPEDE follow-up of a definite survival benefit in this group,” Dr. James noted. In these patients, chemotherapy has an upfront “quality of life penalty,” but that is offset by the later quality of life gains from delaying relapses (and thus time to further treatment) and, when nonmetastatic disease becomes metastatic, reducing events such as fractures and spinal cord compression.
“These later gains essentially wipe out the quality of life cost, if you like, from docetaxel, giving you a net gain almost as big in magnitude as the gain in metastatic patients,” he summarized. “We think this is a really important new finding.”
In a cost breakdown, adding docetaxel to hormone therapy increased drug costs in patients with both nonmetastatic and metastatic disease. Costs for end of life care, adverse events, and monitoring changed little in either group
Adding docetaxel increased costs for management by about 1,000 pounds sterling in patients with nonmetastatic disease (likely related to the chemotherapy administration) and about 2,000 pounds sterling in patients with metastatic disease (likely related to chemotherapy administration and longer survival).
Of special note, with addition of docetaxel, costs for other life-prolonging therapies – abiraterone, enzalutamide (Xtandi), radium (Xofigo), and similar treatments – fell by about 2,500 pounds sterling in nonmetastatic disease and 1,000 pounds sterling in metastatic disease. These savings are attributable to a shorter period of time spent in the relapsed state for patients who receive docetaxel, Dr. James explained. And savings are much greater for patients with nonmetastatic disease because they spend a much shorter time post relapse, given that the extended failure-free survival with docetaxel does not fully translate to extended overall survival.
When it comes to total lifetime costs, “basically, your downstream savings almost completely wipe out, even in the metastatic patients, the upfront costs,” he summarized.
Dr. James disclosed that he receives honoraria from Sanofi/Aventis, Janssen, Astellas Medivation, Bayer Health, and Merck Sharp & Dohme; has a consulting or advisory role with Janssen, Sanofi/Aventis, Merck Sharp & Dohme, Roche, Astellas Medivation, and Bayer; and is on the speakers’ bureau for Bayer, Janssen, Roche, and Ipsen; in addition, his institution receives research funding from Janssen, Astellas Medivation, Bayer, Sanofi/Aventis, and Roche. The study was funded by Cancer Research UK and the Medical Research Council, United Kingdom.
SOURCE: James ND et al. GUCS Abstract 162.
REPORTING FROM GUCS 2018
Key clinical point:
Major finding: Compared with hormone therapy alone, adding docetaxel increased quality-adjusted life-years by about 0.4 among men with nonmetastatic disease and 0.5 among men with metastatic disease.
Data source: A health economic and quality of life analysis of data from a randomized controlled trial among 9,000 men with advanced (nonmetastatic and metastatic) prostate cancer starting first-line hormone therapy (STAMPEDE trial).
Disclosures: Dr. James disclosed that he receives honoraria from Sanofi/Aventis, Janssen, Astellas Medivation, Bayer Health, and Merck Sharp & Dohme; has a consulting or advisory role with Janssen, Sanofi/Aventis, Merck Sharp & Dohme, Roche, Astellas Medivation, and Bayer; and is on the speakers’ bureau for Bayer, Janssen, Roche, and Ipsen; in addition, his institution receives research funding from Janssen, Astellas Medivation, Bayer, Sanofi/Aventis, and Roche. The study was funded by Cancer Research UK and the Medical Research Council, UK.
Source: James ND et al. GUCS Abstract 162.
Atezolizumab-bevacizumab combo tops sunitinib as first-line therapy for RCC
The combination of the immune checkpoint inhibitor atezolizumab and bevacizumab has efficacy and tolerability superior to that of sunitinib alone as first-line therapy for metastatic renal cell carcinoma, finds the IMmotion151 trial.
“Sunitinib has been the reference standard for this disease for the last 10 years,” lead study author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium. But strategies using immunotherapy have generated considerable excitement as possible new treatment options.
With a median follow-up of 15 months, compared with sunitinib, the combination of atezolizumab and bevacizumab prolonged investigator-assessed progression-free survival by 3.5 months among patients whose tumors were positive for PD-L1, defined as staining of at least 1% of tumor-infiltrating immune cells by immunohistochemistry. The difference translated to a 26% reduction in the risk of progression or death. However, the combination also had a significant edge in the trial population as a whole.
Overall survival and response rate likewise favored the combination of atezolizumab and bevacizumab. In addition, it was well tolerated, with a lower rate and severity of most adverse events. The exception was a higher rate of proteinuria, an established side effect of bevacizumab, with the combination.
“This trial met its primary endpoint,” Dr. Motzer concluded. “These study results support the consideration of atezolizumab plus bevacizumab as a first-line treatment option for PD-L1–positive patients with advanced renal cell carcinoma.”
Full results of IMmotion151 will be reported at the symposium, which runs Feb. 8-10 and is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Findings in context
“This study represents an important breakthrough in kidney cancer therapy,” said Sumanta K. Pal, MD, presscast moderator and ASCO expert. “For several years now, we’ve hosted debates on which treatment strategy is best for this disease, targeted therapy or immune therapy. Now this study, which is really the first of its kind, points to a combination of both as being highly effective in delaying cancer growth and showing an early trend toward improving survival as well.”
It is also noteworthy that the combination has good tolerability that appears better in several respects to that seen with sunitinib, he said. “In my opinion, the side effect profile also compares favorably to what we have seen to date with a dual immunotherapy regimen, namely, nivolumab (Opdivo) and ipilimumab.” Although that combination has also been shown to be more efficacious than sunitinib, nearly 60% of treated patients need steroids for immune-related side effects, compared with only 16% treated with the atezolizumab-bevacizumab combination in IMmotion151.
“I would agree with Dr. Motzer that this data supports consideration of atezolizumab and bevacizumab as a first-line option,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif. “I was intrigued to see that there seemed to be benefit with the combination of atezolizumab and bevacizumab irrespective of the presence or absence of PD-L1.”
Study details
About 40% of patients in IMmotion151 had PD-L1–positive tumors. Median investigator-assessed progression-free survival among these patients, a co-primary endpoint, was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02). More modest but still significant benefit was evident among the trial’s entire intention-to-treat population (11.2 vs. 8.4 months; hazard ratio, 0.83; P = .02).
An interim analysis showed that median overall survival among the PD-L1–positive cohort was not reached with atezolizumab-bevacizumab and was 23.3 months with sunitinib (hazard ratio, 0.68; P = .05). Overall survival among the entire trial population, another co-primary endpoint, was not reached in either treatment arm.
The PD-L1–positive cohort had an overall response rate of 43% with atezolizumab-bevacizumab and 35% with sunitinib (complete response rates of 9% and 4%). Corresponding values in the entire trial population were 37% and 33% (5% and 2%).
“Independent review of progression-free survival and response, where the scans are sent off to a committee and they read them blinded to the treatment arm, differed from investigator-assessed outcomes,” Dr. Motzer noted, with lesser benefit from the combination seen in the PD-L1–positive patients. “We are doing further analysis to see if we can identify why there was this difference.”
“One of the main benefits of atezolizumab plus bevacizumab is its safety profile. As an investigator on this study and other studies, I can attest to that: it’s very well tolerated,” he said.
The sunitinib group had higher rates of most treatment-related adverse events, both any grade and grade 3 or worse, especially palmar-plantar erythrodysesthesia, fatigue, and gastrointestinal events. The pattern was similar in the PD-L1–positive subset.
“We also have done an extensive quality of life analysis,” Dr. Motzer said, with some results to be reported at the symposium. “It appears that patients treated with atezolizumab plus bevacizumab have better quality of life compared to sunitinib by a particular scale that assesses trouble with symptoms.”
Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.
SOURCE: Motzer RJ et al. GU Cancers Symposium Abstract 578
The combination of the immune checkpoint inhibitor atezolizumab and bevacizumab has efficacy and tolerability superior to that of sunitinib alone as first-line therapy for metastatic renal cell carcinoma, finds the IMmotion151 trial.
“Sunitinib has been the reference standard for this disease for the last 10 years,” lead study author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium. But strategies using immunotherapy have generated considerable excitement as possible new treatment options.
With a median follow-up of 15 months, compared with sunitinib, the combination of atezolizumab and bevacizumab prolonged investigator-assessed progression-free survival by 3.5 months among patients whose tumors were positive for PD-L1, defined as staining of at least 1% of tumor-infiltrating immune cells by immunohistochemistry. The difference translated to a 26% reduction in the risk of progression or death. However, the combination also had a significant edge in the trial population as a whole.
Overall survival and response rate likewise favored the combination of atezolizumab and bevacizumab. In addition, it was well tolerated, with a lower rate and severity of most adverse events. The exception was a higher rate of proteinuria, an established side effect of bevacizumab, with the combination.
“This trial met its primary endpoint,” Dr. Motzer concluded. “These study results support the consideration of atezolizumab plus bevacizumab as a first-line treatment option for PD-L1–positive patients with advanced renal cell carcinoma.”
Full results of IMmotion151 will be reported at the symposium, which runs Feb. 8-10 and is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Findings in context
“This study represents an important breakthrough in kidney cancer therapy,” said Sumanta K. Pal, MD, presscast moderator and ASCO expert. “For several years now, we’ve hosted debates on which treatment strategy is best for this disease, targeted therapy or immune therapy. Now this study, which is really the first of its kind, points to a combination of both as being highly effective in delaying cancer growth and showing an early trend toward improving survival as well.”
It is also noteworthy that the combination has good tolerability that appears better in several respects to that seen with sunitinib, he said. “In my opinion, the side effect profile also compares favorably to what we have seen to date with a dual immunotherapy regimen, namely, nivolumab (Opdivo) and ipilimumab.” Although that combination has also been shown to be more efficacious than sunitinib, nearly 60% of treated patients need steroids for immune-related side effects, compared with only 16% treated with the atezolizumab-bevacizumab combination in IMmotion151.
“I would agree with Dr. Motzer that this data supports consideration of atezolizumab and bevacizumab as a first-line option,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif. “I was intrigued to see that there seemed to be benefit with the combination of atezolizumab and bevacizumab irrespective of the presence or absence of PD-L1.”
Study details
About 40% of patients in IMmotion151 had PD-L1–positive tumors. Median investigator-assessed progression-free survival among these patients, a co-primary endpoint, was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02). More modest but still significant benefit was evident among the trial’s entire intention-to-treat population (11.2 vs. 8.4 months; hazard ratio, 0.83; P = .02).
An interim analysis showed that median overall survival among the PD-L1–positive cohort was not reached with atezolizumab-bevacizumab and was 23.3 months with sunitinib (hazard ratio, 0.68; P = .05). Overall survival among the entire trial population, another co-primary endpoint, was not reached in either treatment arm.
The PD-L1–positive cohort had an overall response rate of 43% with atezolizumab-bevacizumab and 35% with sunitinib (complete response rates of 9% and 4%). Corresponding values in the entire trial population were 37% and 33% (5% and 2%).
“Independent review of progression-free survival and response, where the scans are sent off to a committee and they read them blinded to the treatment arm, differed from investigator-assessed outcomes,” Dr. Motzer noted, with lesser benefit from the combination seen in the PD-L1–positive patients. “We are doing further analysis to see if we can identify why there was this difference.”
“One of the main benefits of atezolizumab plus bevacizumab is its safety profile. As an investigator on this study and other studies, I can attest to that: it’s very well tolerated,” he said.
The sunitinib group had higher rates of most treatment-related adverse events, both any grade and grade 3 or worse, especially palmar-plantar erythrodysesthesia, fatigue, and gastrointestinal events. The pattern was similar in the PD-L1–positive subset.
“We also have done an extensive quality of life analysis,” Dr. Motzer said, with some results to be reported at the symposium. “It appears that patients treated with atezolizumab plus bevacizumab have better quality of life compared to sunitinib by a particular scale that assesses trouble with symptoms.”
Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.
SOURCE: Motzer RJ et al. GU Cancers Symposium Abstract 578
The combination of the immune checkpoint inhibitor atezolizumab and bevacizumab has efficacy and tolerability superior to that of sunitinib alone as first-line therapy for metastatic renal cell carcinoma, finds the IMmotion151 trial.
“Sunitinib has been the reference standard for this disease for the last 10 years,” lead study author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium. But strategies using immunotherapy have generated considerable excitement as possible new treatment options.
With a median follow-up of 15 months, compared with sunitinib, the combination of atezolizumab and bevacizumab prolonged investigator-assessed progression-free survival by 3.5 months among patients whose tumors were positive for PD-L1, defined as staining of at least 1% of tumor-infiltrating immune cells by immunohistochemistry. The difference translated to a 26% reduction in the risk of progression or death. However, the combination also had a significant edge in the trial population as a whole.
Overall survival and response rate likewise favored the combination of atezolizumab and bevacizumab. In addition, it was well tolerated, with a lower rate and severity of most adverse events. The exception was a higher rate of proteinuria, an established side effect of bevacizumab, with the combination.
“This trial met its primary endpoint,” Dr. Motzer concluded. “These study results support the consideration of atezolizumab plus bevacizumab as a first-line treatment option for PD-L1–positive patients with advanced renal cell carcinoma.”
Full results of IMmotion151 will be reported at the symposium, which runs Feb. 8-10 and is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Findings in context
“This study represents an important breakthrough in kidney cancer therapy,” said Sumanta K. Pal, MD, presscast moderator and ASCO expert. “For several years now, we’ve hosted debates on which treatment strategy is best for this disease, targeted therapy or immune therapy. Now this study, which is really the first of its kind, points to a combination of both as being highly effective in delaying cancer growth and showing an early trend toward improving survival as well.”
It is also noteworthy that the combination has good tolerability that appears better in several respects to that seen with sunitinib, he said. “In my opinion, the side effect profile also compares favorably to what we have seen to date with a dual immunotherapy regimen, namely, nivolumab (Opdivo) and ipilimumab.” Although that combination has also been shown to be more efficacious than sunitinib, nearly 60% of treated patients need steroids for immune-related side effects, compared with only 16% treated with the atezolizumab-bevacizumab combination in IMmotion151.
“I would agree with Dr. Motzer that this data supports consideration of atezolizumab and bevacizumab as a first-line option,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif. “I was intrigued to see that there seemed to be benefit with the combination of atezolizumab and bevacizumab irrespective of the presence or absence of PD-L1.”
Study details
About 40% of patients in IMmotion151 had PD-L1–positive tumors. Median investigator-assessed progression-free survival among these patients, a co-primary endpoint, was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02). More modest but still significant benefit was evident among the trial’s entire intention-to-treat population (11.2 vs. 8.4 months; hazard ratio, 0.83; P = .02).
An interim analysis showed that median overall survival among the PD-L1–positive cohort was not reached with atezolizumab-bevacizumab and was 23.3 months with sunitinib (hazard ratio, 0.68; P = .05). Overall survival among the entire trial population, another co-primary endpoint, was not reached in either treatment arm.
The PD-L1–positive cohort had an overall response rate of 43% with atezolizumab-bevacizumab and 35% with sunitinib (complete response rates of 9% and 4%). Corresponding values in the entire trial population were 37% and 33% (5% and 2%).
“Independent review of progression-free survival and response, where the scans are sent off to a committee and they read them blinded to the treatment arm, differed from investigator-assessed outcomes,” Dr. Motzer noted, with lesser benefit from the combination seen in the PD-L1–positive patients. “We are doing further analysis to see if we can identify why there was this difference.”
“One of the main benefits of atezolizumab plus bevacizumab is its safety profile. As an investigator on this study and other studies, I can attest to that: it’s very well tolerated,” he said.
The sunitinib group had higher rates of most treatment-related adverse events, both any grade and grade 3 or worse, especially palmar-plantar erythrodysesthesia, fatigue, and gastrointestinal events. The pattern was similar in the PD-L1–positive subset.
“We also have done an extensive quality of life analysis,” Dr. Motzer said, with some results to be reported at the symposium. “It appears that patients treated with atezolizumab plus bevacizumab have better quality of life compared to sunitinib by a particular scale that assesses trouble with symptoms.”
Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.
SOURCE: Motzer RJ et al. GU Cancers Symposium Abstract 578
REPORTING FROM GUCS 2018
Key clinical point:
Major finding: Among patients with PD-L1-positive disease, median investigator-assessed progression-free survival was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02).
Data source: A randomized phase 3 trial among 915 patients with treatment-naive advanced or metastatic RCC (IMmotion151 trial).
Disclosures: Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.
Source: Motzer RJ et al. GU Cancers Symposium Abstract 578
New model predicts survival in atezolizumab-treated advanced urothelial carcinoma
A new model containing six basic laboratory and imaging factors predicts survival of patients with advanced urothelial carcinoma who are given the immune checkpoint inhibitor atezolizumab(Tecentriq), investigators reported in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.
“In the past couple of years, there have been five new programmed death 1 [PD-1] and programmed death ligand 1 [PD-L1] inhibitors [checkpoint-inhibitors] approved by the U.S. FDA [Food and Drug Administration] for patients with advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy, and one of these is atezolizumab,” said lead study author Gregory R. Pond, PhD, of McMaster University, Hamilton, Ont.
However, “there is no available prognostic model for predicting which patients will have improved overall survival in this setting,” he said. “At the moment, we don’t know which therapy to give to which patient. These sorts of prognostic models will help us identify which patients might benefit the most from which therapy.”
Dr. Pond and colleagues analyzed data from patients with advanced urothelial carcinoma treated with atezolizumab in the postplatinum setting. They developed and trained the model in a cohort of 310 patients from the phase 2 IMvigor210 trial and validated it in a cohort of 95 patients from the phase 1 PCD4989g trial.
The model ultimately contained six prognostic factors: elevated neutrophil-lymphocyte ratio (5 or higher), impaired functional status (Eastern Cooperative Oncology Group performance status of 1 or higher), elevated platelet count (400 x 109/L or higher), anemia (hemoglobin level less than 10 g/dL), elevated lactate dehydrogenase level (280 U/L or higher), and the presence of liver metastasis.
Main results showed that median overall survival for patients with 0-1, 2-3, and 4 or more factors was 19.6, 5.9, and 2.8 months in the IMvigor210 cohort, and 19.4, 7.2, and 2.6 months in the PCD4989g cohort, respectively.
“We have developed a prognostic model for overall survival, which we now propose for patients with advanced urothelial carcinoma receiving postplatinum atezolizumab,” Dr. Pond summarized. “The initial results of our study are very promising in both the training and validation datasets.
“The model does require further evaluation and further refinements,” he acknowledged. “For example, we need to look at and evaluate how the model performs in larger sample sizes, and we also want to see how it works with other checkpoint inhibitors.” The investigators also plan to assess its performance relative to that of a PD-L1 immunohistochemical assay.
Full results of the study will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Findings in context
Response of advanced urothelial carcinoma to immune checkpoint inhibitors ranges widely, with one-quarter of patients or fewer seeing tumor shrinkage, and a small proportion seeing longer-term survival, according to ASCO expert and presscast moderator Sumanta K. Pal, MD.
“Until the results of this study, there was no way to easily discern prognosis and identify who might stand to benefit most,” he said. “This easily applied score developed by Dr. Pond and colleagues based on parameters readily available in the patient’s chart provides tremendous input.
“While I would not necessarily withhold therapy on the basis of an anticipated poor prognosis, I would consider using this information in counseling patients who want to be better informed about potential outcomes with immunotherapy,” commented Dr. Pal, who is a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.
Many studies are assessing combinations of immunotherapies with one another and with chemotherapy, he noted. “If these studies are positive, there would be a massive paradigm shift in how we manage advanced bladder cancer. At that point in time, we would have to determine if the model established by Dr. Pond and colleagues remains relevant in that climate.”
Dr. Pond disclosed that an immediate family member is an employee of Roche Canada. Genentech provided data for this study.
SOURCE: Pond GR et al. GU Cancers Symposium, Abstract 413
A new model containing six basic laboratory and imaging factors predicts survival of patients with advanced urothelial carcinoma who are given the immune checkpoint inhibitor atezolizumab(Tecentriq), investigators reported in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.
“In the past couple of years, there have been five new programmed death 1 [PD-1] and programmed death ligand 1 [PD-L1] inhibitors [checkpoint-inhibitors] approved by the U.S. FDA [Food and Drug Administration] for patients with advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy, and one of these is atezolizumab,” said lead study author Gregory R. Pond, PhD, of McMaster University, Hamilton, Ont.
However, “there is no available prognostic model for predicting which patients will have improved overall survival in this setting,” he said. “At the moment, we don’t know which therapy to give to which patient. These sorts of prognostic models will help us identify which patients might benefit the most from which therapy.”
Dr. Pond and colleagues analyzed data from patients with advanced urothelial carcinoma treated with atezolizumab in the postplatinum setting. They developed and trained the model in a cohort of 310 patients from the phase 2 IMvigor210 trial and validated it in a cohort of 95 patients from the phase 1 PCD4989g trial.
The model ultimately contained six prognostic factors: elevated neutrophil-lymphocyte ratio (5 or higher), impaired functional status (Eastern Cooperative Oncology Group performance status of 1 or higher), elevated platelet count (400 x 109/L or higher), anemia (hemoglobin level less than 10 g/dL), elevated lactate dehydrogenase level (280 U/L or higher), and the presence of liver metastasis.
Main results showed that median overall survival for patients with 0-1, 2-3, and 4 or more factors was 19.6, 5.9, and 2.8 months in the IMvigor210 cohort, and 19.4, 7.2, and 2.6 months in the PCD4989g cohort, respectively.
“We have developed a prognostic model for overall survival, which we now propose for patients with advanced urothelial carcinoma receiving postplatinum atezolizumab,” Dr. Pond summarized. “The initial results of our study are very promising in both the training and validation datasets.
“The model does require further evaluation and further refinements,” he acknowledged. “For example, we need to look at and evaluate how the model performs in larger sample sizes, and we also want to see how it works with other checkpoint inhibitors.” The investigators also plan to assess its performance relative to that of a PD-L1 immunohistochemical assay.
Full results of the study will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Findings in context
Response of advanced urothelial carcinoma to immune checkpoint inhibitors ranges widely, with one-quarter of patients or fewer seeing tumor shrinkage, and a small proportion seeing longer-term survival, according to ASCO expert and presscast moderator Sumanta K. Pal, MD.
“Until the results of this study, there was no way to easily discern prognosis and identify who might stand to benefit most,” he said. “This easily applied score developed by Dr. Pond and colleagues based on parameters readily available in the patient’s chart provides tremendous input.
“While I would not necessarily withhold therapy on the basis of an anticipated poor prognosis, I would consider using this information in counseling patients who want to be better informed about potential outcomes with immunotherapy,” commented Dr. Pal, who is a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.
Many studies are assessing combinations of immunotherapies with one another and with chemotherapy, he noted. “If these studies are positive, there would be a massive paradigm shift in how we manage advanced bladder cancer. At that point in time, we would have to determine if the model established by Dr. Pond and colleagues remains relevant in that climate.”
Dr. Pond disclosed that an immediate family member is an employee of Roche Canada. Genentech provided data for this study.
SOURCE: Pond GR et al. GU Cancers Symposium, Abstract 413
A new model containing six basic laboratory and imaging factors predicts survival of patients with advanced urothelial carcinoma who are given the immune checkpoint inhibitor atezolizumab(Tecentriq), investigators reported in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.
“In the past couple of years, there have been five new programmed death 1 [PD-1] and programmed death ligand 1 [PD-L1] inhibitors [checkpoint-inhibitors] approved by the U.S. FDA [Food and Drug Administration] for patients with advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy, and one of these is atezolizumab,” said lead study author Gregory R. Pond, PhD, of McMaster University, Hamilton, Ont.
However, “there is no available prognostic model for predicting which patients will have improved overall survival in this setting,” he said. “At the moment, we don’t know which therapy to give to which patient. These sorts of prognostic models will help us identify which patients might benefit the most from which therapy.”
Dr. Pond and colleagues analyzed data from patients with advanced urothelial carcinoma treated with atezolizumab in the postplatinum setting. They developed and trained the model in a cohort of 310 patients from the phase 2 IMvigor210 trial and validated it in a cohort of 95 patients from the phase 1 PCD4989g trial.
The model ultimately contained six prognostic factors: elevated neutrophil-lymphocyte ratio (5 or higher), impaired functional status (Eastern Cooperative Oncology Group performance status of 1 or higher), elevated platelet count (400 x 109/L or higher), anemia (hemoglobin level less than 10 g/dL), elevated lactate dehydrogenase level (280 U/L or higher), and the presence of liver metastasis.
Main results showed that median overall survival for patients with 0-1, 2-3, and 4 or more factors was 19.6, 5.9, and 2.8 months in the IMvigor210 cohort, and 19.4, 7.2, and 2.6 months in the PCD4989g cohort, respectively.
“We have developed a prognostic model for overall survival, which we now propose for patients with advanced urothelial carcinoma receiving postplatinum atezolizumab,” Dr. Pond summarized. “The initial results of our study are very promising in both the training and validation datasets.
“The model does require further evaluation and further refinements,” he acknowledged. “For example, we need to look at and evaluate how the model performs in larger sample sizes, and we also want to see how it works with other checkpoint inhibitors.” The investigators also plan to assess its performance relative to that of a PD-L1 immunohistochemical assay.
Full results of the study will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Findings in context
Response of advanced urothelial carcinoma to immune checkpoint inhibitors ranges widely, with one-quarter of patients or fewer seeing tumor shrinkage, and a small proportion seeing longer-term survival, according to ASCO expert and presscast moderator Sumanta K. Pal, MD.
“Until the results of this study, there was no way to easily discern prognosis and identify who might stand to benefit most,” he said. “This easily applied score developed by Dr. Pond and colleagues based on parameters readily available in the patient’s chart provides tremendous input.
“While I would not necessarily withhold therapy on the basis of an anticipated poor prognosis, I would consider using this information in counseling patients who want to be better informed about potential outcomes with immunotherapy,” commented Dr. Pal, who is a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.
Many studies are assessing combinations of immunotherapies with one another and with chemotherapy, he noted. “If these studies are positive, there would be a massive paradigm shift in how we manage advanced bladder cancer. At that point in time, we would have to determine if the model established by Dr. Pond and colleagues remains relevant in that climate.”
Dr. Pond disclosed that an immediate family member is an employee of Roche Canada. Genentech provided data for this study.
SOURCE: Pond GR et al. GU Cancers Symposium, Abstract 413
REPORTING FROM GUCS 2018
Key clinical point:
Major finding: Median overall survival for patients with 0-1, 2-3, and 4 or more factors was 19.6, 5.9, and 2.8 months in the development cohort, and 19.4, 7.2 and 2.6 months in the validation cohort, respectively.
Data source: A study among patients given atezolizumab for advanced urothelial carcinoma with a development cohort (310 patients from the phase 2 IMvigor210 trial) and a validation cohort (95 patients from the phase 1 PCD4989g trial).
Disclosures: Dr. Pond disclosed that an immediate family member is an employee of Roche Canada. Genentech provided data for this study.
Source: Pond GR et al. GU Cancers Symposium Abstract 413
Apalutamide wins big in SPARTAN prostate cancer trial
The androgen receptor antagonist apalutamide is highly effective for treating nonmetastatic castration-resistant prostate cancer that carries high risk for metastasis based on a rapidly rising prostate-specific antigen (PSA) level, according to results of the randomized phase 3 SPARTAN trial.
“Metastatic castration-resistant prostate cancer is a uniformly fatal disease, with a median survival of around 2.5 years. The aim of this study was to see if the development of metastases in the transition from nonmetastatic to metastatic castration-resistant prostate cancer could be slowed,” lead study author Eric J. Small, MD, professor of medicine at the University of California, San Francisco, commented in a press briefing held in advance of the 2018 Genitourinary Cancers Symposium.
He and his coinvestigators randomized 1,207 men with high-risk nonmetastatic castration-resistant prostate cancer 2:1 to apalutamide (an investigational next-generation competitive inhibitor of the androgen receptor, also known as ARN-509) or placebo, with continuation of androgen-deprivation therapy in both groups. After development of metastases, patients were offered open-label abiraterone (Zytiga), the standard of care for this population, with prednisone.
Main results showed that, compared with placebo, apalutamide prolonged the time to metastasis (ascertained by central review of standard imaging) or death by more than 2 years, Dr. Small reported. The difference translated to a nearly three-fourths reduction in the risk of these events. In addition, the drug was well tolerated and had a rate of serious adverse events similar to that seen with placebo.
“This is a positive trial,” he summarized. “Overall, these data suggest that apalutamide should now be considered as a new standard of care for men with high-risk nonmetastatic castration-resistant prostate cancer.”
The metastasis-free survival findings led to unblinding of the trial in July 2017, and all patients were offered open-label apalutamide. Full results of SPARTAN will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Parsing the findings
“Until the results of studies presented at this meeting, there was really no obvious standard of care for these patients,” commented ASCO Expert and presscast moderator Sumanta K. Pal, MD. The gain in metastasis-free survival in SPARTAN was “very clinically meaningful.”
Results of the similar PROSPER trial, which compared enzalutamide (Xtandi) with placebo, will also be presented at the symposium, he noted. “We know from a press release issued in September of 2017 that this study also showed a significant delay in the time to onset of metastatic disease. It will be interesting to juxtapose these data once available. Enzalutamide is a drug familiar to the prostate cancer community given existing approvals in the setting of more advanced disease. The familiarity that oncologists already have with enzalutamide may help with clinical adoption.”
Ultimately, imaging advances that allow for earlier detection of metastases may shrink the population of men with nonmetastatic castration-resistant prostate cancer, according to Dr. Pal, who is also a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.
“The SPARTAN trial used a more conventional imaging approach, with CT scans and technetium bone scans,” he pointed out. “While it’s true that this is the current standard, imaging techniques such as fluciclovine PET, PSMA [prostate-specific membrane antigen] PET, may potentially improve our ability to detect disease spread earlier and thereby change our management strategy.”
Study details
The patients with nonmetastatic castration-resistant prostate cancer enrolled in SPARTAN had a calculated PSA-doubling time of 10 months or less, a feature identifying those most at risk for developing metastases.
At a median follow-up of 20.3 months, median metastasis-free survival was 40.5 months with apalutamide versus 16.2 months with placebo (hazard ratio, 0.28; P less than .001), Dr. Small reported. An interim analysis of overall survival showed a trend favoring apalutamide (P = .07).
Fully 61% of patients in the apalutamide group were still on treatment at data cutoff, compared with 30% of placebo-treated patients.
Both groups had low rates of discontinuation attributable to adverse events (10.7% and 6.3%). Apalutamide-treated patients did not have any decrease from baseline in patient-reported health-related quality of life scores, which were similar to those of placebo-treated counterparts.
Dr. Small disclosed that he has a consulting or advisory role with Fortis, Gilead Sciences, and Valeant Pharmaceuticals International; has stock and other ownership interests with Fortis and Harpoon Therapeutics; and receives honoraria from Janssen-Cilag; in addition, his institution receives research funding from Janssen. The study was funded by Aragon Pharmaceuticals, a wholly-owned subsidiary of Johnson & Johnson.
The androgen receptor antagonist apalutamide is highly effective for treating nonmetastatic castration-resistant prostate cancer that carries high risk for metastasis based on a rapidly rising prostate-specific antigen (PSA) level, according to results of the randomized phase 3 SPARTAN trial.
“Metastatic castration-resistant prostate cancer is a uniformly fatal disease, with a median survival of around 2.5 years. The aim of this study was to see if the development of metastases in the transition from nonmetastatic to metastatic castration-resistant prostate cancer could be slowed,” lead study author Eric J. Small, MD, professor of medicine at the University of California, San Francisco, commented in a press briefing held in advance of the 2018 Genitourinary Cancers Symposium.
He and his coinvestigators randomized 1,207 men with high-risk nonmetastatic castration-resistant prostate cancer 2:1 to apalutamide (an investigational next-generation competitive inhibitor of the androgen receptor, also known as ARN-509) or placebo, with continuation of androgen-deprivation therapy in both groups. After development of metastases, patients were offered open-label abiraterone (Zytiga), the standard of care for this population, with prednisone.
Main results showed that, compared with placebo, apalutamide prolonged the time to metastasis (ascertained by central review of standard imaging) or death by more than 2 years, Dr. Small reported. The difference translated to a nearly three-fourths reduction in the risk of these events. In addition, the drug was well tolerated and had a rate of serious adverse events similar to that seen with placebo.
“This is a positive trial,” he summarized. “Overall, these data suggest that apalutamide should now be considered as a new standard of care for men with high-risk nonmetastatic castration-resistant prostate cancer.”
The metastasis-free survival findings led to unblinding of the trial in July 2017, and all patients were offered open-label apalutamide. Full results of SPARTAN will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Parsing the findings
“Until the results of studies presented at this meeting, there was really no obvious standard of care for these patients,” commented ASCO Expert and presscast moderator Sumanta K. Pal, MD. The gain in metastasis-free survival in SPARTAN was “very clinically meaningful.”
Results of the similar PROSPER trial, which compared enzalutamide (Xtandi) with placebo, will also be presented at the symposium, he noted. “We know from a press release issued in September of 2017 that this study also showed a significant delay in the time to onset of metastatic disease. It will be interesting to juxtapose these data once available. Enzalutamide is a drug familiar to the prostate cancer community given existing approvals in the setting of more advanced disease. The familiarity that oncologists already have with enzalutamide may help with clinical adoption.”
Ultimately, imaging advances that allow for earlier detection of metastases may shrink the population of men with nonmetastatic castration-resistant prostate cancer, according to Dr. Pal, who is also a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.
“The SPARTAN trial used a more conventional imaging approach, with CT scans and technetium bone scans,” he pointed out. “While it’s true that this is the current standard, imaging techniques such as fluciclovine PET, PSMA [prostate-specific membrane antigen] PET, may potentially improve our ability to detect disease spread earlier and thereby change our management strategy.”
Study details
The patients with nonmetastatic castration-resistant prostate cancer enrolled in SPARTAN had a calculated PSA-doubling time of 10 months or less, a feature identifying those most at risk for developing metastases.
At a median follow-up of 20.3 months, median metastasis-free survival was 40.5 months with apalutamide versus 16.2 months with placebo (hazard ratio, 0.28; P less than .001), Dr. Small reported. An interim analysis of overall survival showed a trend favoring apalutamide (P = .07).
Fully 61% of patients in the apalutamide group were still on treatment at data cutoff, compared with 30% of placebo-treated patients.
Both groups had low rates of discontinuation attributable to adverse events (10.7% and 6.3%). Apalutamide-treated patients did not have any decrease from baseline in patient-reported health-related quality of life scores, which were similar to those of placebo-treated counterparts.
Dr. Small disclosed that he has a consulting or advisory role with Fortis, Gilead Sciences, and Valeant Pharmaceuticals International; has stock and other ownership interests with Fortis and Harpoon Therapeutics; and receives honoraria from Janssen-Cilag; in addition, his institution receives research funding from Janssen. The study was funded by Aragon Pharmaceuticals, a wholly-owned subsidiary of Johnson & Johnson.
The androgen receptor antagonist apalutamide is highly effective for treating nonmetastatic castration-resistant prostate cancer that carries high risk for metastasis based on a rapidly rising prostate-specific antigen (PSA) level, according to results of the randomized phase 3 SPARTAN trial.
“Metastatic castration-resistant prostate cancer is a uniformly fatal disease, with a median survival of around 2.5 years. The aim of this study was to see if the development of metastases in the transition from nonmetastatic to metastatic castration-resistant prostate cancer could be slowed,” lead study author Eric J. Small, MD, professor of medicine at the University of California, San Francisco, commented in a press briefing held in advance of the 2018 Genitourinary Cancers Symposium.
He and his coinvestigators randomized 1,207 men with high-risk nonmetastatic castration-resistant prostate cancer 2:1 to apalutamide (an investigational next-generation competitive inhibitor of the androgen receptor, also known as ARN-509) or placebo, with continuation of androgen-deprivation therapy in both groups. After development of metastases, patients were offered open-label abiraterone (Zytiga), the standard of care for this population, with prednisone.
Main results showed that, compared with placebo, apalutamide prolonged the time to metastasis (ascertained by central review of standard imaging) or death by more than 2 years, Dr. Small reported. The difference translated to a nearly three-fourths reduction in the risk of these events. In addition, the drug was well tolerated and had a rate of serious adverse events similar to that seen with placebo.
“This is a positive trial,” he summarized. “Overall, these data suggest that apalutamide should now be considered as a new standard of care for men with high-risk nonmetastatic castration-resistant prostate cancer.”
The metastasis-free survival findings led to unblinding of the trial in July 2017, and all patients were offered open-label apalutamide. Full results of SPARTAN will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Parsing the findings
“Until the results of studies presented at this meeting, there was really no obvious standard of care for these patients,” commented ASCO Expert and presscast moderator Sumanta K. Pal, MD. The gain in metastasis-free survival in SPARTAN was “very clinically meaningful.”
Results of the similar PROSPER trial, which compared enzalutamide (Xtandi) with placebo, will also be presented at the symposium, he noted. “We know from a press release issued in September of 2017 that this study also showed a significant delay in the time to onset of metastatic disease. It will be interesting to juxtapose these data once available. Enzalutamide is a drug familiar to the prostate cancer community given existing approvals in the setting of more advanced disease. The familiarity that oncologists already have with enzalutamide may help with clinical adoption.”
Ultimately, imaging advances that allow for earlier detection of metastases may shrink the population of men with nonmetastatic castration-resistant prostate cancer, according to Dr. Pal, who is also a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.
“The SPARTAN trial used a more conventional imaging approach, with CT scans and technetium bone scans,” he pointed out. “While it’s true that this is the current standard, imaging techniques such as fluciclovine PET, PSMA [prostate-specific membrane antigen] PET, may potentially improve our ability to detect disease spread earlier and thereby change our management strategy.”
Study details
The patients with nonmetastatic castration-resistant prostate cancer enrolled in SPARTAN had a calculated PSA-doubling time of 10 months or less, a feature identifying those most at risk for developing metastases.
At a median follow-up of 20.3 months, median metastasis-free survival was 40.5 months with apalutamide versus 16.2 months with placebo (hazard ratio, 0.28; P less than .001), Dr. Small reported. An interim analysis of overall survival showed a trend favoring apalutamide (P = .07).
Fully 61% of patients in the apalutamide group were still on treatment at data cutoff, compared with 30% of placebo-treated patients.
Both groups had low rates of discontinuation attributable to adverse events (10.7% and 6.3%). Apalutamide-treated patients did not have any decrease from baseline in patient-reported health-related quality of life scores, which were similar to those of placebo-treated counterparts.
Dr. Small disclosed that he has a consulting or advisory role with Fortis, Gilead Sciences, and Valeant Pharmaceuticals International; has stock and other ownership interests with Fortis and Harpoon Therapeutics; and receives honoraria from Janssen-Cilag; in addition, his institution receives research funding from Janssen. The study was funded by Aragon Pharmaceuticals, a wholly-owned subsidiary of Johnson & Johnson.
REPORTING FROM GUCS 2018
Key clinical point:
Major finding: Median metastasis-free survival was 40.5 months with apalutamide versus 16.2 months with placebo (HR, 0.28; P less than .001).
Data source: A phase 3 randomized controlled trial among 1,207 men with high-risk nonmetastatic castration-resistant prostate cancer (SPARTAN trial).
Disclosures: Dr. Small disclosed that he has a consulting or advisory role with Fortis, Gilead Sciences, and Valeant Pharmaceuticals International; has stock and other ownership interests with Fortis and Harpoon Therapeutics; and receives honoraria from Janssen-Cilag; in addition, his institution receives research funding from Janssen. The study was funded by Aragon Pharmaceuticals, a wholly-owned subsidiary of Johnson & Johnson.