ASCO: Genitourinary Cancers Symposium 2014

SAN FRANCISCO – The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is a valid tool for predicting survival in patients starting second-line targeted therapy for this disease, new data show.

In fact, it outperforms the leading model derived a decade ago, researchers reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The new model uses six clinical and laboratory factors to stratify patients into prognostic risk groups. It builds on the widely used three-factor Memorial Sloan-Kettering Cancer Center (MSKCC) second-line prognostic model (J. Clin. Oncol. 2004;22:454-63).

Results of the retrospective cohort study showed that the IMDC model performed well for risk stratification in this setting, with patients in the intermediate- and high-risk groups having roughly two and six times the risk of death, respectively, compared with peers in the favorable risk group, reported Dr. Jenny J. Ko of the British Columbia Cancer Agency, Vancouver. Also, it was superior to the MSKCC model for predicting survival as assessed by three statistical tests.

"The six-factor IMDC prognostic model has been validated in and can be applied to patients previously treated with targeted therapy, in addition to previously validated populations in the first-line targeted therapy and non–clear cell setting," she commented.

"The model fits better into the context of the contemporary treatment era, where targeted therapies are used in a sequential fashion," Dr. Ko added.

The study population was heterogeneous, she acknowledged. But "this can also mean that the cohort was generalizable, as our cohort includes trial and off-trial patients, and it also includes community and academic centers."

Invited discussant Dr. Daniel Canter of the Fox Chase Cancer Center, Philadelphia, noted that the durations of second-line therapy and survival after starting this therapy were fairly short, highlighting the need for better therapies.

The choice of first-line therapy for metastatic renal cell carcinoma (mRCC) may shift in the future away from sunitinib (Sutent) and sorafenib (Nexavar), used in the vast majority of the patients studied, he noted.

"My observation is that the medical oncologists that I work with seem to be using pazopanib (Votrient) more now as a first-line therapy because of the improved toxicity," Dr. Canter noted, and doing so may ultimately affect survival. "Obviously, a future question is the role of pazopanib. And ... an algorithm to define second-line choices is clearly something where there is an opportunity for work to be done."

Dr. Ko and her team studied 1,021 consecutive patients with mRCC from 19 centers who were starting second-line targeted therapy. (About a fifth had received immunotherapy before their first-line targeted therapy and were therefore on third-line therapy of any type.)

Eighty-five percent of patients had undergone nephrectomy. Their first-line targeted therapy had most often been sunitinib (67%) or sorafenib (20%).

The second-line therapies given included sorafenib (29%), sunitinib (22%), everolimus (Afinitor) (22%), and temsirolimus (Torisel) (12%), among others.

In a multivariate analysis, five of the six IMDC factors (Karnofsky performance status less than 80%; interval between diagnosis and treatment of less than 1 year; anemia; thrombocytosis; and neutrophilia) individually predicted an elevated risk of death after starting second-line therapy, reported Dr. Ko, who disclosed no conflicts of interest related to the research. Hypercalcemia did not, but few patients had this risk factor.

The median time on second-line targeted therapy was 3.9 months, and the median overall survival after starting this therapy was 12.5 months.

Compared with patients in the favorable IMDC risk group (having none of the risk factors), patients in the intermediate-risk group (having one or two) and patients in the high-risk group (having three or more) had significantly elevated risks of death (hazard ratios, 1.89 and 5.73).

In a likelihood ratio test, comparing the two models, the chi-square value was highly significant, suggesting that inclusion of the three additional factors in the IMDC model enhanced predictive performance over that with the MSKCC model.

Finally, in a reclassification calibration analysis, the chi-square value was much lower for the IMDC model than for the MSKCC model (6.2 vs. 54.2), indicating that the observed vs. predicted number of deaths at 1 year was better for the former.

SAN FRANCISCO – The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is a valid tool for predicting survival in patients starting second-line targeted therapy for this disease, new data show.

In fact, it outperforms the leading model derived a decade ago, researchers reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The new model uses six clinical and laboratory factors to stratify patients into prognostic risk groups. It builds on the widely used three-factor Memorial Sloan-Kettering Cancer Center (MSKCC) second-line prognostic model (J. Clin. Oncol. 2004;22:454-63).

Results of the retrospective cohort study showed that the IMDC model performed well for risk stratification in this setting, with patients in the intermediate- and high-risk groups having roughly two and six times the risk of death, respectively, compared with peers in the favorable risk group, reported Dr. Jenny J. Ko of the British Columbia Cancer Agency, Vancouver. Also, it was superior to the MSKCC model for predicting survival as assessed by three statistical tests.

"The six-factor IMDC prognostic model has been validated in and can be applied to patients previously treated with targeted therapy, in addition to previously validated populations in the first-line targeted therapy and non–clear cell setting," she commented.

"The model fits better into the context of the contemporary treatment era, where targeted therapies are used in a sequential fashion," Dr. Ko added.

The study population was heterogeneous, she acknowledged. But "this can also mean that the cohort was generalizable, as our cohort includes trial and off-trial patients, and it also includes community and academic centers."

Invited discussant Dr. Daniel Canter of the Fox Chase Cancer Center, Philadelphia, noted that the durations of second-line therapy and survival after starting this therapy were fairly short, highlighting the need for better therapies.

The choice of first-line therapy for metastatic renal cell carcinoma (mRCC) may shift in the future away from sunitinib (Sutent) and sorafenib (Nexavar), used in the vast majority of the patients studied, he noted.

"My observation is that the medical oncologists that I work with seem to be using pazopanib (Votrient) more now as a first-line therapy because of the improved toxicity," Dr. Canter noted, and doing so may ultimately affect survival. "Obviously, a future question is the role of pazopanib. And ... an algorithm to define second-line choices is clearly something where there is an opportunity for work to be done."

Dr. Ko and her team studied 1,021 consecutive patients with mRCC from 19 centers who were starting second-line targeted therapy. (About a fifth had received immunotherapy before their first-line targeted therapy and were therefore on third-line therapy of any type.)

Eighty-five percent of patients had undergone nephrectomy. Their first-line targeted therapy had most often been sunitinib (67%) or sorafenib (20%).

The second-line therapies given included sorafenib (29%), sunitinib (22%), everolimus (Afinitor) (22%), and temsirolimus (Torisel) (12%), among others.

In a multivariate analysis, five of the six IMDC factors (Karnofsky performance status less than 80%; interval between diagnosis and treatment of less than 1 year; anemia; thrombocytosis; and neutrophilia) individually predicted an elevated risk of death after starting second-line therapy, reported Dr. Ko, who disclosed no conflicts of interest related to the research. Hypercalcemia did not, but few patients had this risk factor.

The median time on second-line targeted therapy was 3.9 months, and the median overall survival after starting this therapy was 12.5 months.

Compared with patients in the favorable IMDC risk group (having none of the risk factors), patients in the intermediate-risk group (having one or two) and patients in the high-risk group (having three or more) had significantly elevated risks of death (hazard ratios, 1.89 and 5.73).

In a likelihood ratio test, comparing the two models, the chi-square value was highly significant, suggesting that inclusion of the three additional factors in the IMDC model enhanced predictive performance over that with the MSKCC model.

Finally, in a reclassification calibration analysis, the chi-square value was much lower for the IMDC model than for the MSKCC model (6.2 vs. 54.2), indicating that the observed vs. predicted number of deaths at 1 year was better for the former.

SAN FRANCISCO – The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is a valid tool for predicting survival in patients starting second-line targeted therapy for this disease, new data show.

In fact, it outperforms the leading model derived a decade ago, researchers reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The new model uses six clinical and laboratory factors to stratify patients into prognostic risk groups. It builds on the widely used three-factor Memorial Sloan-Kettering Cancer Center (MSKCC) second-line prognostic model (J. Clin. Oncol. 2004;22:454-63).

Results of the retrospective cohort study showed that the IMDC model performed well for risk stratification in this setting, with patients in the intermediate- and high-risk groups having roughly two and six times the risk of death, respectively, compared with peers in the favorable risk group, reported Dr. Jenny J. Ko of the British Columbia Cancer Agency, Vancouver. Also, it was superior to the MSKCC model for predicting survival as assessed by three statistical tests.

"The six-factor IMDC prognostic model has been validated in and can be applied to patients previously treated with targeted therapy, in addition to previously validated populations in the first-line targeted therapy and non–clear cell setting," she commented.

"The model fits better into the context of the contemporary treatment era, where targeted therapies are used in a sequential fashion," Dr. Ko added.

The study population was heterogeneous, she acknowledged. But "this can also mean that the cohort was generalizable, as our cohort includes trial and off-trial patients, and it also includes community and academic centers."

Invited discussant Dr. Daniel Canter of the Fox Chase Cancer Center, Philadelphia, noted that the durations of second-line therapy and survival after starting this therapy were fairly short, highlighting the need for better therapies.

The choice of first-line therapy for metastatic renal cell carcinoma (mRCC) may shift in the future away from sunitinib (Sutent) and sorafenib (Nexavar), used in the vast majority of the patients studied, he noted.

"My observation is that the medical oncologists that I work with seem to be using pazopanib (Votrient) more now as a first-line therapy because of the improved toxicity," Dr. Canter noted, and doing so may ultimately affect survival. "Obviously, a future question is the role of pazopanib. And ... an algorithm to define second-line choices is clearly something where there is an opportunity for work to be done."

Dr. Ko and her team studied 1,021 consecutive patients with mRCC from 19 centers who were starting second-line targeted therapy. (About a fifth had received immunotherapy before their first-line targeted therapy and were therefore on third-line therapy of any type.)

Eighty-five percent of patients had undergone nephrectomy. Their first-line targeted therapy had most often been sunitinib (67%) or sorafenib (20%).

The second-line therapies given included sorafenib (29%), sunitinib (22%), everolimus (Afinitor) (22%), and temsirolimus (Torisel) (12%), among others.

In a multivariate analysis, five of the six IMDC factors (Karnofsky performance status less than 80%; interval between diagnosis and treatment of less than 1 year; anemia; thrombocytosis; and neutrophilia) individually predicted an elevated risk of death after starting second-line therapy, reported Dr. Ko, who disclosed no conflicts of interest related to the research. Hypercalcemia did not, but few patients had this risk factor.

The median time on second-line targeted therapy was 3.9 months, and the median overall survival after starting this therapy was 12.5 months.

Compared with patients in the favorable IMDC risk group (having none of the risk factors), patients in the intermediate-risk group (having one or two) and patients in the high-risk group (having three or more) had significantly elevated risks of death (hazard ratios, 1.89 and 5.73).

In a likelihood ratio test, comparing the two models, the chi-square value was highly significant, suggesting that inclusion of the three additional factors in the IMDC model enhanced predictive performance over that with the MSKCC model.

Finally, in a reclassification calibration analysis, the chi-square value was much lower for the IMDC model than for the MSKCC model (6.2 vs. 54.2), indicating that the observed vs. predicted number of deaths at 1 year was better for the former.

SAN FRANCISCO – Only selected patients with synchronous metastases from renal cell carcinoma derive a survival benefit from a cytoreductive nephrectomy, a retrospective cohort study showed.

Researchers studied more than 1,600 patients from the International mRCC (metastatic renal cell carcinoma) Database Consortium who developed metastases while their primary tumor was still in place.

The main analyses showed that as a whole, patients who underwent cytoreductive nephrectomy lived longer than their counterparts who did not have this surgery.

However, in stratified analyses, the surgery significantly prolonged survival only among patients who had a life expectancy exceeding 12 months and patients who had three or fewer risk factors by International mRCC Database Consortium (IMDC) criteria.

Risk factors include Karnofsky performance status less than 80%, an interval between diagnosis and treatment of less than 1 year, anemia, thrombocytosis, neutrophilia, and hypercalcemia

"Overall, I think we can say that cytoreductive nephrectomy may be beneficial in the age of targeted therapy. However, not all patients should have it," commented first author Dr. Daniel Y.C. Heng of the University of Calgary (Alta.).

"Patients with four or more IMDC risk factors and patients with limited life expectancy probably shouldn’t have a cytoreductive nephrectomy," he said. "Of course, there are probably exceptions to that rule; if patients are really symptomatic in the primary, for example, or have bleeding, maybe there are exceptions.

"But I think this is a very interesting and useful way to help select our patients for cytoreductive nephrectomy. Certainly, we are awaiting the CARMENA and SURTIME phase III randomized controlled trials to prospectively evaluate this, and hopefully, we will be able to look at the IMDC risk factors to see if they can aid in patient selection in a prospectively validated way," Dr. Heng said at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Cytoreductive nephrectomy carries risks of morbidity and mortality, and some patients may be unable to go on to receive systemic therapy, noted invited discussant Dr. Daniel Canter of the Fox Chase Cancer Center, Philadelphia.

"What I take home as the most important point of this talk is that we need to make better choices and risk stratify these patients before surgery," he said.

A key question arising from the new data is whether the IMDC risk groups should be redefined, according to Dr. Canter; for example, patients with three risk factors are currently placed in the poor risk group, yet they derived significant benefit from surgery in this study. "So is there room for further refinement in this model?" he asked.

"With such a large cohort, I think that adding to this data with complication rates and perioperative mortality would certainly be important in terms of future treatment decision making," he commented.

Session attendee Dr. Adam Metwalli of the National Cancer Institute asked, "Are there specific risk factors that seem to disproportionately cluster among those who have four or five that would help to distinguish them from the ones who have zero to three?"

"By far, the most important prognostic factor is Karnofsky performance status, and that makes sense," Dr. Heng replied. "It’s partially the ‘look test’ and how you think a patient will fare. So, that by far has the biggest contribution."

Introducing the study, he noted that cytoreductive nephrectomy has previously been found to prolong survival by about 6 months in patients with metastatic renal cell carcinoma treated in the immunotherapy era.

"But of course now we are in the age of targeted therapy, with VEGF [vascular endothelial growth factor] inhibitors and mTOR [mammalian target of rapamycin] inhibitors. These are drugs that are much more active than in the era of old immunotherapy. So it begs the question, is cytoreductive nephrectomy still relevant?" Dr. Heng said.

The researchers studied 1,658 patients from 20 institutions who had mRCC with synchronous metastases, of whom 59% underwent cytoreductive nephrectomy.

They had a median age of 59 years, and about half were in the IMDC intermediate-risk group. The most common prior targeted therapy was sunitinib (Sutent), received by about three-fourths, reported Dr. Heng.

In unadjusted analyses, median overall survival was a significant 11 months longer for patients who underwent cytoreductive nephrectomy compared with their counterparts who did not (20.6 vs. 9.5 months). After adjustment for IMDC risk factors, the surgery was associated with a 40% reduction in the risk of death in the entire cohort (hazard ratio, 0.60; P less than .0001).

However, in analyses stratified by patient life expectancy, there was a significant survival benefit of cytoreductive nephrectomy only among patients expected to live 12-18 months (3.3-month incremental benefit; adjusted hazard ratio, 0.85; P = .049) or 18-24 months (5.2-month incremental benefit; adjusted hazard ratio, 0.72; P less than .0001).

Similarly, in analyses stratified by the number of risk factors present out of the six IMDC risk factors, there was a significant survival benefit of cytoreductive nephrectomy only among patients with three or fewer factors (incremental benefit of 6-10 months, P less than .005 for each).

The impact of overall tumor burden and the size of the primary tumor were not considered in this analysis but will be in subsequent analyses, according to Dr. Heng.

He disclosed that he is a consultant/adviser to Aveo, Bayer, Bristol-Myers Squibb, Novartis, and Pfizer.

SAN FRANCISCO – Only selected patients with synchronous metastases from renal cell carcinoma derive a survival benefit from a cytoreductive nephrectomy, a retrospective cohort study showed.

Researchers studied more than 1,600 patients from the International mRCC (metastatic renal cell carcinoma) Database Consortium who developed metastases while their primary tumor was still in place.

The main analyses showed that as a whole, patients who underwent cytoreductive nephrectomy lived longer than their counterparts who did not have this surgery.

However, in stratified analyses, the surgery significantly prolonged survival only among patients who had a life expectancy exceeding 12 months and patients who had three or fewer risk factors by International mRCC Database Consortium (IMDC) criteria.

Risk factors include Karnofsky performance status less than 80%, an interval between diagnosis and treatment of less than 1 year, anemia, thrombocytosis, neutrophilia, and hypercalcemia

"Overall, I think we can say that cytoreductive nephrectomy may be beneficial in the age of targeted therapy. However, not all patients should have it," commented first author Dr. Daniel Y.C. Heng of the University of Calgary (Alta.).

"Patients with four or more IMDC risk factors and patients with limited life expectancy probably shouldn’t have a cytoreductive nephrectomy," he said. "Of course, there are probably exceptions to that rule; if patients are really symptomatic in the primary, for example, or have bleeding, maybe there are exceptions.

"But I think this is a very interesting and useful way to help select our patients for cytoreductive nephrectomy. Certainly, we are awaiting the CARMENA and SURTIME phase III randomized controlled trials to prospectively evaluate this, and hopefully, we will be able to look at the IMDC risk factors to see if they can aid in patient selection in a prospectively validated way," Dr. Heng said at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Cytoreductive nephrectomy carries risks of morbidity and mortality, and some patients may be unable to go on to receive systemic therapy, noted invited discussant Dr. Daniel Canter of the Fox Chase Cancer Center, Philadelphia.

"What I take home as the most important point of this talk is that we need to make better choices and risk stratify these patients before surgery," he said.

A key question arising from the new data is whether the IMDC risk groups should be redefined, according to Dr. Canter; for example, patients with three risk factors are currently placed in the poor risk group, yet they derived significant benefit from surgery in this study. "So is there room for further refinement in this model?" he asked.

"With such a large cohort, I think that adding to this data with complication rates and perioperative mortality would certainly be important in terms of future treatment decision making," he commented.

Session attendee Dr. Adam Metwalli of the National Cancer Institute asked, "Are there specific risk factors that seem to disproportionately cluster among those who have four or five that would help to distinguish them from the ones who have zero to three?"

"By far, the most important prognostic factor is Karnofsky performance status, and that makes sense," Dr. Heng replied. "It’s partially the ‘look test’ and how you think a patient will fare. So, that by far has the biggest contribution."

Introducing the study, he noted that cytoreductive nephrectomy has previously been found to prolong survival by about 6 months in patients with metastatic renal cell carcinoma treated in the immunotherapy era.

"But of course now we are in the age of targeted therapy, with VEGF [vascular endothelial growth factor] inhibitors and mTOR [mammalian target of rapamycin] inhibitors. These are drugs that are much more active than in the era of old immunotherapy. So it begs the question, is cytoreductive nephrectomy still relevant?" Dr. Heng said.

The researchers studied 1,658 patients from 20 institutions who had mRCC with synchronous metastases, of whom 59% underwent cytoreductive nephrectomy.

They had a median age of 59 years, and about half were in the IMDC intermediate-risk group. The most common prior targeted therapy was sunitinib (Sutent), received by about three-fourths, reported Dr. Heng.

In unadjusted analyses, median overall survival was a significant 11 months longer for patients who underwent cytoreductive nephrectomy compared with their counterparts who did not (20.6 vs. 9.5 months). After adjustment for IMDC risk factors, the surgery was associated with a 40% reduction in the risk of death in the entire cohort (hazard ratio, 0.60; P less than .0001).

However, in analyses stratified by patient life expectancy, there was a significant survival benefit of cytoreductive nephrectomy only among patients expected to live 12-18 months (3.3-month incremental benefit; adjusted hazard ratio, 0.85; P = .049) or 18-24 months (5.2-month incremental benefit; adjusted hazard ratio, 0.72; P less than .0001).

Similarly, in analyses stratified by the number of risk factors present out of the six IMDC risk factors, there was a significant survival benefit of cytoreductive nephrectomy only among patients with three or fewer factors (incremental benefit of 6-10 months, P less than .005 for each).

The impact of overall tumor burden and the size of the primary tumor were not considered in this analysis but will be in subsequent analyses, according to Dr. Heng.

He disclosed that he is a consultant/adviser to Aveo, Bayer, Bristol-Myers Squibb, Novartis, and Pfizer.

SAN FRANCISCO – Only selected patients with synchronous metastases from renal cell carcinoma derive a survival benefit from a cytoreductive nephrectomy, a retrospective cohort study showed.

Researchers studied more than 1,600 patients from the International mRCC (metastatic renal cell carcinoma) Database Consortium who developed metastases while their primary tumor was still in place.

The main analyses showed that as a whole, patients who underwent cytoreductive nephrectomy lived longer than their counterparts who did not have this surgery.

However, in stratified analyses, the surgery significantly prolonged survival only among patients who had a life expectancy exceeding 12 months and patients who had three or fewer risk factors by International mRCC Database Consortium (IMDC) criteria.

Risk factors include Karnofsky performance status less than 80%, an interval between diagnosis and treatment of less than 1 year, anemia, thrombocytosis, neutrophilia, and hypercalcemia

"Overall, I think we can say that cytoreductive nephrectomy may be beneficial in the age of targeted therapy. However, not all patients should have it," commented first author Dr. Daniel Y.C. Heng of the University of Calgary (Alta.).

"Patients with four or more IMDC risk factors and patients with limited life expectancy probably shouldn’t have a cytoreductive nephrectomy," he said. "Of course, there are probably exceptions to that rule; if patients are really symptomatic in the primary, for example, or have bleeding, maybe there are exceptions.

"But I think this is a very interesting and useful way to help select our patients for cytoreductive nephrectomy. Certainly, we are awaiting the CARMENA and SURTIME phase III randomized controlled trials to prospectively evaluate this, and hopefully, we will be able to look at the IMDC risk factors to see if they can aid in patient selection in a prospectively validated way," Dr. Heng said at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Cytoreductive nephrectomy carries risks of morbidity and mortality, and some patients may be unable to go on to receive systemic therapy, noted invited discussant Dr. Daniel Canter of the Fox Chase Cancer Center, Philadelphia.

"What I take home as the most important point of this talk is that we need to make better choices and risk stratify these patients before surgery," he said.

A key question arising from the new data is whether the IMDC risk groups should be redefined, according to Dr. Canter; for example, patients with three risk factors are currently placed in the poor risk group, yet they derived significant benefit from surgery in this study. "So is there room for further refinement in this model?" he asked.

"With such a large cohort, I think that adding to this data with complication rates and perioperative mortality would certainly be important in terms of future treatment decision making," he commented.

Session attendee Dr. Adam Metwalli of the National Cancer Institute asked, "Are there specific risk factors that seem to disproportionately cluster among those who have four or five that would help to distinguish them from the ones who have zero to three?"

"By far, the most important prognostic factor is Karnofsky performance status, and that makes sense," Dr. Heng replied. "It’s partially the ‘look test’ and how you think a patient will fare. So, that by far has the biggest contribution."

Introducing the study, he noted that cytoreductive nephrectomy has previously been found to prolong survival by about 6 months in patients with metastatic renal cell carcinoma treated in the immunotherapy era.

"But of course now we are in the age of targeted therapy, with VEGF [vascular endothelial growth factor] inhibitors and mTOR [mammalian target of rapamycin] inhibitors. These are drugs that are much more active than in the era of old immunotherapy. So it begs the question, is cytoreductive nephrectomy still relevant?" Dr. Heng said.

The researchers studied 1,658 patients from 20 institutions who had mRCC with synchronous metastases, of whom 59% underwent cytoreductive nephrectomy.

They had a median age of 59 years, and about half were in the IMDC intermediate-risk group. The most common prior targeted therapy was sunitinib (Sutent), received by about three-fourths, reported Dr. Heng.

In unadjusted analyses, median overall survival was a significant 11 months longer for patients who underwent cytoreductive nephrectomy compared with their counterparts who did not (20.6 vs. 9.5 months). After adjustment for IMDC risk factors, the surgery was associated with a 40% reduction in the risk of death in the entire cohort (hazard ratio, 0.60; P less than .0001).

However, in analyses stratified by patient life expectancy, there was a significant survival benefit of cytoreductive nephrectomy only among patients expected to live 12-18 months (3.3-month incremental benefit; adjusted hazard ratio, 0.85; P = .049) or 18-24 months (5.2-month incremental benefit; adjusted hazard ratio, 0.72; P less than .0001).

Similarly, in analyses stratified by the number of risk factors present out of the six IMDC risk factors, there was a significant survival benefit of cytoreductive nephrectomy only among patients with three or fewer factors (incremental benefit of 6-10 months, P less than .005 for each).

The impact of overall tumor burden and the size of the primary tumor were not considered in this analysis but will be in subsequent analyses, according to Dr. Heng.

He disclosed that he is a consultant/adviser to Aveo, Bayer, Bristol-Myers Squibb, Novartis, and Pfizer.

SAN FRANCISCO – Patients with muscle-invasive bladder cancer who have a near-complete response to induction chemoradiation can safely skip a cystectomy, suggested a study reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Researchers led by Dr. Timur Mitin, a radiation oncologist at Massachusetts General Hospital in Boston, conducted a pooled analysis of 119 patients from two Radiation Therapy Oncology Group (RTOG) trials that tested trimodality therapy, whereby patients undergo maximal transurethral resection of the bladder tumor (TURBT), induction chemoradiation, cystoscopic evaluation of response, and consolidation chemoradiation, with or without adjuvant chemotherapy.

In contrast to the historical practice of allowing only patients having a complete response (T0) to induction chemoradiation to proceed with bladder-sparing therapy, the RTOG trials allowed patients having a near-complete response (Ta or Tis) to do the same.

Results showed that, after a median follow-up of almost 6 years, there were no significant differences between the complete and near-complete responders with respect to rates of bladder recurrence, salvage cystectomy, and overall survival, Dr. Mitin reported.

"Many physicians have been reluctant to subject patients to radical cystectomy if, after the induction chemoradiation therapy, they find a very small amount of superficial tumor, Ta or Tis," he commented. On the basis of these patients’ similarly good outcomes, "we recommend that patients with a near-complete response to the induction phase continue with their bladder-sparing therapy."

"I think this was a wonderful analysis," session cochair Dr. Jason A. Efstathiou, also of Massachusetts General Hospital, said in an interview.

"The RTOG has a long history of exploring bladder-sparing trimodality therapy as an option for select patients. If you select those patients well, as this abstract suggested – those who have a complete response or a near-complete response to induction chemoradiation – these patients do in fact very well. So we do believe that, for the right patient, trimodality therapy is an appropriate option, an option to up-front cystectomy. And I think his data [were] very reassuring: For patients who respond well to such treatment initially, they have a very good chance of doing well in the long term and even being cured," he said.

"Ultimately, what will be practice changing is the continued multidisciplinary approach to this disease, which means newly diagnosed patients with muscle-invasive disease are seen by urologic surgeons, by medical oncologists, and by radiation oncologists, and that sort of a consensus plan is developed that the patient chooses. So that movement will be practice changing," Dr. Efstathiou added. "And I think patient advocacy – patients learning of trimodality therapy as an option for up-front treatment – will also play a big role in perhaps the increased use of this management strategy."

The study patients were treated on RTOG 9906 (the first trial to relax the response criteria for allowing patients to go on to consolidation therapy) and RTOG 0233.

Pooled analyses compared 101 patients who had a complete response (T0) with 18 patients who had a near-complete response (Ta or Tis) to induction chemoradiation, all of whom were treated with bladder-sparing trimodality therapy.

Baseline demographic and clinical characteristics did not differ significantly between the complete responders and the near-complete responders, Dr. Mitin reported.

After a median follow-up of 5.9 years, the two groups did not differ significantly with respect to rates of any bladder recurrence (36% vs. 28%) or, specifically, an invasive bladder recurrence (36% vs. 20%).

The groups also were statistically indistinguishable with respect to rates of salvage cystectomy, disease-specific survival, and bladder-intact survival, as well as overall survival (72% vs. 61%).

Dr. Mitin disclosed no conflicts of interest related to the research.

SAN FRANCISCO – Patients with muscle-invasive bladder cancer who have a near-complete response to induction chemoradiation can safely skip a cystectomy, suggested a study reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Researchers led by Dr. Timur Mitin, a radiation oncologist at Massachusetts General Hospital in Boston, conducted a pooled analysis of 119 patients from two Radiation Therapy Oncology Group (RTOG) trials that tested trimodality therapy, whereby patients undergo maximal transurethral resection of the bladder tumor (TURBT), induction chemoradiation, cystoscopic evaluation of response, and consolidation chemoradiation, with or without adjuvant chemotherapy.

In contrast to the historical practice of allowing only patients having a complete response (T0) to induction chemoradiation to proceed with bladder-sparing therapy, the RTOG trials allowed patients having a near-complete response (Ta or Tis) to do the same.

Results showed that, after a median follow-up of almost 6 years, there were no significant differences between the complete and near-complete responders with respect to rates of bladder recurrence, salvage cystectomy, and overall survival, Dr. Mitin reported.

"Many physicians have been reluctant to subject patients to radical cystectomy if, after the induction chemoradiation therapy, they find a very small amount of superficial tumor, Ta or Tis," he commented. On the basis of these patients’ similarly good outcomes, "we recommend that patients with a near-complete response to the induction phase continue with their bladder-sparing therapy."

"I think this was a wonderful analysis," session cochair Dr. Jason A. Efstathiou, also of Massachusetts General Hospital, said in an interview.

"The RTOG has a long history of exploring bladder-sparing trimodality therapy as an option for select patients. If you select those patients well, as this abstract suggested – those who have a complete response or a near-complete response to induction chemoradiation – these patients do in fact very well. So we do believe that, for the right patient, trimodality therapy is an appropriate option, an option to up-front cystectomy. And I think his data [were] very reassuring: For patients who respond well to such treatment initially, they have a very good chance of doing well in the long term and even being cured," he said.

"Ultimately, what will be practice changing is the continued multidisciplinary approach to this disease, which means newly diagnosed patients with muscle-invasive disease are seen by urologic surgeons, by medical oncologists, and by radiation oncologists, and that sort of a consensus plan is developed that the patient chooses. So that movement will be practice changing," Dr. Efstathiou added. "And I think patient advocacy – patients learning of trimodality therapy as an option for up-front treatment – will also play a big role in perhaps the increased use of this management strategy."

The study patients were treated on RTOG 9906 (the first trial to relax the response criteria for allowing patients to go on to consolidation therapy) and RTOG 0233.

Pooled analyses compared 101 patients who had a complete response (T0) with 18 patients who had a near-complete response (Ta or Tis) to induction chemoradiation, all of whom were treated with bladder-sparing trimodality therapy.

Baseline demographic and clinical characteristics did not differ significantly between the complete responders and the near-complete responders, Dr. Mitin reported.

After a median follow-up of 5.9 years, the two groups did not differ significantly with respect to rates of any bladder recurrence (36% vs. 28%) or, specifically, an invasive bladder recurrence (36% vs. 20%).

The groups also were statistically indistinguishable with respect to rates of salvage cystectomy, disease-specific survival, and bladder-intact survival, as well as overall survival (72% vs. 61%).

Dr. Mitin disclosed no conflicts of interest related to the research.

SAN FRANCISCO – Patients with muscle-invasive bladder cancer who have a near-complete response to induction chemoradiation can safely skip a cystectomy, suggested a study reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Researchers led by Dr. Timur Mitin, a radiation oncologist at Massachusetts General Hospital in Boston, conducted a pooled analysis of 119 patients from two Radiation Therapy Oncology Group (RTOG) trials that tested trimodality therapy, whereby patients undergo maximal transurethral resection of the bladder tumor (TURBT), induction chemoradiation, cystoscopic evaluation of response, and consolidation chemoradiation, with or without adjuvant chemotherapy.

In contrast to the historical practice of allowing only patients having a complete response (T0) to induction chemoradiation to proceed with bladder-sparing therapy, the RTOG trials allowed patients having a near-complete response (Ta or Tis) to do the same.

Results showed that, after a median follow-up of almost 6 years, there were no significant differences between the complete and near-complete responders with respect to rates of bladder recurrence, salvage cystectomy, and overall survival, Dr. Mitin reported.

"Many physicians have been reluctant to subject patients to radical cystectomy if, after the induction chemoradiation therapy, they find a very small amount of superficial tumor, Ta or Tis," he commented. On the basis of these patients’ similarly good outcomes, "we recommend that patients with a near-complete response to the induction phase continue with their bladder-sparing therapy."

"I think this was a wonderful analysis," session cochair Dr. Jason A. Efstathiou, also of Massachusetts General Hospital, said in an interview.

"The RTOG has a long history of exploring bladder-sparing trimodality therapy as an option for select patients. If you select those patients well, as this abstract suggested – those who have a complete response or a near-complete response to induction chemoradiation – these patients do in fact very well. So we do believe that, for the right patient, trimodality therapy is an appropriate option, an option to up-front cystectomy. And I think his data [were] very reassuring: For patients who respond well to such treatment initially, they have a very good chance of doing well in the long term and even being cured," he said.

"Ultimately, what will be practice changing is the continued multidisciplinary approach to this disease, which means newly diagnosed patients with muscle-invasive disease are seen by urologic surgeons, by medical oncologists, and by radiation oncologists, and that sort of a consensus plan is developed that the patient chooses. So that movement will be practice changing," Dr. Efstathiou added. "And I think patient advocacy – patients learning of trimodality therapy as an option for up-front treatment – will also play a big role in perhaps the increased use of this management strategy."

The study patients were treated on RTOG 9906 (the first trial to relax the response criteria for allowing patients to go on to consolidation therapy) and RTOG 0233.

Pooled analyses compared 101 patients who had a complete response (T0) with 18 patients who had a near-complete response (Ta or Tis) to induction chemoradiation, all of whom were treated with bladder-sparing trimodality therapy.

Baseline demographic and clinical characteristics did not differ significantly between the complete responders and the near-complete responders, Dr. Mitin reported.

After a median follow-up of 5.9 years, the two groups did not differ significantly with respect to rates of any bladder recurrence (36% vs. 28%) or, specifically, an invasive bladder recurrence (36% vs. 20%).

The groups also were statistically indistinguishable with respect to rates of salvage cystectomy, disease-specific survival, and bladder-intact survival, as well as overall survival (72% vs. 61%).

Dr. Mitin disclosed no conflicts of interest related to the research.

SAN FRANCISCO – Use of radium-223 in men with castration-resistant prostate cancer who have bone metastases appears safe in the longer term, according to data collected 1.5 years after treatment in the ALSYMPCA trial.

Patients in the phase III trial had received placebo or up to six injections of radium-223 (Xofigo, formerly Alpharadin), a first-in-class alpha-emitting radiopharmaceutical taken up by bone, during the trial’s active treatment phase.

A total of 574 entered the trial’s follow-up program designed to look at safety with respect to bone and marrow toxicity and second cancers, lead author Dr. Sten Nilsson reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The rate of grade 3/4 myelosuppression was about 3% in the radium-223 group (compared with 1% in the placebo group), and a single patient developed aplastic anemia, reported Dr. Nilsson of the Karolinska University Hospital in Stockholm. There were no cases of treatment-related hematologic, bone, or solid organ cancers, or myelodysplastic syndrome.

"We know from the ALSYMPCA study and also from prior studies with radium-223 that it has a very benign safety profile, and we can see from this long-term follow-up that this remained during the study period," he commented. The findings "support further evaluation of combining radium-223 with other agents to treat patients with castration-resistant prostate cancer and bone metastases."

These findings "show for those of you who are concerned about long-term marrow toxicity or of the development of a second primary within that 1.5-year period, it looks like one can rest easy, that there are no surprises coming down the pike, and that indeed it looks like this is a drug that prolongs survival with a relatively low cost to patients in terms of quality of life or damage to their normal organs," said invited discussant Dr. Michael J. Morris, head of the prostate cancer section at the Memorial-Sloan Kettering Cancer Center in New York.

"The one patient who had aplastic anemia was heavily pretreated, but otherwise, there is a side effect profile that is tantalizingly close to zero at 1.5 years," he noted. "Although the drug is eliminated by virtue of the GI tract, we didn’t really see any GI toxicity that is long term, no GI second primaries and no hematologic second primaries."

At the same time, Dr. Morris called for research to address a host of unanswered questions about the efficacy of radium-223, such as the specific target in bone responsible for the survival benefit and the optimal dose to use. "If you look at a mathematical model of the geometry of the bone marrow, the heterogeneous deposition of hydroxyapatite within that geometry, and the placement of the progenitor cells, it does seem at least hypothetically that one could go much higher than this dose and still not risk significant marrow toxicity," he noted.

A session attendee commented that she has had difficulty giving chemotherapy to a few patients who had previously received radium-223. "Do you have any data or are you collecting a database on the rates of myelosuppression, febrile neutropenia, and the doses you can deliver in these patients?" she asked Dr. Nilsson.

"We don’t have any firm data, but we are looking into that," he replied. "We have patients who have participated in the ALSYMPCA trial who have received docetaxel afterwards without any major problems. Also we have some patients who have received both docetaxel and cabazitaxel afterwards. So we believe that there are no problems with doing that. But surely we need further data [to be certain]."

Another attendee asked, "What do you think the best future use of radium is – [in the progressive disease setting or earlier, in the adjuvant setting?"

"Well, the studies have been performed in progressive disease, and that is where we base our knowledge," Dr. Nilsson replied. "Of course, like with other drugs, it would be interesting to look at what happens if you move it further upward and give it earlier in the disease. There are trials now in planning or ongoing where you give radium earlier, and of course it would be very interesting to see what the results are if you combine, for example, radium with hormonal therapy in a patient who presents with bone metastatic disease."

The ALSYMPCA trial, sponsored by Bayer in collaboration with Algeta, randomized 921 men in 2:1 ratio to radium-223 or placebo, each added to best standard of care and given over a 24-week period.

The main results, previously reported, showed that the agent prolonged overall survival and the time to first symptomatic skeletal events, and was associated with fewer adverse events and a low rate of myelosuppression (N. Engl. J. Med. 2013;369:213-23). These results led to approval of radium-223 by the Food and Drug Administration for the treatment of castration-resistant metastatic prostate cancer in men with symptomatic bone metastases.

After stopping treatment, 406 patients from the radium-223 group and 168 from the placebo group entered the trial’s posttreatment follow-up program. Nearly 60% had previously received docetaxel (Taxotere), and roughly 40% were receiving bisphosphonates, usually zoledronate (Zometa).

The majority of patients – 83% and 71%, respectively – had received all of the six planned injections of study drug, reported Dr. Nilsson.

There was a high rate of withdrawal of patients during the follow-up period, 79% in the radium-223 group and 86% in the placebo group, in the majority of cases due to death.

The median duration of follow-up was 10.4 months for the radium-223 group and 7.6 months for the placebo group.

Analyses of hematologic adverse events showed that the two groups had an identical rate of grade 3/4 anemia, at 1%.

The radium-223 group had a single case of grade 3/4 aplastic anemia, diagnosed by bone marrow biopsy and considered treatment related. "This was a patient who had received samarium and chemotherapy, and repeated external beam radiotherapy to his bone metastatic disease," Dr. Nilsson noted.

In addition, there were two cases each of grade 3/4 leukopenia and neutropenia in the radium-223 group, for an overall myelosuppression rate of about 3%.

Analyses of nonhematologic adverse events showed that the radium-223 group had single cases of grade 3-5 multiorgan failure, pneumonia, and pathologic fracture, while the placebo group had a single case of grade 3-5 cardiopulmonary failure.

None of the patients were reported to have developed acute myeloid leukemia, myelodysplastic syndrome, or primary bone cancer.

Primary cancers in other organs were seen in two patients in the radium-223 group (bladder cancer and lymph node metastases not originating from prostate cancer) and three in the placebo group (two cases of skin cancer and one of rectal cancer); all were considered unrelated to the study drug, according to Dr. Nilsson.

Dr. Nilsson disclosed that he is a consultant/adviser to Algeta and Bayer HealthCare. The trial was sponsored by Bayer in collaboration with Algeta. Dr. Morris disclosed that he is a consultant to Bayer.

SAN FRANCISCO – Use of radium-223 in men with castration-resistant prostate cancer who have bone metastases appears safe in the longer term, according to data collected 1.5 years after treatment in the ALSYMPCA trial.

Patients in the phase III trial had received placebo or up to six injections of radium-223 (Xofigo, formerly Alpharadin), a first-in-class alpha-emitting radiopharmaceutical taken up by bone, during the trial’s active treatment phase.

A total of 574 entered the trial’s follow-up program designed to look at safety with respect to bone and marrow toxicity and second cancers, lead author Dr. Sten Nilsson reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The rate of grade 3/4 myelosuppression was about 3% in the radium-223 group (compared with 1% in the placebo group), and a single patient developed aplastic anemia, reported Dr. Nilsson of the Karolinska University Hospital in Stockholm. There were no cases of treatment-related hematologic, bone, or solid organ cancers, or myelodysplastic syndrome.

"We know from the ALSYMPCA study and also from prior studies with radium-223 that it has a very benign safety profile, and we can see from this long-term follow-up that this remained during the study period," he commented. The findings "support further evaluation of combining radium-223 with other agents to treat patients with castration-resistant prostate cancer and bone metastases."

These findings "show for those of you who are concerned about long-term marrow toxicity or of the development of a second primary within that 1.5-year period, it looks like one can rest easy, that there are no surprises coming down the pike, and that indeed it looks like this is a drug that prolongs survival with a relatively low cost to patients in terms of quality of life or damage to their normal organs," said invited discussant Dr. Michael J. Morris, head of the prostate cancer section at the Memorial-Sloan Kettering Cancer Center in New York.

"The one patient who had aplastic anemia was heavily pretreated, but otherwise, there is a side effect profile that is tantalizingly close to zero at 1.5 years," he noted. "Although the drug is eliminated by virtue of the GI tract, we didn’t really see any GI toxicity that is long term, no GI second primaries and no hematologic second primaries."

At the same time, Dr. Morris called for research to address a host of unanswered questions about the efficacy of radium-223, such as the specific target in bone responsible for the survival benefit and the optimal dose to use. "If you look at a mathematical model of the geometry of the bone marrow, the heterogeneous deposition of hydroxyapatite within that geometry, and the placement of the progenitor cells, it does seem at least hypothetically that one could go much higher than this dose and still not risk significant marrow toxicity," he noted.

A session attendee commented that she has had difficulty giving chemotherapy to a few patients who had previously received radium-223. "Do you have any data or are you collecting a database on the rates of myelosuppression, febrile neutropenia, and the doses you can deliver in these patients?" she asked Dr. Nilsson.

"We don’t have any firm data, but we are looking into that," he replied. "We have patients who have participated in the ALSYMPCA trial who have received docetaxel afterwards without any major problems. Also we have some patients who have received both docetaxel and cabazitaxel afterwards. So we believe that there are no problems with doing that. But surely we need further data [to be certain]."

Another attendee asked, "What do you think the best future use of radium is – [in the progressive disease setting or earlier, in the adjuvant setting?"

"Well, the studies have been performed in progressive disease, and that is where we base our knowledge," Dr. Nilsson replied. "Of course, like with other drugs, it would be interesting to look at what happens if you move it further upward and give it earlier in the disease. There are trials now in planning or ongoing where you give radium earlier, and of course it would be very interesting to see what the results are if you combine, for example, radium with hormonal therapy in a patient who presents with bone metastatic disease."

The ALSYMPCA trial, sponsored by Bayer in collaboration with Algeta, randomized 921 men in 2:1 ratio to radium-223 or placebo, each added to best standard of care and given over a 24-week period.

The main results, previously reported, showed that the agent prolonged overall survival and the time to first symptomatic skeletal events, and was associated with fewer adverse events and a low rate of myelosuppression (N. Engl. J. Med. 2013;369:213-23). These results led to approval of radium-223 by the Food and Drug Administration for the treatment of castration-resistant metastatic prostate cancer in men with symptomatic bone metastases.

After stopping treatment, 406 patients from the radium-223 group and 168 from the placebo group entered the trial’s posttreatment follow-up program. Nearly 60% had previously received docetaxel (Taxotere), and roughly 40% were receiving bisphosphonates, usually zoledronate (Zometa).

The majority of patients – 83% and 71%, respectively – had received all of the six planned injections of study drug, reported Dr. Nilsson.

There was a high rate of withdrawal of patients during the follow-up period, 79% in the radium-223 group and 86% in the placebo group, in the majority of cases due to death.

The median duration of follow-up was 10.4 months for the radium-223 group and 7.6 months for the placebo group.

Analyses of hematologic adverse events showed that the two groups had an identical rate of grade 3/4 anemia, at 1%.

The radium-223 group had a single case of grade 3/4 aplastic anemia, diagnosed by bone marrow biopsy and considered treatment related. "This was a patient who had received samarium and chemotherapy, and repeated external beam radiotherapy to his bone metastatic disease," Dr. Nilsson noted.

In addition, there were two cases each of grade 3/4 leukopenia and neutropenia in the radium-223 group, for an overall myelosuppression rate of about 3%.

Analyses of nonhematologic adverse events showed that the radium-223 group had single cases of grade 3-5 multiorgan failure, pneumonia, and pathologic fracture, while the placebo group had a single case of grade 3-5 cardiopulmonary failure.

None of the patients were reported to have developed acute myeloid leukemia, myelodysplastic syndrome, or primary bone cancer.

Primary cancers in other organs were seen in two patients in the radium-223 group (bladder cancer and lymph node metastases not originating from prostate cancer) and three in the placebo group (two cases of skin cancer and one of rectal cancer); all were considered unrelated to the study drug, according to Dr. Nilsson.

Dr. Nilsson disclosed that he is a consultant/adviser to Algeta and Bayer HealthCare. The trial was sponsored by Bayer in collaboration with Algeta. Dr. Morris disclosed that he is a consultant to Bayer.

SAN FRANCISCO – Use of radium-223 in men with castration-resistant prostate cancer who have bone metastases appears safe in the longer term, according to data collected 1.5 years after treatment in the ALSYMPCA trial.

Patients in the phase III trial had received placebo or up to six injections of radium-223 (Xofigo, formerly Alpharadin), a first-in-class alpha-emitting radiopharmaceutical taken up by bone, during the trial’s active treatment phase.

A total of 574 entered the trial’s follow-up program designed to look at safety with respect to bone and marrow toxicity and second cancers, lead author Dr. Sten Nilsson reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The rate of grade 3/4 myelosuppression was about 3% in the radium-223 group (compared with 1% in the placebo group), and a single patient developed aplastic anemia, reported Dr. Nilsson of the Karolinska University Hospital in Stockholm. There were no cases of treatment-related hematologic, bone, or solid organ cancers, or myelodysplastic syndrome.

"We know from the ALSYMPCA study and also from prior studies with radium-223 that it has a very benign safety profile, and we can see from this long-term follow-up that this remained during the study period," he commented. The findings "support further evaluation of combining radium-223 with other agents to treat patients with castration-resistant prostate cancer and bone metastases."

These findings "show for those of you who are concerned about long-term marrow toxicity or of the development of a second primary within that 1.5-year period, it looks like one can rest easy, that there are no surprises coming down the pike, and that indeed it looks like this is a drug that prolongs survival with a relatively low cost to patients in terms of quality of life or damage to their normal organs," said invited discussant Dr. Michael J. Morris, head of the prostate cancer section at the Memorial-Sloan Kettering Cancer Center in New York.

"The one patient who had aplastic anemia was heavily pretreated, but otherwise, there is a side effect profile that is tantalizingly close to zero at 1.5 years," he noted. "Although the drug is eliminated by virtue of the GI tract, we didn’t really see any GI toxicity that is long term, no GI second primaries and no hematologic second primaries."

At the same time, Dr. Morris called for research to address a host of unanswered questions about the efficacy of radium-223, such as the specific target in bone responsible for the survival benefit and the optimal dose to use. "If you look at a mathematical model of the geometry of the bone marrow, the heterogeneous deposition of hydroxyapatite within that geometry, and the placement of the progenitor cells, it does seem at least hypothetically that one could go much higher than this dose and still not risk significant marrow toxicity," he noted.

A session attendee commented that she has had difficulty giving chemotherapy to a few patients who had previously received radium-223. "Do you have any data or are you collecting a database on the rates of myelosuppression, febrile neutropenia, and the doses you can deliver in these patients?" she asked Dr. Nilsson.

"We don’t have any firm data, but we are looking into that," he replied. "We have patients who have participated in the ALSYMPCA trial who have received docetaxel afterwards without any major problems. Also we have some patients who have received both docetaxel and cabazitaxel afterwards. So we believe that there are no problems with doing that. But surely we need further data [to be certain]."

Another attendee asked, "What do you think the best future use of radium is – [in the progressive disease setting or earlier, in the adjuvant setting?"

"Well, the studies have been performed in progressive disease, and that is where we base our knowledge," Dr. Nilsson replied. "Of course, like with other drugs, it would be interesting to look at what happens if you move it further upward and give it earlier in the disease. There are trials now in planning or ongoing where you give radium earlier, and of course it would be very interesting to see what the results are if you combine, for example, radium with hormonal therapy in a patient who presents with bone metastatic disease."

The ALSYMPCA trial, sponsored by Bayer in collaboration with Algeta, randomized 921 men in 2:1 ratio to radium-223 or placebo, each added to best standard of care and given over a 24-week period.

The main results, previously reported, showed that the agent prolonged overall survival and the time to first symptomatic skeletal events, and was associated with fewer adverse events and a low rate of myelosuppression (N. Engl. J. Med. 2013;369:213-23). These results led to approval of radium-223 by the Food and Drug Administration for the treatment of castration-resistant metastatic prostate cancer in men with symptomatic bone metastases.

After stopping treatment, 406 patients from the radium-223 group and 168 from the placebo group entered the trial’s posttreatment follow-up program. Nearly 60% had previously received docetaxel (Taxotere), and roughly 40% were receiving bisphosphonates, usually zoledronate (Zometa).

The majority of patients – 83% and 71%, respectively – had received all of the six planned injections of study drug, reported Dr. Nilsson.

There was a high rate of withdrawal of patients during the follow-up period, 79% in the radium-223 group and 86% in the placebo group, in the majority of cases due to death.

The median duration of follow-up was 10.4 months for the radium-223 group and 7.6 months for the placebo group.

Analyses of hematologic adverse events showed that the two groups had an identical rate of grade 3/4 anemia, at 1%.

The radium-223 group had a single case of grade 3/4 aplastic anemia, diagnosed by bone marrow biopsy and considered treatment related. "This was a patient who had received samarium and chemotherapy, and repeated external beam radiotherapy to his bone metastatic disease," Dr. Nilsson noted.

In addition, there were two cases each of grade 3/4 leukopenia and neutropenia in the radium-223 group, for an overall myelosuppression rate of about 3%.

Analyses of nonhematologic adverse events showed that the radium-223 group had single cases of grade 3-5 multiorgan failure, pneumonia, and pathologic fracture, while the placebo group had a single case of grade 3-5 cardiopulmonary failure.

None of the patients were reported to have developed acute myeloid leukemia, myelodysplastic syndrome, or primary bone cancer.

Primary cancers in other organs were seen in two patients in the radium-223 group (bladder cancer and lymph node metastases not originating from prostate cancer) and three in the placebo group (two cases of skin cancer and one of rectal cancer); all were considered unrelated to the study drug, according to Dr. Nilsson.

Dr. Nilsson disclosed that he is a consultant/adviser to Algeta and Bayer HealthCare. The trial was sponsored by Bayer in collaboration with Algeta. Dr. Morris disclosed that he is a consultant to Bayer.

SAN FRANCISCO – New findings on cardiovascular and metabolic risks in men receiving androgen deprivation therapy for nonmetastatic prostate cancer may help individualize decisions about whether to initiate this therapy and how long to continue it.

In a population-based cohort study of more than 3,500 men followed up for 15 years, taking androgen deprivation therapy (ADT) for 2 years or less did not significantly increase the risk of either cardiovascular disease or diabetes, researchers reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Taking it for more than 2 years did increase these risks, but only for men about 75 years of age or older at baseline, first author Dr. Alicia K. Morgans of Vanderbilt University, Nashville, Tennessee, reported in a poster presentation.

As would be expected, comorbidities were also a risk factor for both cardiovascular disease and diabetes.

"There may be a different risk-benefit ratio of ADT in younger men as compared to older men," Dr. Morgans commented in an interview.

"The take-home message is that younger men don’t need to worry so much about the development of diabetes and cardiovascular disease directly related to ADT. Certainly, their other comorbidities may predispose them to developing that complication, but not related to ADT," she elaborated.

"For older men, especially men who have more complicated medical histories with more comorbidities, it is something that they need to consider, and potentially, if they have the ability to choose not to have ADT, if they have a more complicated medical picture and are older, they may want to opt against it," she added.

While acknowledging the potentially heightened risks of these conditions with ADT, guidelines are vague as to monitoring for them, according to Dr. Morgans. "We simply say at this point: watch. Watch for the development of diabetes, watch for the development of cardiovascular disease. And there are no age criteria for that either," she said, so these new data may help in that arena, too.

The investigators analyzed data from the Prostate Cancer Outcomes Study for men aged 39-89 years from six U.S. geographic regions with nonmetastatic prostate cancer diagnosed during 1994-1995 and followed up through 2009-2010.

The presence of cardiovascular disease and diabetes was ascertained from patient surveys at baseline; at 6 months; and at 1, 2, 5, and 15 years, and from death certificates.

Analyses were based on 3,526 men who survived at least 2 years after diagnosis. They had a median age of about 68 years at baseline, and roughly half had at least one comorbidity.

Overall, 23% took ADT for 2 years or less, 9% took ADT for more than 2 years, and the rest did not take any. The median duration of follow-up was about 10 years.

Main results showed that taking ADT for 2 years or less did not significantly increase the risk of developing cardiovascular disease or diabetes, regardless of age at the start of therapy, Dr. Morgans reported.

In contrast, among patients who took ADT for more than 2 years, the risks increased with age at baseline and became significant in the mid-70s. Specifically, men older than 74 years had a significantly elevated risk of cardiovascular disease and men older than 76 years had a significantly elevated risk of diabetes.

Risks also rose with the number of comorbidities, but tumor grade, extent of prostate cancer, and race did not significantly affect these outcomes.

Dr. Morgans disclosed no relevant conflicts of interest.

SAN FRANCISCO – New findings on cardiovascular and metabolic risks in men receiving androgen deprivation therapy for nonmetastatic prostate cancer may help individualize decisions about whether to initiate this therapy and how long to continue it.

In a population-based cohort study of more than 3,500 men followed up for 15 years, taking androgen deprivation therapy (ADT) for 2 years or less did not significantly increase the risk of either cardiovascular disease or diabetes, researchers reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Taking it for more than 2 years did increase these risks, but only for men about 75 years of age or older at baseline, first author Dr. Alicia K. Morgans of Vanderbilt University, Nashville, Tennessee, reported in a poster presentation.

As would be expected, comorbidities were also a risk factor for both cardiovascular disease and diabetes.

"There may be a different risk-benefit ratio of ADT in younger men as compared to older men," Dr. Morgans commented in an interview.

"The take-home message is that younger men don’t need to worry so much about the development of diabetes and cardiovascular disease directly related to ADT. Certainly, their other comorbidities may predispose them to developing that complication, but not related to ADT," she elaborated.

"For older men, especially men who have more complicated medical histories with more comorbidities, it is something that they need to consider, and potentially, if they have the ability to choose not to have ADT, if they have a more complicated medical picture and are older, they may want to opt against it," she added.

While acknowledging the potentially heightened risks of these conditions with ADT, guidelines are vague as to monitoring for them, according to Dr. Morgans. "We simply say at this point: watch. Watch for the development of diabetes, watch for the development of cardiovascular disease. And there are no age criteria for that either," she said, so these new data may help in that arena, too.

The investigators analyzed data from the Prostate Cancer Outcomes Study for men aged 39-89 years from six U.S. geographic regions with nonmetastatic prostate cancer diagnosed during 1994-1995 and followed up through 2009-2010.

The presence of cardiovascular disease and diabetes was ascertained from patient surveys at baseline; at 6 months; and at 1, 2, 5, and 15 years, and from death certificates.

Analyses were based on 3,526 men who survived at least 2 years after diagnosis. They had a median age of about 68 years at baseline, and roughly half had at least one comorbidity.

Overall, 23% took ADT for 2 years or less, 9% took ADT for more than 2 years, and the rest did not take any. The median duration of follow-up was about 10 years.

Main results showed that taking ADT for 2 years or less did not significantly increase the risk of developing cardiovascular disease or diabetes, regardless of age at the start of therapy, Dr. Morgans reported.

In contrast, among patients who took ADT for more than 2 years, the risks increased with age at baseline and became significant in the mid-70s. Specifically, men older than 74 years had a significantly elevated risk of cardiovascular disease and men older than 76 years had a significantly elevated risk of diabetes.

Risks also rose with the number of comorbidities, but tumor grade, extent of prostate cancer, and race did not significantly affect these outcomes.

Dr. Morgans disclosed no relevant conflicts of interest.

SAN FRANCISCO – New findings on cardiovascular and metabolic risks in men receiving androgen deprivation therapy for nonmetastatic prostate cancer may help individualize decisions about whether to initiate this therapy and how long to continue it.

In a population-based cohort study of more than 3,500 men followed up for 15 years, taking androgen deprivation therapy (ADT) for 2 years or less did not significantly increase the risk of either cardiovascular disease or diabetes, researchers reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Taking it for more than 2 years did increase these risks, but only for men about 75 years of age or older at baseline, first author Dr. Alicia K. Morgans of Vanderbilt University, Nashville, Tennessee, reported in a poster presentation.

As would be expected, comorbidities were also a risk factor for both cardiovascular disease and diabetes.

"There may be a different risk-benefit ratio of ADT in younger men as compared to older men," Dr. Morgans commented in an interview.

"The take-home message is that younger men don’t need to worry so much about the development of diabetes and cardiovascular disease directly related to ADT. Certainly, their other comorbidities may predispose them to developing that complication, but not related to ADT," she elaborated.

"For older men, especially men who have more complicated medical histories with more comorbidities, it is something that they need to consider, and potentially, if they have the ability to choose not to have ADT, if they have a more complicated medical picture and are older, they may want to opt against it," she added.

While acknowledging the potentially heightened risks of these conditions with ADT, guidelines are vague as to monitoring for them, according to Dr. Morgans. "We simply say at this point: watch. Watch for the development of diabetes, watch for the development of cardiovascular disease. And there are no age criteria for that either," she said, so these new data may help in that arena, too.

The investigators analyzed data from the Prostate Cancer Outcomes Study for men aged 39-89 years from six U.S. geographic regions with nonmetastatic prostate cancer diagnosed during 1994-1995 and followed up through 2009-2010.

The presence of cardiovascular disease and diabetes was ascertained from patient surveys at baseline; at 6 months; and at 1, 2, 5, and 15 years, and from death certificates.

Analyses were based on 3,526 men who survived at least 2 years after diagnosis. They had a median age of about 68 years at baseline, and roughly half had at least one comorbidity.

Overall, 23% took ADT for 2 years or less, 9% took ADT for more than 2 years, and the rest did not take any. The median duration of follow-up was about 10 years.

Main results showed that taking ADT for 2 years or less did not significantly increase the risk of developing cardiovascular disease or diabetes, regardless of age at the start of therapy, Dr. Morgans reported.

In contrast, among patients who took ADT for more than 2 years, the risks increased with age at baseline and became significant in the mid-70s. Specifically, men older than 74 years had a significantly elevated risk of cardiovascular disease and men older than 76 years had a significantly elevated risk of diabetes.

Risks also rose with the number of comorbidities, but tumor grade, extent of prostate cancer, and race did not significantly affect these outcomes.

Dr. Morgans disclosed no relevant conflicts of interest.

Almost one-fifth of adult cancer clinical trials fail to reach completion for reasons unrelated to efficacy or adverse effects, according to data being reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. Poor accrual is the leading cause.

Trials were more likely to fail completion if they were phase II, single center, funded by industry, or conducted solely in the United States. Trials among patients with genitourinary cancers were no more or less likely to fail than trials among patients with other cancers.

"These findings really underscore the clinical trial accrual problem that we have in the United States. Not only does poor accrual lead to more expensive trials and trials that generate answers much more slowly, but it also prevents many trials from generating answers at all," senior author Dr. Matthew D. Galsky, director of the genitourinary medical oncology program, Icahn School of Medicine at Mount Sinai, New York, said in a press briefing at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The study is not meant to indict any specific stakeholders, Dr. Galsky stressed. "Rather, what we wanted to do was hold up a mirror to our activities as a cancer clinical trials community and really ask whether the system is optimized to bring better treatments to our patients as efficiently as possible. And clearly there is some work to do.

"Based on this analysis and others, it’s apparent that we need better collaboration and communication within the system and to use novel approaches to increase accrual to cancer clinical trials, which has really been quite steady at 3% to 5% of the adult cancer population for decades."

"This is a really interesting presentation which casts some light on one of the major frustrations that I think ... our whole community shares in designing and implementing clinical trials," said press briefing moderator Dr. Charles J. Ryan, leader of the genitourinary medical oncology program at the University of California, San Francisco. "Hopefully, this may be the beginning of a broader discussion that helps improve some of the efficiencies here."

Dr. Galsky speculated that the explanation for poor accrual is multifactorial. "Clearly, we need to engage patients more in the design of trials. We need to design trials that are more pragmatic; eligibility for trials is often so restrictive that only the patients who are the fittest and represent kind of an extreme of cancer patients can actually enroll," he said.

Other issues likely include financial barriers (such as whether insurers reimburse the costs of care for patients in trials); geographic accessibility; and the time and regulatory burdens of participating, especially as they affect community oncology practices. "Addressing the cancer clinical trials enterprise at large requires making the burden of participation lower because that does address accrual, that does address generalizability, that does address accessibility. It’s a problem that needs to be part of this conversation," Dr. Galsky maintained.

Dr. Ryan, the moderator, cited rapid treatment advances as yet another possible reason for poor accrual. "Some trials may take 2 or 3 years to accrue. During the first year, the standards of care may be one thing, and during the third year, the standards of care may have changed. We are really seeing very rapid evolution in our standards of care, so that could be one issue," he elaborated.

Introducing the study, Dr. Galsky noted that trials that fail to complete (that is, close without enrolling the intended number of patients) represent a major inefficiency of the cancer clinical trials enterprise. "Such trials contribute little knowledge, waste finite resources, and potentially divert patients from participating in other trials," he said.

The Institute of Medicine previously issued a report suggesting that about 40% of trials sponsored by the National Cancer Institute fail to achieve completion. But such trials account for only about 15% of all cancer trials.

The researchers analyzed 7,776 phase II or III interventional adult cancer clinical trials registered on ClinicalTrials.gov that had start dates between 2005 and 2011. They searched for those that had failed to reach completion, meaning that the trial had been stopped and had a "terminated" or "withdrawn" status.

The trials had a total of about 48,000 patients. Overall, 10% were trials in prostate, kidney, bladder, or testicular cancer.

The cumulative incidence of failure to reach completion for reasons unrelated to the efficacy or safety of the intervention was about 20%, according to Dr. Galsky.

Among all noncompleted trials, the largest share, 39%, failed to achieve completion because of poor accrual, topping other reasons such as logistics and efficacy/safety.

Trials were more likely to fail completion if they were funded by industry as compared with the federal government (hazard ratio, 1.97), were phase II as compared with phase III (HR, 1.29), or were single center as compared with multicenter (HR, 1.93).

On the other hand, trials were less likely to fail completion if they were conducted solely outside the United States (HR, 0.65) or both in and outside the United States (HR, 0.67), as compared with solely in the United States.

Dr. Galsky disclosed no relevant conflicts of interest.

Almost one-fifth of adult cancer clinical trials fail to reach completion for reasons unrelated to efficacy or adverse effects, according to data being reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. Poor accrual is the leading cause.

Trials were more likely to fail completion if they were phase II, single center, funded by industry, or conducted solely in the United States. Trials among patients with genitourinary cancers were no more or less likely to fail than trials among patients with other cancers.

"These findings really underscore the clinical trial accrual problem that we have in the United States. Not only does poor accrual lead to more expensive trials and trials that generate answers much more slowly, but it also prevents many trials from generating answers at all," senior author Dr. Matthew D. Galsky, director of the genitourinary medical oncology program, Icahn School of Medicine at Mount Sinai, New York, said in a press briefing at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The study is not meant to indict any specific stakeholders, Dr. Galsky stressed. "Rather, what we wanted to do was hold up a mirror to our activities as a cancer clinical trials community and really ask whether the system is optimized to bring better treatments to our patients as efficiently as possible. And clearly there is some work to do.

"Based on this analysis and others, it’s apparent that we need better collaboration and communication within the system and to use novel approaches to increase accrual to cancer clinical trials, which has really been quite steady at 3% to 5% of the adult cancer population for decades."

"This is a really interesting presentation which casts some light on one of the major frustrations that I think ... our whole community shares in designing and implementing clinical trials," said press briefing moderator Dr. Charles J. Ryan, leader of the genitourinary medical oncology program at the University of California, San Francisco. "Hopefully, this may be the beginning of a broader discussion that helps improve some of the efficiencies here."

Dr. Galsky speculated that the explanation for poor accrual is multifactorial. "Clearly, we need to engage patients more in the design of trials. We need to design trials that are more pragmatic; eligibility for trials is often so restrictive that only the patients who are the fittest and represent kind of an extreme of cancer patients can actually enroll," he said.

Other issues likely include financial barriers (such as whether insurers reimburse the costs of care for patients in trials); geographic accessibility; and the time and regulatory burdens of participating, especially as they affect community oncology practices. "Addressing the cancer clinical trials enterprise at large requires making the burden of participation lower because that does address accrual, that does address generalizability, that does address accessibility. It’s a problem that needs to be part of this conversation," Dr. Galsky maintained.

Dr. Ryan, the moderator, cited rapid treatment advances as yet another possible reason for poor accrual. "Some trials may take 2 or 3 years to accrue. During the first year, the standards of care may be one thing, and during the third year, the standards of care may have changed. We are really seeing very rapid evolution in our standards of care, so that could be one issue," he elaborated.

Introducing the study, Dr. Galsky noted that trials that fail to complete (that is, close without enrolling the intended number of patients) represent a major inefficiency of the cancer clinical trials enterprise. "Such trials contribute little knowledge, waste finite resources, and potentially divert patients from participating in other trials," he said.

The Institute of Medicine previously issued a report suggesting that about 40% of trials sponsored by the National Cancer Institute fail to achieve completion. But such trials account for only about 15% of all cancer trials.

The researchers analyzed 7,776 phase II or III interventional adult cancer clinical trials registered on ClinicalTrials.gov that had start dates between 2005 and 2011. They searched for those that had failed to reach completion, meaning that the trial had been stopped and had a "terminated" or "withdrawn" status.

The trials had a total of about 48,000 patients. Overall, 10% were trials in prostate, kidney, bladder, or testicular cancer.

The cumulative incidence of failure to reach completion for reasons unrelated to the efficacy or safety of the intervention was about 20%, according to Dr. Galsky.

Among all noncompleted trials, the largest share, 39%, failed to achieve completion because of poor accrual, topping other reasons such as logistics and efficacy/safety.

Trials were more likely to fail completion if they were funded by industry as compared with the federal government (hazard ratio, 1.97), were phase II as compared with phase III (HR, 1.29), or were single center as compared with multicenter (HR, 1.93).

On the other hand, trials were less likely to fail completion if they were conducted solely outside the United States (HR, 0.65) or both in and outside the United States (HR, 0.67), as compared with solely in the United States.

Dr. Galsky disclosed no relevant conflicts of interest.

Almost one-fifth of adult cancer clinical trials fail to reach completion for reasons unrelated to efficacy or adverse effects, according to data being reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. Poor accrual is the leading cause.

Trials were more likely to fail completion if they were phase II, single center, funded by industry, or conducted solely in the United States. Trials among patients with genitourinary cancers were no more or less likely to fail than trials among patients with other cancers.

"These findings really underscore the clinical trial accrual problem that we have in the United States. Not only does poor accrual lead to more expensive trials and trials that generate answers much more slowly, but it also prevents many trials from generating answers at all," senior author Dr. Matthew D. Galsky, director of the genitourinary medical oncology program, Icahn School of Medicine at Mount Sinai, New York, said in a press briefing at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The study is not meant to indict any specific stakeholders, Dr. Galsky stressed. "Rather, what we wanted to do was hold up a mirror to our activities as a cancer clinical trials community and really ask whether the system is optimized to bring better treatments to our patients as efficiently as possible. And clearly there is some work to do.

"Based on this analysis and others, it’s apparent that we need better collaboration and communication within the system and to use novel approaches to increase accrual to cancer clinical trials, which has really been quite steady at 3% to 5% of the adult cancer population for decades."

"This is a really interesting presentation which casts some light on one of the major frustrations that I think ... our whole community shares in designing and implementing clinical trials," said press briefing moderator Dr. Charles J. Ryan, leader of the genitourinary medical oncology program at the University of California, San Francisco. "Hopefully, this may be the beginning of a broader discussion that helps improve some of the efficiencies here."

Dr. Galsky speculated that the explanation for poor accrual is multifactorial. "Clearly, we need to engage patients more in the design of trials. We need to design trials that are more pragmatic; eligibility for trials is often so restrictive that only the patients who are the fittest and represent kind of an extreme of cancer patients can actually enroll," he said.

Other issues likely include financial barriers (such as whether insurers reimburse the costs of care for patients in trials); geographic accessibility; and the time and regulatory burdens of participating, especially as they affect community oncology practices. "Addressing the cancer clinical trials enterprise at large requires making the burden of participation lower because that does address accrual, that does address generalizability, that does address accessibility. It’s a problem that needs to be part of this conversation," Dr. Galsky maintained.

Dr. Ryan, the moderator, cited rapid treatment advances as yet another possible reason for poor accrual. "Some trials may take 2 or 3 years to accrue. During the first year, the standards of care may be one thing, and during the third year, the standards of care may have changed. We are really seeing very rapid evolution in our standards of care, so that could be one issue," he elaborated.

Introducing the study, Dr. Galsky noted that trials that fail to complete (that is, close without enrolling the intended number of patients) represent a major inefficiency of the cancer clinical trials enterprise. "Such trials contribute little knowledge, waste finite resources, and potentially divert patients from participating in other trials," he said.

The Institute of Medicine previously issued a report suggesting that about 40% of trials sponsored by the National Cancer Institute fail to achieve completion. But such trials account for only about 15% of all cancer trials.

The researchers analyzed 7,776 phase II or III interventional adult cancer clinical trials registered on ClinicalTrials.gov that had start dates between 2005 and 2011. They searched for those that had failed to reach completion, meaning that the trial had been stopped and had a "terminated" or "withdrawn" status.

The trials had a total of about 48,000 patients. Overall, 10% were trials in prostate, kidney, bladder, or testicular cancer.

The cumulative incidence of failure to reach completion for reasons unrelated to the efficacy or safety of the intervention was about 20%, according to Dr. Galsky.

Among all noncompleted trials, the largest share, 39%, failed to achieve completion because of poor accrual, topping other reasons such as logistics and efficacy/safety.

Trials were more likely to fail completion if they were funded by industry as compared with the federal government (hazard ratio, 1.97), were phase II as compared with phase III (HR, 1.29), or were single center as compared with multicenter (HR, 1.93).

On the other hand, trials were less likely to fail completion if they were conducted solely outside the United States (HR, 0.65) or both in and outside the United States (HR, 0.67), as compared with solely in the United States.

Dr. Galsky disclosed no relevant conflicts of interest.

Angiotensin system inhibitors prolong survival of patients with metastatic renal cell carcinoma, according to a retrospective study being presented at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Patients taking one of these antihypertensive agents lived on average about 10 months longer than their counterparts not taking them, reported lead author Dr. Rana R. McKay, a clinical oncology fellow at the Dana-Farber Cancer Institute in Boston.

In analyses stratified according to type of cancer treatment, benefit was restricted to patients whose cancer was being treated with agents that target vascular endothelial growth factor (VEGF), which is known to have interactions with the angiotensin system that affect cell proliferation and angiogenesis.

"This is the largest analysis to our knowledge evaluating the role of ASIs [angiotensin system inhibitors] on outcomes not just in metastatic renal cell carcinoma but for all cancers," Dr. McKay commented in a press briefing held before the symposium.

"We demonstrated that ASI users had significantly improved survival when compared to ASI nonusers, even after adjustment for the development of treatment-associated hypertension. ASIs appear to have a synergistic activity in patients on VEGF-targeted therapy," she said.

"Although lab-based and prospective studies are required to explore this relationship further, in patients with metastatic renal cell carcinoma who warrant an antihypertensive agent, ASIs may be the agent of choice for patients without any contraindications for their use," Dr. McKay proposed.

It is noteworthy that nearly half of the patients studied had hypertension at baseline, according to press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the genitourinary medical oncology program.

"There is quite a significant effect here, and it really makes sense given the mechanism of action of VEGF-targeted therapy. I’m sure there will be a lot of interest going forward with this in prospective data," he commented.

There is good rationale for investigating ASIs – a collective term for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) – in renal cell carcinoma, according to Dr. McKay.

"VEGF is an established target in metastatic kidney cancer. Increasing evidence suggests that angiotensin II is an important regulator of vascular homeostasis and modulates VEGF-dependent angiogenesis," she explained.

The investigators reviewed data from a clinical trials database of 4,736 patients with metastatic renal cell carcinoma treated on Pfizer-sponsored phase II and III clinical trials between 2003 and 2013.

The largest share of patients (42%) had intermediate-risk disease according to IMDC (International mRCC Database Consortium) risk classification. In all, 70% had undergone nephrectomy, and 48% had hypertension at baseline.

Overall, 31% of patients in the cohort were using ASIs at baseline or started one in the first 30 days of their trial. Another 17% were using some other type of antihypertensive, and the remaining 52% were not using any.

In the entire study cohort, overall survival was 27 months for ASI users and 17 months for all other patients (hazard ratio, 1.21; P = .0009).

Among patients whose cancer was being treated with VEGF-targeted therapy, overall survival was better for ASI users than for all other patients (HR, 1.36; P less than .0001). But there was no such benefit for patients whose cancers were being treated with mammalian target of rapamycin (mTOR) inhibitors or for patients whose cancer was being treated with interferon-alpha.

In additional findings, among patients taking any kind of antihypertensive and receiving VEGF-targeted therapy, survival was better for ASI users than for users of other types of antihypertensives (31 vs. 22 months; HR, 1.38; P = .0003).

Dr. McKay disclosed no relevant conflicts of interest.

Angiotensin system inhibitors prolong survival of patients with metastatic renal cell carcinoma, according to a retrospective study being presented at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Patients taking one of these antihypertensive agents lived on average about 10 months longer than their counterparts not taking them, reported lead author Dr. Rana R. McKay, a clinical oncology fellow at the Dana-Farber Cancer Institute in Boston.

In analyses stratified according to type of cancer treatment, benefit was restricted to patients whose cancer was being treated with agents that target vascular endothelial growth factor (VEGF), which is known to have interactions with the angiotensin system that affect cell proliferation and angiogenesis.

"This is the largest analysis to our knowledge evaluating the role of ASIs [angiotensin system inhibitors] on outcomes not just in metastatic renal cell carcinoma but for all cancers," Dr. McKay commented in a press briefing held before the symposium.

"We demonstrated that ASI users had significantly improved survival when compared to ASI nonusers, even after adjustment for the development of treatment-associated hypertension. ASIs appear to have a synergistic activity in patients on VEGF-targeted therapy," she said.

"Although lab-based and prospective studies are required to explore this relationship further, in patients with metastatic renal cell carcinoma who warrant an antihypertensive agent, ASIs may be the agent of choice for patients without any contraindications for their use," Dr. McKay proposed.

It is noteworthy that nearly half of the patients studied had hypertension at baseline, according to press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the genitourinary medical oncology program.

"There is quite a significant effect here, and it really makes sense given the mechanism of action of VEGF-targeted therapy. I’m sure there will be a lot of interest going forward with this in prospective data," he commented.

There is good rationale for investigating ASIs – a collective term for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) – in renal cell carcinoma, according to Dr. McKay.

"VEGF is an established target in metastatic kidney cancer. Increasing evidence suggests that angiotensin II is an important regulator of vascular homeostasis and modulates VEGF-dependent angiogenesis," she explained.

The investigators reviewed data from a clinical trials database of 4,736 patients with metastatic renal cell carcinoma treated on Pfizer-sponsored phase II and III clinical trials between 2003 and 2013.

The largest share of patients (42%) had intermediate-risk disease according to IMDC (International mRCC Database Consortium) risk classification. In all, 70% had undergone nephrectomy, and 48% had hypertension at baseline.

Overall, 31% of patients in the cohort were using ASIs at baseline or started one in the first 30 days of their trial. Another 17% were using some other type of antihypertensive, and the remaining 52% were not using any.

In the entire study cohort, overall survival was 27 months for ASI users and 17 months for all other patients (hazard ratio, 1.21; P = .0009).

Among patients whose cancer was being treated with VEGF-targeted therapy, overall survival was better for ASI users than for all other patients (HR, 1.36; P less than .0001). But there was no such benefit for patients whose cancers were being treated with mammalian target of rapamycin (mTOR) inhibitors or for patients whose cancer was being treated with interferon-alpha.

In additional findings, among patients taking any kind of antihypertensive and receiving VEGF-targeted therapy, survival was better for ASI users than for users of other types of antihypertensives (31 vs. 22 months; HR, 1.38; P = .0003).

Dr. McKay disclosed no relevant conflicts of interest.

Angiotensin system inhibitors prolong survival of patients with metastatic renal cell carcinoma, according to a retrospective study being presented at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Patients taking one of these antihypertensive agents lived on average about 10 months longer than their counterparts not taking them, reported lead author Dr. Rana R. McKay, a clinical oncology fellow at the Dana-Farber Cancer Institute in Boston.

In analyses stratified according to type of cancer treatment, benefit was restricted to patients whose cancer was being treated with agents that target vascular endothelial growth factor (VEGF), which is known to have interactions with the angiotensin system that affect cell proliferation and angiogenesis.

"This is the largest analysis to our knowledge evaluating the role of ASIs [angiotensin system inhibitors] on outcomes not just in metastatic renal cell carcinoma but for all cancers," Dr. McKay commented in a press briefing held before the symposium.

"We demonstrated that ASI users had significantly improved survival when compared to ASI nonusers, even after adjustment for the development of treatment-associated hypertension. ASIs appear to have a synergistic activity in patients on VEGF-targeted therapy," she said.

"Although lab-based and prospective studies are required to explore this relationship further, in patients with metastatic renal cell carcinoma who warrant an antihypertensive agent, ASIs may be the agent of choice for patients without any contraindications for their use," Dr. McKay proposed.

It is noteworthy that nearly half of the patients studied had hypertension at baseline, according to press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the genitourinary medical oncology program.

"There is quite a significant effect here, and it really makes sense given the mechanism of action of VEGF-targeted therapy. I’m sure there will be a lot of interest going forward with this in prospective data," he commented.

There is good rationale for investigating ASIs – a collective term for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) – in renal cell carcinoma, according to Dr. McKay.

"VEGF is an established target in metastatic kidney cancer. Increasing evidence suggests that angiotensin II is an important regulator of vascular homeostasis and modulates VEGF-dependent angiogenesis," she explained.

The investigators reviewed data from a clinical trials database of 4,736 patients with metastatic renal cell carcinoma treated on Pfizer-sponsored phase II and III clinical trials between 2003 and 2013.

The largest share of patients (42%) had intermediate-risk disease according to IMDC (International mRCC Database Consortium) risk classification. In all, 70% had undergone nephrectomy, and 48% had hypertension at baseline.

Overall, 31% of patients in the cohort were using ASIs at baseline or started one in the first 30 days of their trial. Another 17% were using some other type of antihypertensive, and the remaining 52% were not using any.

In the entire study cohort, overall survival was 27 months for ASI users and 17 months for all other patients (hazard ratio, 1.21; P = .0009).

Among patients whose cancer was being treated with VEGF-targeted therapy, overall survival was better for ASI users than for all other patients (HR, 1.36; P less than .0001). But there was no such benefit for patients whose cancers were being treated with mammalian target of rapamycin (mTOR) inhibitors or for patients whose cancer was being treated with interferon-alpha.

In additional findings, among patients taking any kind of antihypertensive and receiving VEGF-targeted therapy, survival was better for ASI users than for users of other types of antihypertensives (31 vs. 22 months; HR, 1.38; P = .0003).

Dr. McKay disclosed no relevant conflicts of interest.

Adding radiation therapy to lifelong antiandrogen therapy dramatically cuts the long-term risk of death from prostate cancer in men with locally advanced disease, according to updated results of the Scandinavian Prostate Cancer Group’s Study VII.

Compared with antiandrogen therapy alone, the combination more than halved the 10- and 15-year rates of prostate cancer–specific mortality, lead author Dr. Sophie Dorothea Fosså reported in a press briefing preceding the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. In fact, the benefit increased with the duration of follow-up.

"Given the high mortality reduction and, what is important, only 8% prostate cancer–specific mortality at 10 years, our conclusion is that this combination of radiotherapy and hormones may be considered as a standard curative treatment option in these patients," she commented. "And it is actually ... more or less comparable to a modern prostatectomy series."

Approximately 30%-40% of the patients studied would likely undergo prostatectomy today, estimated Dr. Fosså, who is a professor in the department of oncology at Oslo University Hospital. But it remains unclear whether that treatment is better because other studies testing the combination of radiation therapy and antiandrogens have used much lower doses of radiation, now known to be inadequate.

"Therefore, a randomized trial is absolutely necessary. There is a new trial planned in the Scandinavian Prostate Cancer Group of radiotherapy plus at least 3 years with antiandrogens compared to prostatectomy," she said, noting that shorter durations of hormone treatment are now the norm.

Press briefing moderator Dr. Charles J. Ryan of the division of hematology/oncology at the University of California, San Francisco, and leader of the genitourinary medical oncology program there, said that the study presented is noteworthy for several reasons.

"One is it’s very interesting to see that these results continue to improve over time, which is somewhat different than some other randomized trials where sometimes results actually worsen over time," he elaborated. "Also of note is that this is the use of an antiandrogen as opposed to medical castration lifelong; that’s something that makes this trial somewhat unique."

Men from Norway, Sweden, and Denmark were eligible for the Scandinavian Prostate Cancer Group’s study if they had locally advanced or high-risk prostate cancer and were aged 75 years or younger; 80% had extension of disease beyond the prostatic capsule. Such patients were not considered surgical candidates in 1996, when the trial began, according to Dr. Fosså.

All 875 patients received 3 months of medical castration therapy, consisting of leuprolide injection (Procren Depot) plus oral flutamide (Eulexin). Half then received lifelong antiandrogen therapy alone (oral flutamide), whereas the other half received that therapy plus initial radiation therapy consisting of 75 Gy to the prostate, "which, at that time, was a relatively high dose," she noted.

Initial results, previously reported after a median follow-up of 7.6 years, showed a 12% reduction in prostate cancer–specific mortality in patients with the addition of radiation therapy (Lancet 2009;373:301-8).

Updated results, now after median follow-up of 10.7 years, showed the 10-year cumulative prostate cancer–specific mortality was more than halved by the addition of radiation therapy, from 19% to just 8%, reported to Dr. Fosså, who disclosed no relevant conflicts of interests related to the research.

The trial therefore far exceeded its primary endpoint of a reduction of at least 10% in 10-year prostate cancer–specific mortality from the addition of radiation therapy.

There was also a reduction in overall mortality at this time point, from 35% without radiation therapy to 26% with it.

The 15-year cumulative prostate cancer–specific mortality was also more than halved by the addition of radiation therapy, from 31% to 12%, and overall mortality was reduced by a quarter, from 57% to 43%.

Adding radiation therapy to lifelong antiandrogen therapy dramatically cuts the long-term risk of death from prostate cancer in men with locally advanced disease, according to updated results of the Scandinavian Prostate Cancer Group’s Study VII.

Compared with antiandrogen therapy alone, the combination more than halved the 10- and 15-year rates of prostate cancer–specific mortality, lead author Dr. Sophie Dorothea Fosså reported in a press briefing preceding the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. In fact, the benefit increased with the duration of follow-up.

"Given the high mortality reduction and, what is important, only 8% prostate cancer–specific mortality at 10 years, our conclusion is that this combination of radiotherapy and hormones may be considered as a standard curative treatment option in these patients," she commented. "And it is actually ... more or less comparable to a modern prostatectomy series."

Approximately 30%-40% of the patients studied would likely undergo prostatectomy today, estimated Dr. Fosså, who is a professor in the department of oncology at Oslo University Hospital. But it remains unclear whether that treatment is better because other studies testing the combination of radiation therapy and antiandrogens have used much lower doses of radiation, now known to be inadequate.

"Therefore, a randomized trial is absolutely necessary. There is a new trial planned in the Scandinavian Prostate Cancer Group of radiotherapy plus at least 3 years with antiandrogens compared to prostatectomy," she said, noting that shorter durations of hormone treatment are now the norm.

Press briefing moderator Dr. Charles J. Ryan of the division of hematology/oncology at the University of California, San Francisco, and leader of the genitourinary medical oncology program there, said that the study presented is noteworthy for several reasons.

"One is it’s very interesting to see that these results continue to improve over time, which is somewhat different than some other randomized trials where sometimes results actually worsen over time," he elaborated. "Also of note is that this is the use of an antiandrogen as opposed to medical castration lifelong; that’s something that makes this trial somewhat unique."

Men from Norway, Sweden, and Denmark were eligible for the Scandinavian Prostate Cancer Group’s study if they had locally advanced or high-risk prostate cancer and were aged 75 years or younger; 80% had extension of disease beyond the prostatic capsule. Such patients were not considered surgical candidates in 1996, when the trial began, according to Dr. Fosså.

All 875 patients received 3 months of medical castration therapy, consisting of leuprolide injection (Procren Depot) plus oral flutamide (Eulexin). Half then received lifelong antiandrogen therapy alone (oral flutamide), whereas the other half received that therapy plus initial radiation therapy consisting of 75 Gy to the prostate, "which, at that time, was a relatively high dose," she noted.

Initial results, previously reported after a median follow-up of 7.6 years, showed a 12% reduction in prostate cancer–specific mortality in patients with the addition of radiation therapy (Lancet 2009;373:301-8).

Updated results, now after median follow-up of 10.7 years, showed the 10-year cumulative prostate cancer–specific mortality was more than halved by the addition of radiation therapy, from 19% to just 8%, reported to Dr. Fosså, who disclosed no relevant conflicts of interests related to the research.

The trial therefore far exceeded its primary endpoint of a reduction of at least 10% in 10-year prostate cancer–specific mortality from the addition of radiation therapy.

There was also a reduction in overall mortality at this time point, from 35% without radiation therapy to 26% with it.

The 15-year cumulative prostate cancer–specific mortality was also more than halved by the addition of radiation therapy, from 31% to 12%, and overall mortality was reduced by a quarter, from 57% to 43%.

Adding radiation therapy to lifelong antiandrogen therapy dramatically cuts the long-term risk of death from prostate cancer in men with locally advanced disease, according to updated results of the Scandinavian Prostate Cancer Group’s Study VII.

Compared with antiandrogen therapy alone, the combination more than halved the 10- and 15-year rates of prostate cancer–specific mortality, lead author Dr. Sophie Dorothea Fosså reported in a press briefing preceding the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. In fact, the benefit increased with the duration of follow-up.

"Given the high mortality reduction and, what is important, only 8% prostate cancer–specific mortality at 10 years, our conclusion is that this combination of radiotherapy and hormones may be considered as a standard curative treatment option in these patients," she commented. "And it is actually ... more or less comparable to a modern prostatectomy series."

Approximately 30%-40% of the patients studied would likely undergo prostatectomy today, estimated Dr. Fosså, who is a professor in the department of oncology at Oslo University Hospital. But it remains unclear whether that treatment is better because other studies testing the combination of radiation therapy and antiandrogens have used much lower doses of radiation, now known to be inadequate.

"Therefore, a randomized trial is absolutely necessary. There is a new trial planned in the Scandinavian Prostate Cancer Group of radiotherapy plus at least 3 years with antiandrogens compared to prostatectomy," she said, noting that shorter durations of hormone treatment are now the norm.

Press briefing moderator Dr. Charles J. Ryan of the division of hematology/oncology at the University of California, San Francisco, and leader of the genitourinary medical oncology program there, said that the study presented is noteworthy for several reasons.

"One is it’s very interesting to see that these results continue to improve over time, which is somewhat different than some other randomized trials where sometimes results actually worsen over time," he elaborated. "Also of note is that this is the use of an antiandrogen as opposed to medical castration lifelong; that’s something that makes this trial somewhat unique."

Men from Norway, Sweden, and Denmark were eligible for the Scandinavian Prostate Cancer Group’s study if they had locally advanced or high-risk prostate cancer and were aged 75 years or younger; 80% had extension of disease beyond the prostatic capsule. Such patients were not considered surgical candidates in 1996, when the trial began, according to Dr. Fosså.

All 875 patients received 3 months of medical castration therapy, consisting of leuprolide injection (Procren Depot) plus oral flutamide (Eulexin). Half then received lifelong antiandrogen therapy alone (oral flutamide), whereas the other half received that therapy plus initial radiation therapy consisting of 75 Gy to the prostate, "which, at that time, was a relatively high dose," she noted.

Initial results, previously reported after a median follow-up of 7.6 years, showed a 12% reduction in prostate cancer–specific mortality in patients with the addition of radiation therapy (Lancet 2009;373:301-8).

Updated results, now after median follow-up of 10.7 years, showed the 10-year cumulative prostate cancer–specific mortality was more than halved by the addition of radiation therapy, from 19% to just 8%, reported to Dr. Fosså, who disclosed no relevant conflicts of interests related to the research.

The trial therefore far exceeded its primary endpoint of a reduction of at least 10% in 10-year prostate cancer–specific mortality from the addition of radiation therapy.

There was also a reduction in overall mortality at this time point, from 35% without radiation therapy to 26% with it.

The 15-year cumulative prostate cancer–specific mortality was also more than halved by the addition of radiation therapy, from 31% to 12%, and overall mortality was reduced by a quarter, from 57% to 43%.

The androgen receptor–blocker enzalutamide is efficacious and safe in men with metastatic castration-resistant prostate cancer who have not received chemotherapy, according to interim results of the randomized phase III PREVAIL trial.

Patients who received enzalutamide (Xtandi) were 29% less likely to die and 81% less likely to experience radiographic progression than patients who received a placebo, researchers are reporting at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Enzalutamide also prolonged the median time to chemotherapy by 17 months and was associated with a nearly 12 times higher rate of response.

Safety results showed that the drug was well tolerated and not associated with an increase in the rate of treatment discontinuation because of adverse events.

"As a result of these observations, it is my view that enzalutamide provides a meaningful clinical benefit to men with metastatic prostate cancer," lead author Dr. Tomasz Beer, professor of medicine and deputy director of the Knight Cancer Institute at Oregon Health and Science University, Portland, commented in a press briefing before the symposium.

The PREVAIL trial’s findings would apply to roughly 50,000 men each year in the United States, he estimated. "For folks who develop metastatic prostate cancer, by and large, all of them at some point or another would be expected to have this metastatic hormone-resistant state that is represented in this study population."

The favorable interim results prompted the investigators to stop the trial early, in October 2013, and offer enzalutamide to patients in the placebo arm. The manufacturer, Medivation, plans to file with the Food and Drug Administration for a new indication for enzalutamide, which is currently approved for the treatment of castration-resistant metastatic prostate cancer in men who have received chemotherapy.

"This is a very important study from the perspective that this applies to patients who have not yet had chemotherapy, which may expand the regulatory approval of enzalutamide. And one key fact for me is that although chemotherapy is sort of held up as the benchmark for this disease, the reality is that our current data suggest that less than 50% of men with castration-resistant prostate cancer actually receive chemotherapy," noted press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the Genitourinary Medical Oncology Program.

"So this treatment should change the regulatory status of enzalutamide and would open up this possibility of therapy for a very large group of patients who currently have really only one or two treatment options available to them," Dr. Ryan commented.

Dr. Beer declined to directly compare the efficacy results of PREVAIL with those of Cougar 302, a similar trial of the oral antiandrogen abiraterone (Zytiga) that led to its approval in this patient population.

But he noted that the trials’ populations differed in some respects that may be important; for example, about 12% of patients in PREVAIL had visceral metastases, compared with none in Cougar 302. Also, the former study excluded patients with a history of seizure, whereas the latter excluded those with cardiac risk factors.

Should enzalutamide gain approval for this new indication, the choice between enzalutamide and abiraterone would likely be individualized, taking into account these factors as well as others such as the need to coadminister steroids and follow dietary restrictions with abiraterone, according to Dr. Beer.

"That’s a decision that every clinician and patient will make in the clinic individually ... I don’t think there is a blanket answer to that question for all patients," he said. "We have two active drugs, we are fortunate to have those, and my real hope is that the work we are currently doing on the research front as a part of the [Stand Up to Cancer] West Coast Dream Team and other such efforts will enable us to further define which patient populations benefit the most from which therapeutic approach and be able to answer this question in a scientific manner in the future."

The two drugs may be compared in a head-to-head trial and will likely be tested in sequence, in combination, and in earlier stages of the disease, he added.

In fact, Dr. Ryan, the press briefing moderator, pointed out that just last week, the U.S. cooperative group system launched a trial comparing the combination of enzalutamide and abiraterone with enzalutamide monotherapy.

PREVAIL was sponsored by Medivation and enrolled 1,717 men with metastatic prostate cancer who had experienced progression on androgen deprivation therapy but had not received chemotherapy. They had no or only mild symptoms.

The men were randomized evenly to double-blind treatment with enzalutamide (160 mg/day) or a placebo.

With a median follow-up of about 20 months, enzalutamide was associated with better overall survival (hazard ratio, 0.71; P less than .0001) and better radiographic progression-free survival (HR, 0.19; P less than .0001). In post hoc analyses, the findings were much the same in the small subset of patients who had visceral metastases, according to Dr. Beer.

The response rate was 59% with enzalutamide (20% complete response; 39% partial response), compared with just 5% with placebo (P less than .0001).

Enzalutamide also delayed the median time to receipt of chemotherapy – "a pragmatic measure of real-world treatment effect," he noted – from 11 to 28 months (HR, 0.35; P less than .0001).

The rate of grade 3 or worse adverse events was 43% with enzalutamide and 37% with placebo. The most common toxicities of any grade were fatigue, back pain, constipation, and arthralgia. The rate of treatment discontinuation from adverse events was identical at 6% in each arm.

Two patients (0.1%) – one in each study arm – experienced seizure, which has been a concern with enzalutamide; both were subsequently determined to have a history of seizure unknown to their enrolling physician, which would have excluded them from the trial.

"What that tells us is that with appropriate patient selection, this clinical trial demonstrates that the drug can be administered very safely from the perspective of seizure risk," Dr. Beer said. "In point of fact, in patients who didn’t have a prior history of seizures, there were no seizures at all in this trial."

Dr. Beer disclosed that he receives research funding from Cougar Biotechnology, Janssen Biotech, Astellas Pharma, and Medivation. The trial was sponsored by Medivation.

The androgen receptor–blocker enzalutamide is efficacious and safe in men with metastatic castration-resistant prostate cancer who have not received chemotherapy, according to interim results of the randomized phase III PREVAIL trial.

Patients who received enzalutamide (Xtandi) were 29% less likely to die and 81% less likely to experience radiographic progression than patients who received a placebo, researchers are reporting at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Enzalutamide also prolonged the median time to chemotherapy by 17 months and was associated with a nearly 12 times higher rate of response.

Safety results showed that the drug was well tolerated and not associated with an increase in the rate of treatment discontinuation because of adverse events.

"As a result of these observations, it is my view that enzalutamide provides a meaningful clinical benefit to men with metastatic prostate cancer," lead author Dr. Tomasz Beer, professor of medicine and deputy director of the Knight Cancer Institute at Oregon Health and Science University, Portland, commented in a press briefing before the symposium.

The PREVAIL trial’s findings would apply to roughly 50,000 men each year in the United States, he estimated. "For folks who develop metastatic prostate cancer, by and large, all of them at some point or another would be expected to have this metastatic hormone-resistant state that is represented in this study population."

The favorable interim results prompted the investigators to stop the trial early, in October 2013, and offer enzalutamide to patients in the placebo arm. The manufacturer, Medivation, plans to file with the Food and Drug Administration for a new indication for enzalutamide, which is currently approved for the treatment of castration-resistant metastatic prostate cancer in men who have received chemotherapy.

"This is a very important study from the perspective that this applies to patients who have not yet had chemotherapy, which may expand the regulatory approval of enzalutamide. And one key fact for me is that although chemotherapy is sort of held up as the benchmark for this disease, the reality is that our current data suggest that less than 50% of men with castration-resistant prostate cancer actually receive chemotherapy," noted press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the Genitourinary Medical Oncology Program.

"So this treatment should change the regulatory status of enzalutamide and would open up this possibility of therapy for a very large group of patients who currently have really only one or two treatment options available to them," Dr. Ryan commented.

Dr. Beer declined to directly compare the efficacy results of PREVAIL with those of Cougar 302, a similar trial of the oral antiandrogen abiraterone (Zytiga) that led to its approval in this patient population.

But he noted that the trials’ populations differed in some respects that may be important; for example, about 12% of patients in PREVAIL had visceral metastases, compared with none in Cougar 302. Also, the former study excluded patients with a history of seizure, whereas the latter excluded those with cardiac risk factors.

Should enzalutamide gain approval for this new indication, the choice between enzalutamide and abiraterone would likely be individualized, taking into account these factors as well as others such as the need to coadminister steroids and follow dietary restrictions with abiraterone, according to Dr. Beer.

"That’s a decision that every clinician and patient will make in the clinic individually ... I don’t think there is a blanket answer to that question for all patients," he said. "We have two active drugs, we are fortunate to have those, and my real hope is that the work we are currently doing on the research front as a part of the [Stand Up to Cancer] West Coast Dream Team and other such efforts will enable us to further define which patient populations benefit the most from which therapeutic approach and be able to answer this question in a scientific manner in the future."

The two drugs may be compared in a head-to-head trial and will likely be tested in sequence, in combination, and in earlier stages of the disease, he added.

In fact, Dr. Ryan, the press briefing moderator, pointed out that just last week, the U.S. cooperative group system launched a trial comparing the combination of enzalutamide and abiraterone with enzalutamide monotherapy.

PREVAIL was sponsored by Medivation and enrolled 1,717 men with metastatic prostate cancer who had experienced progression on androgen deprivation therapy but had not received chemotherapy. They had no or only mild symptoms.

The men were randomized evenly to double-blind treatment with enzalutamide (160 mg/day) or a placebo.

With a median follow-up of about 20 months, enzalutamide was associated with better overall survival (hazard ratio, 0.71; P less than .0001) and better radiographic progression-free survival (HR, 0.19; P less than .0001). In post hoc analyses, the findings were much the same in the small subset of patients who had visceral metastases, according to Dr. Beer.

The response rate was 59% with enzalutamide (20% complete response; 39% partial response), compared with just 5% with placebo (P less than .0001).

Enzalutamide also delayed the median time to receipt of chemotherapy – "a pragmatic measure of real-world treatment effect," he noted – from 11 to 28 months (HR, 0.35; P less than .0001).

The rate of grade 3 or worse adverse events was 43% with enzalutamide and 37% with placebo. The most common toxicities of any grade were fatigue, back pain, constipation, and arthralgia. The rate of treatment discontinuation from adverse events was identical at 6% in each arm.

Two patients (0.1%) – one in each study arm – experienced seizure, which has been a concern with enzalutamide; both were subsequently determined to have a history of seizure unknown to their enrolling physician, which would have excluded them from the trial.

"What that tells us is that with appropriate patient selection, this clinical trial demonstrates that the drug can be administered very safely from the perspective of seizure risk," Dr. Beer said. "In point of fact, in patients who didn’t have a prior history of seizures, there were no seizures at all in this trial."

Dr. Beer disclosed that he receives research funding from Cougar Biotechnology, Janssen Biotech, Astellas Pharma, and Medivation. The trial was sponsored by Medivation.

The androgen receptor–blocker enzalutamide is efficacious and safe in men with metastatic castration-resistant prostate cancer who have not received chemotherapy, according to interim results of the randomized phase III PREVAIL trial.

Patients who received enzalutamide (Xtandi) were 29% less likely to die and 81% less likely to experience radiographic progression than patients who received a placebo, researchers are reporting at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Enzalutamide also prolonged the median time to chemotherapy by 17 months and was associated with a nearly 12 times higher rate of response.

Safety results showed that the drug was well tolerated and not associated with an increase in the rate of treatment discontinuation because of adverse events.

"As a result of these observations, it is my view that enzalutamide provides a meaningful clinical benefit to men with metastatic prostate cancer," lead author Dr. Tomasz Beer, professor of medicine and deputy director of the Knight Cancer Institute at Oregon Health and Science University, Portland, commented in a press briefing before the symposium.

The PREVAIL trial’s findings would apply to roughly 50,000 men each year in the United States, he estimated. "For folks who develop metastatic prostate cancer, by and large, all of them at some point or another would be expected to have this metastatic hormone-resistant state that is represented in this study population."

The favorable interim results prompted the investigators to stop the trial early, in October 2013, and offer enzalutamide to patients in the placebo arm. The manufacturer, Medivation, plans to file with the Food and Drug Administration for a new indication for enzalutamide, which is currently approved for the treatment of castration-resistant metastatic prostate cancer in men who have received chemotherapy.

"This is a very important study from the perspective that this applies to patients who have not yet had chemotherapy, which may expand the regulatory approval of enzalutamide. And one key fact for me is that although chemotherapy is sort of held up as the benchmark for this disease, the reality is that our current data suggest that less than 50% of men with castration-resistant prostate cancer actually receive chemotherapy," noted press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the Genitourinary Medical Oncology Program.

"So this treatment should change the regulatory status of enzalutamide and would open up this possibility of therapy for a very large group of patients who currently have really only one or two treatment options available to them," Dr. Ryan commented.

Dr. Beer declined to directly compare the efficacy results of PREVAIL with those of Cougar 302, a similar trial of the oral antiandrogen abiraterone (Zytiga) that led to its approval in this patient population.

But he noted that the trials’ populations differed in some respects that may be important; for example, about 12% of patients in PREVAIL had visceral metastases, compared with none in Cougar 302. Also, the former study excluded patients with a history of seizure, whereas the latter excluded those with cardiac risk factors.

Should enzalutamide gain approval for this new indication, the choice between enzalutamide and abiraterone would likely be individualized, taking into account these factors as well as others such as the need to coadminister steroids and follow dietary restrictions with abiraterone, according to Dr. Beer.

"That’s a decision that every clinician and patient will make in the clinic individually ... I don’t think there is a blanket answer to that question for all patients," he said. "We have two active drugs, we are fortunate to have those, and my real hope is that the work we are currently doing on the research front as a part of the [Stand Up to Cancer] West Coast Dream Team and other such efforts will enable us to further define which patient populations benefit the most from which therapeutic approach and be able to answer this question in a scientific manner in the future."

The two drugs may be compared in a head-to-head trial and will likely be tested in sequence, in combination, and in earlier stages of the disease, he added.

In fact, Dr. Ryan, the press briefing moderator, pointed out that just last week, the U.S. cooperative group system launched a trial comparing the combination of enzalutamide and abiraterone with enzalutamide monotherapy.

PREVAIL was sponsored by Medivation and enrolled 1,717 men with metastatic prostate cancer who had experienced progression on androgen deprivation therapy but had not received chemotherapy. They had no or only mild symptoms.

The men were randomized evenly to double-blind treatment with enzalutamide (160 mg/day) or a placebo.

With a median follow-up of about 20 months, enzalutamide was associated with better overall survival (hazard ratio, 0.71; P less than .0001) and better radiographic progression-free survival (HR, 0.19; P less than .0001). In post hoc analyses, the findings were much the same in the small subset of patients who had visceral metastases, according to Dr. Beer.

The response rate was 59% with enzalutamide (20% complete response; 39% partial response), compared with just 5% with placebo (P less than .0001).

Enzalutamide also delayed the median time to receipt of chemotherapy – "a pragmatic measure of real-world treatment effect," he noted – from 11 to 28 months (HR, 0.35; P less than .0001).

The rate of grade 3 or worse adverse events was 43% with enzalutamide and 37% with placebo. The most common toxicities of any grade were fatigue, back pain, constipation, and arthralgia. The rate of treatment discontinuation from adverse events was identical at 6% in each arm.

Two patients (0.1%) – one in each study arm – experienced seizure, which has been a concern with enzalutamide; both were subsequently determined to have a history of seizure unknown to their enrolling physician, which would have excluded them from the trial.

"What that tells us is that with appropriate patient selection, this clinical trial demonstrates that the drug can be administered very safely from the perspective of seizure risk," Dr. Beer said. "In point of fact, in patients who didn’t have a prior history of seizures, there were no seizures at all in this trial."

Dr. Beer disclosed that he receives research funding from Cougar Biotechnology, Janssen Biotech, Astellas Pharma, and Medivation. The trial was sponsored by Medivation.