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CHICAGO – In platinum-sensitive relapsed serous ovarian cancer patients, maintenance olaparib therapy was of most benefit among women with a BRCA mutation, based on results from a randomized phase II trial reported at the annual meeting of the American Society of Clinical Oncology.
The 265 women enrolled in the study had responded to platinum chemotherapy and were assigned evenly to olaparib – an investigational inhibitor of poly(ADP-ribose) polymerase (PARP) – or placebo for maintenance therapy.
Relative to placebo, olaparib reduced the risk of progression or death by a significant 82% (hazard ratio, 0.18) among patients with BRCA mutations and by a lesser but still significant 47% (HR, 0.53) in patients without BRCA mutations, reported first author Dr. Jonathan Ledermann, a professor of medical oncology in the UCL Cancer Institute, University College London.
There was also a greater carryover benefit of olaparib in the BRCA mutation–positive subset, in that they had a longer time to progression or death after the next therapy they received.
"As a result of these compelling data, phase III confirmatory trials are now starting in patients with BRCA mutations later this year," Dr. Lederman said.
Overall, 51% of patients enrolled in the trial, formally known as Study 19 and sponsored by AstraZeneca (the manufacturer of olaparib), had a known deleterious BRCA germline mutation or a BRCA mutation in their tumor.
The main results, previously published, showed that maintenance olaparib prolonged progression-free survival in the trial population overall, with a hazard ratio of 0.35 (N. Engl. J. Med. 2012;366:1382-92). There was no significant gain in overall survival as of an interim analysis, but there was a suggestion of benefit for patients with a BRCA mutation.
Among the BRCA mutation–positive subset, median progression-free survival was 11.2 months with olaparib versus 4.3 months with placebo (HR, 0.18; P less than .00001). Among the BRCA mutation–negative group, median progression-free survival was 5.6 months with olaparib versus 5.5 months with placebo (HR, 0.53; P less than .007).
There was still no overall survival advantage of olaparib in the trial population as a whole, but 23% of patients in the placebo group were switched to a PARP inhibitor. "This may be sufficient ... to actually have a confounding effect on the overall survival of these patients," Dr. Ledermann commented. There was a trend toward better overall survival with olaparib in the BRCA mutation–positive subset.
In addition, olaparib was superior to placebo in terms of the time from randomization to progression after a second, subsequent therapy, both among the BRCA mutation–positive subset (23.8 vs. 15.3 months; HR, 0.46; P less than .0003) and among the BRCA mutation–negative subset (17.1 vs. 14.7 months; HR, 0.64; P = .03).
"This I think translates into a clinically meaningful benefit, in that the effect if you like of olaparib is carried over beyond progression, to the time that they fail a second subsequent therapy," Dr. Ledermann said.
There was no significant difference in quality of life between the olaparib and placebo groups among women having a BRCA mutation.
Tolerability of olaparib did not differ significantly between women with the BRCA mutation–positive subset and the overall trial population. The leading adverse events in the former were low-grade nausea (seen in 73%) and fatigue (seen in 54%).
Dr. Ledermann disclosed that he receives travel grants from AstraZeneca. The trial was sponsored by AstraZeneca.
The trial results show successful PARP inhibitor use as maintenance therapy and avoid the toxicity challenge of combinations with cytotoxic chemotherapy.
Importantly, the BRCA mutation is a robust biomarker for benefit and will be appropriately used to guide phase III studies for this indication. However, this biomarker should not limit all future investigations with PARP. BRCA deficiency is a fraction of the causes of defective DNA repair. Other sites of intervention in the pathway, such as ATM (ataxia telangiectasia mutated) kinase, are warranted. In fact, PARP inhibitor activity independent of BRCA status has been shown in breast cancer, for example.
Maintenance PARP inhibition has thus far not improved survival in ovarian cancer. It may just be that we can’t detect an overall survival benefit in our maintenance studies because of the effect of subsequent therapy. A related issue is thus when to use this strategy. The data suggest that there is enhanced or at least preserved activity as you move along the disease course. So the question is, if we have a strategy that confers about a 6-month progression-free survival advantage, yet may not affect overall survival, where in the disease course should that be used? That’s a critical question that remains to be answered.
Dr. Paul Sabbatini is deputy physician-in-chief for clinical research at Memorial Sloan-Kettering Cancer Center in New York. He was the invited discussant for the study at the meeting. Dr. Sabbatini disclosed no relevant conflicts of interest.
The trial results show successful PARP inhibitor use as maintenance therapy and avoid the toxicity challenge of combinations with cytotoxic chemotherapy.
Importantly, the BRCA mutation is a robust biomarker for benefit and will be appropriately used to guide phase III studies for this indication. However, this biomarker should not limit all future investigations with PARP. BRCA deficiency is a fraction of the causes of defective DNA repair. Other sites of intervention in the pathway, such as ATM (ataxia telangiectasia mutated) kinase, are warranted. In fact, PARP inhibitor activity independent of BRCA status has been shown in breast cancer, for example.
Maintenance PARP inhibition has thus far not improved survival in ovarian cancer. It may just be that we can’t detect an overall survival benefit in our maintenance studies because of the effect of subsequent therapy. A related issue is thus when to use this strategy. The data suggest that there is enhanced or at least preserved activity as you move along the disease course. So the question is, if we have a strategy that confers about a 6-month progression-free survival advantage, yet may not affect overall survival, where in the disease course should that be used? That’s a critical question that remains to be answered.
Dr. Paul Sabbatini is deputy physician-in-chief for clinical research at Memorial Sloan-Kettering Cancer Center in New York. He was the invited discussant for the study at the meeting. Dr. Sabbatini disclosed no relevant conflicts of interest.
The trial results show successful PARP inhibitor use as maintenance therapy and avoid the toxicity challenge of combinations with cytotoxic chemotherapy.
Importantly, the BRCA mutation is a robust biomarker for benefit and will be appropriately used to guide phase III studies for this indication. However, this biomarker should not limit all future investigations with PARP. BRCA deficiency is a fraction of the causes of defective DNA repair. Other sites of intervention in the pathway, such as ATM (ataxia telangiectasia mutated) kinase, are warranted. In fact, PARP inhibitor activity independent of BRCA status has been shown in breast cancer, for example.
Maintenance PARP inhibition has thus far not improved survival in ovarian cancer. It may just be that we can’t detect an overall survival benefit in our maintenance studies because of the effect of subsequent therapy. A related issue is thus when to use this strategy. The data suggest that there is enhanced or at least preserved activity as you move along the disease course. So the question is, if we have a strategy that confers about a 6-month progression-free survival advantage, yet may not affect overall survival, where in the disease course should that be used? That’s a critical question that remains to be answered.
Dr. Paul Sabbatini is deputy physician-in-chief for clinical research at Memorial Sloan-Kettering Cancer Center in New York. He was the invited discussant for the study at the meeting. Dr. Sabbatini disclosed no relevant conflicts of interest.
CHICAGO – In platinum-sensitive relapsed serous ovarian cancer patients, maintenance olaparib therapy was of most benefit among women with a BRCA mutation, based on results from a randomized phase II trial reported at the annual meeting of the American Society of Clinical Oncology.
The 265 women enrolled in the study had responded to platinum chemotherapy and were assigned evenly to olaparib – an investigational inhibitor of poly(ADP-ribose) polymerase (PARP) – or placebo for maintenance therapy.
Relative to placebo, olaparib reduced the risk of progression or death by a significant 82% (hazard ratio, 0.18) among patients with BRCA mutations and by a lesser but still significant 47% (HR, 0.53) in patients without BRCA mutations, reported first author Dr. Jonathan Ledermann, a professor of medical oncology in the UCL Cancer Institute, University College London.
There was also a greater carryover benefit of olaparib in the BRCA mutation–positive subset, in that they had a longer time to progression or death after the next therapy they received.
"As a result of these compelling data, phase III confirmatory trials are now starting in patients with BRCA mutations later this year," Dr. Lederman said.
Overall, 51% of patients enrolled in the trial, formally known as Study 19 and sponsored by AstraZeneca (the manufacturer of olaparib), had a known deleterious BRCA germline mutation or a BRCA mutation in their tumor.
The main results, previously published, showed that maintenance olaparib prolonged progression-free survival in the trial population overall, with a hazard ratio of 0.35 (N. Engl. J. Med. 2012;366:1382-92). There was no significant gain in overall survival as of an interim analysis, but there was a suggestion of benefit for patients with a BRCA mutation.
Among the BRCA mutation–positive subset, median progression-free survival was 11.2 months with olaparib versus 4.3 months with placebo (HR, 0.18; P less than .00001). Among the BRCA mutation–negative group, median progression-free survival was 5.6 months with olaparib versus 5.5 months with placebo (HR, 0.53; P less than .007).
There was still no overall survival advantage of olaparib in the trial population as a whole, but 23% of patients in the placebo group were switched to a PARP inhibitor. "This may be sufficient ... to actually have a confounding effect on the overall survival of these patients," Dr. Ledermann commented. There was a trend toward better overall survival with olaparib in the BRCA mutation–positive subset.
In addition, olaparib was superior to placebo in terms of the time from randomization to progression after a second, subsequent therapy, both among the BRCA mutation–positive subset (23.8 vs. 15.3 months; HR, 0.46; P less than .0003) and among the BRCA mutation–negative subset (17.1 vs. 14.7 months; HR, 0.64; P = .03).
"This I think translates into a clinically meaningful benefit, in that the effect if you like of olaparib is carried over beyond progression, to the time that they fail a second subsequent therapy," Dr. Ledermann said.
There was no significant difference in quality of life between the olaparib and placebo groups among women having a BRCA mutation.
Tolerability of olaparib did not differ significantly between women with the BRCA mutation–positive subset and the overall trial population. The leading adverse events in the former were low-grade nausea (seen in 73%) and fatigue (seen in 54%).
Dr. Ledermann disclosed that he receives travel grants from AstraZeneca. The trial was sponsored by AstraZeneca.
CHICAGO – In platinum-sensitive relapsed serous ovarian cancer patients, maintenance olaparib therapy was of most benefit among women with a BRCA mutation, based on results from a randomized phase II trial reported at the annual meeting of the American Society of Clinical Oncology.
The 265 women enrolled in the study had responded to platinum chemotherapy and were assigned evenly to olaparib – an investigational inhibitor of poly(ADP-ribose) polymerase (PARP) – or placebo for maintenance therapy.
Relative to placebo, olaparib reduced the risk of progression or death by a significant 82% (hazard ratio, 0.18) among patients with BRCA mutations and by a lesser but still significant 47% (HR, 0.53) in patients without BRCA mutations, reported first author Dr. Jonathan Ledermann, a professor of medical oncology in the UCL Cancer Institute, University College London.
There was also a greater carryover benefit of olaparib in the BRCA mutation–positive subset, in that they had a longer time to progression or death after the next therapy they received.
"As a result of these compelling data, phase III confirmatory trials are now starting in patients with BRCA mutations later this year," Dr. Lederman said.
Overall, 51% of patients enrolled in the trial, formally known as Study 19 and sponsored by AstraZeneca (the manufacturer of olaparib), had a known deleterious BRCA germline mutation or a BRCA mutation in their tumor.
The main results, previously published, showed that maintenance olaparib prolonged progression-free survival in the trial population overall, with a hazard ratio of 0.35 (N. Engl. J. Med. 2012;366:1382-92). There was no significant gain in overall survival as of an interim analysis, but there was a suggestion of benefit for patients with a BRCA mutation.
Among the BRCA mutation–positive subset, median progression-free survival was 11.2 months with olaparib versus 4.3 months with placebo (HR, 0.18; P less than .00001). Among the BRCA mutation–negative group, median progression-free survival was 5.6 months with olaparib versus 5.5 months with placebo (HR, 0.53; P less than .007).
There was still no overall survival advantage of olaparib in the trial population as a whole, but 23% of patients in the placebo group were switched to a PARP inhibitor. "This may be sufficient ... to actually have a confounding effect on the overall survival of these patients," Dr. Ledermann commented. There was a trend toward better overall survival with olaparib in the BRCA mutation–positive subset.
In addition, olaparib was superior to placebo in terms of the time from randomization to progression after a second, subsequent therapy, both among the BRCA mutation–positive subset (23.8 vs. 15.3 months; HR, 0.46; P less than .0003) and among the BRCA mutation–negative subset (17.1 vs. 14.7 months; HR, 0.64; P = .03).
"This I think translates into a clinically meaningful benefit, in that the effect if you like of olaparib is carried over beyond progression, to the time that they fail a second subsequent therapy," Dr. Ledermann said.
There was no significant difference in quality of life between the olaparib and placebo groups among women having a BRCA mutation.
Tolerability of olaparib did not differ significantly between women with the BRCA mutation–positive subset and the overall trial population. The leading adverse events in the former were low-grade nausea (seen in 73%) and fatigue (seen in 54%).
Dr. Ledermann disclosed that he receives travel grants from AstraZeneca. The trial was sponsored by AstraZeneca.
AT THE ASCO ANNUAL MEETING 2013
Major finding: The reduction in the risk of progression or death with olaparib versus placebo was greater among patients with a BRCA mutation (hazard ratio, 0.18) than among patients without a BRCA mutation (HR, 0.53).
Data source: A randomized phase II trial of 265 women with platinum-sensitive relapsed serous ovarian cancer (Study 19)
Disclosures: Dr. Ledermann disclosed that he receives travel grants from AstraZeneca. The trial was sponsored by AstraZeneca.
