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A panel of independent advisers recently almost unanimously recommended to restrict a new indication for olaparib (Lynparza) alongside abiraterone (Zytiga) in patients with metastatic castration-resistant prostate cancer.
On April 28, members of the Oncologic Drugs Advisory Committee voted 11 to 1, with one abstention, that only patients whose tumors have a BRCA mutation should receive olaparib as part of the combination first-line treatment for metastatic castration-resistant prostate cancer.
Olaparib is already cleared by the Food and Drug Administration for various ovarian, breast, and pancreatic cancer indications as well as later-line use in certain more advanced prostate cancers. AstraZeneca recently applied for an additional, broad indication for the poly (ADP-ribose) polymerase (PARP) inhibitor as an initial therapy that would include patients without BRCA or homologous recombination repair (HRR) mutations.
In reviewing the application, a phrase agency staff used in their briefing document.
Given these concerns, the FDA reviewers asked the independent ODAC panel to vote on the following question: “As FDA reviews the proposed indication for olaparib in combination with abiraterone for initial treatment of [metastatic castration-resistant prostate cancer], should the indication be restricted to patients whose tumors have a BRCA mutation?”
The ODAC panel voted 11 to 1 in favor of a restricted expansion of olaparib plus abiraterone and prednisone or prednisolone to patients whose tumors have a BRCA mutation. One member – Ravi A. Madan, MD, of the National Cancer Institute – abstained. The FDA staff asked panelists to abstain if they felt the combination treatment should not be approved for any indication.
Overall, the ODAC panel agreed with the FDA staff’s criticism of the research supporting the application: the PROpel study. The trial randomized 796 patients with previously untreated metastatic castration-resistant prostate cancer to olaparib plus abiraterone or abiraterone plus placebo. The median time for radiographic progression-free survival – the study’s primary endpoint – was nearly 25 months in the olaparib group versus 16.6 months in the placebo group.
The combination also demonstrated a 19% reduced risk of death, which was not statistically significant (hazard ratio, 0.81; P = .0544), and a median improvement of 7.4 months in the combination arm (42.1 vs. 34.7 months).
Although the study met its primary endpoint, the results were difficult to interpret given the lack of information about genetic variability in the participants’ tumors. Participants were not prospectively assessed for either BRCA or HRR status. But given the importance of BRCA status as a predictive biomarker for PARP inhibitor efficacy, “this trial design would be considered inappropriate today as the biomarker should have been prospectively evaluated,” the FDA wrote in its briefing document.
In a post hoc analysis performed by the FDA, the agency found that BRCA-positive patients accounted for most of the survival benefit of the combination, though made up only 11% of the PROpel population.
That meant the ODAC members were being asked to evaluate a drug based on “suboptimal data” resulting from a “suboptimal study design,” said Dr. Madan, who is head of the prostate cancer clinical research section in the NCI’s Center for Cancer Research.
Dr. Madan also emphasized concerns the FDA raised about the potential harms for patients whose prostate cancer was not tied to BRCA mutations. In the FDA’s briefing document, the agency said patients treated in the first-line metastatic castration-resistant prostate cancer setting generally have few symptoms at baseline. Adding olaparib among patients lacking the BRCA mutation could expose them to a drug with known side effects but minimal chance to help them.
The PROpel trial also found that patients who received olaparib and abiraterone experienced greater toxicity than those who received abiraterone. These adverse events included venous thromboembolic events, myelosuppression, requirement for blood transfusions, nausea, vomiting, and diarrhea.
Although the FDA is not compelled to follow the recommendations of its advisory committees, it often does.
AstraZeneca expressed some disappointment about the recommendation in a press release. Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, said, “while we are pleased with the recognition of the benefit of Lynparza plus abiraterone for patients with BRCA-mutated metastatic castration-resistant prostate cancer, we are disappointed with the outcome of today’s ODAC meeting. We strongly believe in the results of the PROpel trial, which demonstrated the clinically meaningful benefit for this combination in a broad population of patients regardless of biomarker status.”
One ODAC member, Jorge J. Nieva, MD, did support the expanded approval for olaparib, casting the single “no” vote. Dr. Nieva, an oncologist at the University of Southern California, Los Angeles, disagreed with the FDA’s question about limiting use of the olaparib-abiraterone combination to patients with known BRCA mutations, citing the positive result from the PROpel trial.
People are aware that olaparib provides a great deal more benefit in the BRCA-positive group and may give “only minimal benefit if these tests are not positive,” but “these risks and benefits can be addressed at the patient and physician level,” he said.
But Terrence M. Kungel, MBA, who served as ODAC’s patient representative for the meeting, offered a counterpoint to Dr. Nieva’s assessment. Patients now often struggle to assess the options available to them and then pay for these medicines, with financial toxicity affecting many people with cancer.
“Prostate cancer patients need more treatments that are effective, not more choices,” said Mr. Kungel, who voted with the majority.
A version of this article first appeared on Medscape.com.
A panel of independent advisers recently almost unanimously recommended to restrict a new indication for olaparib (Lynparza) alongside abiraterone (Zytiga) in patients with metastatic castration-resistant prostate cancer.
On April 28, members of the Oncologic Drugs Advisory Committee voted 11 to 1, with one abstention, that only patients whose tumors have a BRCA mutation should receive olaparib as part of the combination first-line treatment for metastatic castration-resistant prostate cancer.
Olaparib is already cleared by the Food and Drug Administration for various ovarian, breast, and pancreatic cancer indications as well as later-line use in certain more advanced prostate cancers. AstraZeneca recently applied for an additional, broad indication for the poly (ADP-ribose) polymerase (PARP) inhibitor as an initial therapy that would include patients without BRCA or homologous recombination repair (HRR) mutations.
In reviewing the application, a phrase agency staff used in their briefing document.
Given these concerns, the FDA reviewers asked the independent ODAC panel to vote on the following question: “As FDA reviews the proposed indication for olaparib in combination with abiraterone for initial treatment of [metastatic castration-resistant prostate cancer], should the indication be restricted to patients whose tumors have a BRCA mutation?”
The ODAC panel voted 11 to 1 in favor of a restricted expansion of olaparib plus abiraterone and prednisone or prednisolone to patients whose tumors have a BRCA mutation. One member – Ravi A. Madan, MD, of the National Cancer Institute – abstained. The FDA staff asked panelists to abstain if they felt the combination treatment should not be approved for any indication.
Overall, the ODAC panel agreed with the FDA staff’s criticism of the research supporting the application: the PROpel study. The trial randomized 796 patients with previously untreated metastatic castration-resistant prostate cancer to olaparib plus abiraterone or abiraterone plus placebo. The median time for radiographic progression-free survival – the study’s primary endpoint – was nearly 25 months in the olaparib group versus 16.6 months in the placebo group.
The combination also demonstrated a 19% reduced risk of death, which was not statistically significant (hazard ratio, 0.81; P = .0544), and a median improvement of 7.4 months in the combination arm (42.1 vs. 34.7 months).
Although the study met its primary endpoint, the results were difficult to interpret given the lack of information about genetic variability in the participants’ tumors. Participants were not prospectively assessed for either BRCA or HRR status. But given the importance of BRCA status as a predictive biomarker for PARP inhibitor efficacy, “this trial design would be considered inappropriate today as the biomarker should have been prospectively evaluated,” the FDA wrote in its briefing document.
In a post hoc analysis performed by the FDA, the agency found that BRCA-positive patients accounted for most of the survival benefit of the combination, though made up only 11% of the PROpel population.
That meant the ODAC members were being asked to evaluate a drug based on “suboptimal data” resulting from a “suboptimal study design,” said Dr. Madan, who is head of the prostate cancer clinical research section in the NCI’s Center for Cancer Research.
Dr. Madan also emphasized concerns the FDA raised about the potential harms for patients whose prostate cancer was not tied to BRCA mutations. In the FDA’s briefing document, the agency said patients treated in the first-line metastatic castration-resistant prostate cancer setting generally have few symptoms at baseline. Adding olaparib among patients lacking the BRCA mutation could expose them to a drug with known side effects but minimal chance to help them.
The PROpel trial also found that patients who received olaparib and abiraterone experienced greater toxicity than those who received abiraterone. These adverse events included venous thromboembolic events, myelosuppression, requirement for blood transfusions, nausea, vomiting, and diarrhea.
Although the FDA is not compelled to follow the recommendations of its advisory committees, it often does.
AstraZeneca expressed some disappointment about the recommendation in a press release. Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, said, “while we are pleased with the recognition of the benefit of Lynparza plus abiraterone for patients with BRCA-mutated metastatic castration-resistant prostate cancer, we are disappointed with the outcome of today’s ODAC meeting. We strongly believe in the results of the PROpel trial, which demonstrated the clinically meaningful benefit for this combination in a broad population of patients regardless of biomarker status.”
One ODAC member, Jorge J. Nieva, MD, did support the expanded approval for olaparib, casting the single “no” vote. Dr. Nieva, an oncologist at the University of Southern California, Los Angeles, disagreed with the FDA’s question about limiting use of the olaparib-abiraterone combination to patients with known BRCA mutations, citing the positive result from the PROpel trial.
People are aware that olaparib provides a great deal more benefit in the BRCA-positive group and may give “only minimal benefit if these tests are not positive,” but “these risks and benefits can be addressed at the patient and physician level,” he said.
But Terrence M. Kungel, MBA, who served as ODAC’s patient representative for the meeting, offered a counterpoint to Dr. Nieva’s assessment. Patients now often struggle to assess the options available to them and then pay for these medicines, with financial toxicity affecting many people with cancer.
“Prostate cancer patients need more treatments that are effective, not more choices,” said Mr. Kungel, who voted with the majority.
A version of this article first appeared on Medscape.com.
A panel of independent advisers recently almost unanimously recommended to restrict a new indication for olaparib (Lynparza) alongside abiraterone (Zytiga) in patients with metastatic castration-resistant prostate cancer.
On April 28, members of the Oncologic Drugs Advisory Committee voted 11 to 1, with one abstention, that only patients whose tumors have a BRCA mutation should receive olaparib as part of the combination first-line treatment for metastatic castration-resistant prostate cancer.
Olaparib is already cleared by the Food and Drug Administration for various ovarian, breast, and pancreatic cancer indications as well as later-line use in certain more advanced prostate cancers. AstraZeneca recently applied for an additional, broad indication for the poly (ADP-ribose) polymerase (PARP) inhibitor as an initial therapy that would include patients without BRCA or homologous recombination repair (HRR) mutations.
In reviewing the application, a phrase agency staff used in their briefing document.
Given these concerns, the FDA reviewers asked the independent ODAC panel to vote on the following question: “As FDA reviews the proposed indication for olaparib in combination with abiraterone for initial treatment of [metastatic castration-resistant prostate cancer], should the indication be restricted to patients whose tumors have a BRCA mutation?”
The ODAC panel voted 11 to 1 in favor of a restricted expansion of olaparib plus abiraterone and prednisone or prednisolone to patients whose tumors have a BRCA mutation. One member – Ravi A. Madan, MD, of the National Cancer Institute – abstained. The FDA staff asked panelists to abstain if they felt the combination treatment should not be approved for any indication.
Overall, the ODAC panel agreed with the FDA staff’s criticism of the research supporting the application: the PROpel study. The trial randomized 796 patients with previously untreated metastatic castration-resistant prostate cancer to olaparib plus abiraterone or abiraterone plus placebo. The median time for radiographic progression-free survival – the study’s primary endpoint – was nearly 25 months in the olaparib group versus 16.6 months in the placebo group.
The combination also demonstrated a 19% reduced risk of death, which was not statistically significant (hazard ratio, 0.81; P = .0544), and a median improvement of 7.4 months in the combination arm (42.1 vs. 34.7 months).
Although the study met its primary endpoint, the results were difficult to interpret given the lack of information about genetic variability in the participants’ tumors. Participants were not prospectively assessed for either BRCA or HRR status. But given the importance of BRCA status as a predictive biomarker for PARP inhibitor efficacy, “this trial design would be considered inappropriate today as the biomarker should have been prospectively evaluated,” the FDA wrote in its briefing document.
In a post hoc analysis performed by the FDA, the agency found that BRCA-positive patients accounted for most of the survival benefit of the combination, though made up only 11% of the PROpel population.
That meant the ODAC members were being asked to evaluate a drug based on “suboptimal data” resulting from a “suboptimal study design,” said Dr. Madan, who is head of the prostate cancer clinical research section in the NCI’s Center for Cancer Research.
Dr. Madan also emphasized concerns the FDA raised about the potential harms for patients whose prostate cancer was not tied to BRCA mutations. In the FDA’s briefing document, the agency said patients treated in the first-line metastatic castration-resistant prostate cancer setting generally have few symptoms at baseline. Adding olaparib among patients lacking the BRCA mutation could expose them to a drug with known side effects but minimal chance to help them.
The PROpel trial also found that patients who received olaparib and abiraterone experienced greater toxicity than those who received abiraterone. These adverse events included venous thromboembolic events, myelosuppression, requirement for blood transfusions, nausea, vomiting, and diarrhea.
Although the FDA is not compelled to follow the recommendations of its advisory committees, it often does.
AstraZeneca expressed some disappointment about the recommendation in a press release. Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, said, “while we are pleased with the recognition of the benefit of Lynparza plus abiraterone for patients with BRCA-mutated metastatic castration-resistant prostate cancer, we are disappointed with the outcome of today’s ODAC meeting. We strongly believe in the results of the PROpel trial, which demonstrated the clinically meaningful benefit for this combination in a broad population of patients regardless of biomarker status.”
One ODAC member, Jorge J. Nieva, MD, did support the expanded approval for olaparib, casting the single “no” vote. Dr. Nieva, an oncologist at the University of Southern California, Los Angeles, disagreed with the FDA’s question about limiting use of the olaparib-abiraterone combination to patients with known BRCA mutations, citing the positive result from the PROpel trial.
People are aware that olaparib provides a great deal more benefit in the BRCA-positive group and may give “only minimal benefit if these tests are not positive,” but “these risks and benefits can be addressed at the patient and physician level,” he said.
But Terrence M. Kungel, MBA, who served as ODAC’s patient representative for the meeting, offered a counterpoint to Dr. Nieva’s assessment. Patients now often struggle to assess the options available to them and then pay for these medicines, with financial toxicity affecting many people with cancer.
“Prostate cancer patients need more treatments that are effective, not more choices,” said Mr. Kungel, who voted with the majority.
A version of this article first appeared on Medscape.com.