FDA committee favors restricting prostate cancer regimen to BRCA-positive subgroup
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An FDA advisory committee recommended that a proposed indication for olaparib with abiraterone acetate as first-line treatment for metastatic castration-resistant prostate cancer be limited to patients whose tumors have BRCA mutations.
The Oncologic Drugs Advisory Committee voted 11 to 1 in favor of the restriction. One committee member abstained.
The FDA is not required to follow the advisory committee’s recommendation but often does so.
Olaparib (Lynparza; AstraZeneca, Merck) is a poly(ADP-ribose) polymerase (PARP) inhibitor. The agent is approved in the United States for treatment of certain patients with metastatic prostate cancer, advanced or recurrent ovarian cancer, early or metastatic breast cancer, and metastatic pancreatic cancer.
A supplemental new drug application seeks approval of olaparib in combination with abiraterone acetate (Zytiga, Janssen) as first-line treatment for metastatic castration-resistant prostate cancer.
The application is based on data from the randomized phase 3 PROpel study, which included 796 men undergoing first-line treatment for metastatic castration-resistant disease after primary androgen deprivation therapy failure.
Researchers randomly assigned men to 1,000 mg once-daily abiraterone acetate plus 5 mg twice-daily prednisone or prednisolone, along with either 300 mg twice-daily olaparib (n = 399) or placebo (n = 397).
Investigator-assessed radiographic PFS served as the primary endpoint. OS served as a secondary endpoint.
As Healio previously reported, results of an interim analysis presented at last year’s ASCO Genitourinary Cancers Symposium showed men assigned olaparib achieved significantly longer radiographic PFS (median, 24.8 months vs. 16.6 months; HR = 0.66, 95% CI, 0.54-0.81).
The benefit persisted regardless of homologous recombination repair (HRR) gene mutation status as determined by circulating tumor DNA testing (HRR gene mutations, HR = 0.5; 95% CI, 0.36-0.79; no HRR gene mutations, HR = 0.76; 95% CI, 0.59-0.97).
Updated results presented at this year’s ASCO Genitourinary Cancers Symposium showed no statistically significant difference in OS between the olaparib and placebo groups (median, 42.1 months vs. 34.7 months; HR = 0.81; 95% CI, 0.67-1).
However, investigators did not perform prespecified or alpha-controlled analyses based on BRCA mutation status, according to the FDA.
The agency released briefing documents prior to the committee meeting that suggested the 11% of trial participants with confirmed BRCA mutations accounted for much of the benefit observed with olaparib.
FDA calculations showed the addition of olaparib to first-line treatment conferred a 76% reduction in risk for disease progression (median PFS, not reached vs. 8 months; HR = 0.24; 95% CI, 0.12-0.46) and a 70% reduction in risk for death (median OS, not reached vs. 23 months; HR = 0.3; 95% CI, 0.15-0.6) among men with BRCA mutations.
In contrast, the olaparib regimen conferred a 15% reduction in risk for progression (median PFS, 22 months vs. 17 months; HR = 0.85; 0.66-1.11) and a slightly elevated risk for death (median OS, 37 months vs. 38 months; HR = 1.06; 95% CI, 0.81-1.39) among men confirmed to have no BRCA mutation, the FDA briefing documents showed.
“The question here is: Does PROpel prove patients with non-BRCA-mutated prostate cancer benefit from olaparib? I believe the answer is, we don’t know,” committee member Christopher H. Lieu, MD, associate professor of medicine at University of Colorado Anschutz Medical Campus, said in explaining why he voted in favor of restricting the indication. “If the applicant and the GU oncology community is convinced there is evidence of meaningful benefit in the biomarker-negative cohort, I think this study would be feasible and could be completed.”
David E. Mitchell, the committee’s consumer representative, also voted in favor of restricting the indication.
“FDA’s job is to approve drugs if they are safe and effective, and I think by restricting this drug to patients who are BRCA positive, we ensure that this drug is going to be safe and effective for those who receive it,” Mitchell said.
Jorge J. Nieva, MD, associate professor of clinical medicine and section head for solid tumors at USC Norris Comprehensive Cancer Center, cast the lone vote against restricting the proposed indication.
“This was a positive clinical trial designed in conjunction with FDA guidance on the endpoints,” Nieva said. “FDA proposed there should be a restriction to 11% of the population, and I don’t think this level of restriction is justified.
“Patients with homologous recombination-deficient (HRD) cancers gain significant benefits from PARP therapy, and this has been seen in multiple clinical trials,” Nieva added. “I worry the approach used in this application can justify removing any subgroup from an application where that subgroup has an OS curve that crosses 1. FDA seems to be looking at these OS curves in a vacuum and is ignoring the corroborating evidence that the HRD population would benefit significantly.”
Reference s :
- FDA. FDA Briefing Document. Oncologic Drugs Advisory Committee Meeting. Available at: www.fda.gov/media/167483/download. Accessed April 28, 2023.
- Merck and AstraZeneca present final results of key secondary overall survival endpoint from phase 3 PROpel Trial at 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium (press release). Available at https://www.merck.com/news/merck-and-astrazeneca-present-final-results-of-key-secondary-overall-survival-endpoint-from-phase-3-propel-trial-at-2023-american-society-of-clinical-oncology-genitourinary-cancers-symposium/. Published Feb. 16, 2023. Accessed April 27, 2023.
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FDA Briefing Document
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