The Oncologic Drugs Advisory Committee voted 11–1 supporting Merck’s and AstraZeneca’s PARP inhibitor for metastatic castration-resistant prostate cancer patients with BRCA mutations.
Pictured: Blue and white sign outside FDA building/Grandbrothers/Adobe Stock
Friday, the FDA’s Oncologic Drugs Advisory Committee (ODAC) threw its support behind Merck’s and AstraZeneca’s PARP inhibitor Lynparza (olaparaib), but only in a subset of metastatic castration-resistant prostate cancer (mCRPC) patients carrying a particular tumor mutation.
Voting 11–1, with one abstention, the ODAC agreed that Lynparza had a favorable risk-benefit profile in mCRPC patients bearing mutations in the BRCA gene and that its approval should be restricted to this population.
Merck and AstraZeneca are proposing to expand Lynparza’s label to include all adult patients regardless of mutation status. In the supplemental New Drug Application (sNDA), which the FDA accepted in August 2022, the pharma partners touted a 34% drop in the risk of radiographic progression or death after treatment with Lynparza in combination with Johnson & Johnson’s Zytiga (abiraterone) and prednisone or prednisolone.
The survival benefit was significant relative to a corresponding placebo-based regimen.
Patients in the Lynparza arm had a mean radiographic progression-free survival (rPFS) of 24.8 months, while placebo counterparts only saw an rPFS of 16.6 months.
When it accepted Lynparza’s sNDA, the FDA also granted the agency’s Priority Review designation. In December 2022, however, the regulator extended the review period for Lynparza and pushed its target action date back by three months, citing the need for more time to evaluate the submission. In March, the FDA announced it would need to convene the ODAC.
In briefing documents published before the meeting, the FDA flagged several issues with Lynparza’s sNDA, particularly the “significant design flaw” of the Phase III PROpel study, which Merck and AstraZeneca drew heavily on for the application.
Patients enrolled in PROpel’s intention-to-treat population were not assessed for their BRCA or (Homologous Recombination Repair) HRR mutations, nor did the study include pre-specified analyses based on these genetic alterations. Moreover, post-hoc assessments by the FDA found that Lynparza’s rPFS benefits were mostly due to its effects in patients with the BRCA mutation.
Among those without the mutation, however, the Lynparza regimen only improved rPFS by a non-significant 15%.
At Friday’s ODAC meeting, external experts agreed with the regulator’s staffers.
“It is difficult to understand how patient-driven research could intentionally decide to exclude BRCA or HRR status, not stratify by these biomarkers and exclude pre-specified analyses by biomarker status,” Terrence Kungel, chairman emeritus, Maine Coalition to Fight Prostate Cancer, said during the meeting to explain his vote supporting the narrow approval for Lynparza.
He also found issue with PROpel’s use of rPFS, which he said had “very little predictive value” of overall survival (OS) in non-BRCA patients, especially given the high mortality rates in mCRPC.
“OS rates are normally determined within five years so why use rPFS especially when it appears to be misleading?” Kungel said. The PROpel randomized Phase III trial design “was inappropriate,” he added.
Susan Galbraith, executive vice president of oncology R&D at AstraZeneca, said in a statement that while the company was “pleased with the recognition of the benefit of Lynparza plus abiraterone” for patients with BRCA-mutated mCRPC, it was disappointed with the ODAC vote and believes the PROpel trial “demonstrated the clinically meaningful benefit for this combination in a broad population of patients regardless of biomarker status.”
Tristan Manalac is an independent science writer based in metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.
