After a panel of independent experts endorsed a narrow approval for AstraZeneca and Merck’s Lynparza in metastatic castration-resistant prostate cancer (mCRPC), the FDA has followed suit.Lynparza can now be used in combination with Johnson & Johnson’s Zytiga and a corticosteroid to treat patients with mCRPC whose tumors have BRCA mutations.
The approval limits Lynparza's use in the mCRPC population to about 10% of patients. The FDA's decision comes after agency staffers and a committee of outside experts argued that the drug only showed a favorable risk-benefit in that population.
Results from the phase 3 PROpel trial showed that the combo cut the risk of disease progression or death by 34% compared with solo Zytiga in newly diagnosed mCRPC patients regardless of mutation status. However, the FDA noted a “significant design flaw” with the trial in its briefing documents ahead of the meeting. Specifically, the FDA argued that the study didn’t enroll patients in separate cohorts based on biomarker status and that it didn't incorporate subgroup analyses based on mutations.
The FDA found that 11% of trial participants who had the BRCA mutations seemed to drive Lynparza’s benefit. In those patients, the drug improved progression-free survival by 76% and cut down the risk of death by 70%. The companies sought to show that the results in the larger non-BRCA group were clinically meaningful, but the FDA argued the efficacy there was "modest."
The advisory committee experts also flagged uncertainty in the non-BRCA population, leading to the vote for the limited approval.
The approval “underscores the importance of BRCA testing at metastatic diagnosis,” AZ's executive vice president of oncology, Dave Fredickson said in a statement. There's a “critical unmet need for new first-line treatment options for patients with BRCA-mutated metastatic castration-resistant prostate cancer," he added.
The combo is approved for the entire mCRPC population in Europe. In the U.S., it's also used to treat patients with homologous recombination repair gene-mutated mCRPC who have progressed after prior treatment with certain other drugs.
Meanwhile, AZ and Merck are seeking to further expand the drug's reach. Lynparza recently posted a trial win in patients with newly diagnosed, advanced ovarian cancer without BRCA mutations in combination with AZ’s Imfinzi plus chemotherapy and bevacizumab. More recently in May, the Lynparza and Imfinzi combination showed positive findings in endometrial cancer, as well.

Reference: https://www.astrazeneca.com/media-centre/press-releases/2023/odac-vote-on-lynparza-combo-in-prostate-cancer.html