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FDA Expert Panel Recommends Lynparza, Zytiga Combo Only for BRCA1/2-Mutated Prostate Cancer Patients

NEW YORK – The US Food and Drug Administration's Oncologic Drugs Advisory Committee on Friday voted in favor of the agency approving AstraZeneca's Lynparza (olaparib), Janssen's Zytiga (abiraterone), and corticosteroids as a combination treatment for metastatic castration-resistant prostate cancer (mCRPC) patients harboring BRCA1/2 mutations, but not for a broader, biomarker-unselected population.

AstraZeneca, which sells the PARP inhibitor Lynparza with Merck, filed a supplemental new drug application last August seeking approval for Lynparza plus Zytiga and prednisone or prednisolone as a treatment for patients with BRCA1/2-wild-type and BRCA1/2-mutated mCRPC based on results of the Phase III PROpel trial. However, after reviewing the data, the FDA's expert committee voted 11 to 1, with one person abstaining, in support of the agency limiting the Lynparza combination to mCRPC patients who have BRCA1/2 mutations.

"Novel treatment options are urgently needed for patients with metastatic castration-resistant prostate cancer. 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," Susan Galbraith, AstraZeneca's executive VP of oncology R&D, said in a statement. "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."

In that study, treatment benefit was greatest in patients with mutations in BRCA1/2 or other genes involved in homologous recombination repair (HRR). In the overall intention-to-treat population, there was a trend toward overall survival benefit among patients receiving Lynparza and Zytiga with prednisone or prednisolone, with a median overall survival of 42.1 months versus 34.7 months among patients who received placebo. However, the 7.4-month difference between arms was not statistically significant.

Median overall survival had not yet been reached at final analysis among patients with HRR-mutations treated with the Lynparza combination, compared with 28.5 months in the placebo group. Meanwhile, patients without HRR mutations had median overall survival of 42.1 months compared to 38.9 months in the placebo group. In patients with BRCA1/2 mutations, similarly, median overall survival had not yet been reached at the time of final analysis, compared to 23.0 months in the placebo group. Patients without BRCA1/2 mutations had a median overall survival of 39.6 months compared to 38 months for those on placebo.

Lynparza is currently approved in the US as a monotherapy for mCRPC patients with HRR gene deficiencies including BRCA1/2 mutations, and in Europe, the drug is approved only for mCRPC patients with BRCA1/2 mutations. In December, the European Commission approved the Lynparza-Zytiga-prednisone combination based on the PROpel data for mCRPC patients who cannot receive chemotherapy.

In a conference call to discuss AstraZeneca's Q1 2023 financial results last Thursday, Galbraith had said that the company planned to make a strong case to ODAC for the combination to be approved for a broad mCRPC population. "If you look at the totality of the data and the totality of the secondary endpoints, it supports a good benefit-risk profile for [Lynparza] in this patient population in combination with [Zytiga]," Galbraith said.