Update on FDA Advisory Committee Vote on LYNPARZA® (olaparib) Plus Abiraterone and Prednisone or Prednisolone in First-Line Metastatic Castration-Resistant Prostate Cancer
RAHWAY, N.J.–(BUSINESS WIRE)– Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the U.S. Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC), by a vote of 11 to 1 with one abstention, supported FDA approval of LYNPARZA plus abiraterone and prednisone or prednisolone (abi/pred) for the first-line treatment of adult patients with BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). The committee voted that FDA should restrict use of LYNPARZA plus abi/pred to these BRCAm mCRPC patients, recommending against approval beyond this patient population.
In August 2022, the FDA accepted the supplemental New Drug Application for LYNPARZA plus abi/pred for priority review based on positive results from the pivotal Phase 3 PROpel trial, which were also published in NEJM Evidence. The ODAC provides the FDA with independent, expert advice and recommendations on marketed and investigational medicines for use in the treatment of cancer. The FDA is not bound by the committee’s guidance but takes its advice into consideration. AstraZeneca and Merck will continue to work with the FDA as the agency completes its review of the application.
Neal Shore, chief medical officer of urology and surgical oncology for GenesisCare, US and PROpel trial investigator, said, “Today’s recommendation by the ODAC is disappointing news for clinicians and prostate cancer patients alike. Preventing or delaying radiographic progression is an important clinical endpoint in assessing oncologic treatment and is very relevant to patients, their caregivers and their families. It is essential that physicians and their patients have an opportunity to choose treatment with the goal of optimizing cancer care outcomes.”
Susan Galbraith, executive vice president, oncology R&D, AstraZeneca, said, “Novel treatments 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. We strongly believe in the results of the PROpel trial, which demonstrated a clinically meaningful benefit for this combination in a broad population of patients regardless of biomarker status.”
Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, said, “With the incidence and mortality of prostate cancer set to double in the coming decades, it is critical that we bring new treatment options with the potential to reduce the risk of disease progression or death to patients at the earliest possible moment in their care. Though we are pleased that the ODAC recommended LYNPARZA for patients with mCRPC who have BRCA mutations, we believe in the potential of LYNPARZA plus abi/pred for a broad range of patients with mCRPC, based on the results of PROpel. We look forward to the outcome of the FDA’s review of the application.”
Results from the PROpel trial showed a statistically significant and clinically meaningful 34% reduction in the risk of radiographic disease progression or death with LYNPARZA plus abi/pred (HR=0.66 [95% CI, 0.54-0.81]; p<0.001) versus placebo plus abi/pred in patients with mCRPC. Median radiographic progression-free survival (rPFS) was 24.8 months versus 16.6 months, respectively.
Further results from the final pre-specified overall survival (OS) analysis were presented at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium (maturity 47.9%, HR=0.81 [95% CI, 0.67-1.00]; p=0.0544). While the observed 7.4-month numerical increase in median OS did not achieve statistical significance, the totality of the efficacy results from PROpel build on the meaningful gains achieved for patients in this setting versus patients treated with abi/pred alone, a current standard of care.
In exploratory analyses of the BRCAm subgroup, patients in the LYNPARZA plus abi/pred arm had fewer rPFS (HR=0.23 [95% CI, 0.12-0.43]) and OS (HR=0.29 [95% CI, 0.14-0.56]) events versus those receiving placebo plus abi/pred. In the subgroup of patients who tested negative for BRCAm by either a tumor tissue-based test or a circulating tumor DNA test, patients in the LYNPARZA plus abi/pred arm also had fewer rPFS events (HR=0.76 [95% CI, 0.61-0.94] versus those receiving placebo plus abi/pred, as well as modestly fewer OS events (HR=0.91 [95% CI, 0.73-1.13]).
The safety and tolerability of LYNPARZA plus abi/pred in PROpel was in line with that observed in prior clinical trials and the known profiles of the individual medicines.The most common adverse events (AEs) (≥20%) were anemia (49.7%), fatigue (38.7%), nausea (30.7%), back pain (21.6%) and diarrhea (20.6%). Grade ≥3 AEs were anemia (16.1%), hypertension (3.8%), urinary tract infection (2.5%), fatigue (2.5%), vomiting (1.5%), diarrhea (1.3%), decreased appetite (1%), back pain (1%) and nausea (0.3%). Approximately 17% of patients who received LYNPARZA in combination with abi/pred discontinued treatment due to an AE.
LYNPARZA in combination with abi/pred is approved in the European Union and several other countries for the treatment of adult patients with mCRPC based on the PROpel trial. In the U.S., LYNPARZA is currently approved for patients with homologous recombination repair gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone based on the Phase 3 PROfound trial. For that U.S. indication, patients are selected for therapy based on an FDA-approved companion diagnostic for LYNPARZA.