On May 31, 2023, the FDA approved #olaparib with #abiraterone and prednisone (or prednisolone) as first line therapy for adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant #prostate cancer (#mCRPC) after failure of primary ADT.

The approval is founded on the results of the randomized, double-blind, placebo-controlled Phase III PROpel trial which included 796 patients with mCRPC undergoing first-line treatment after failure of primary ADT, regardless of HRR status. Patients were randomized 1:1 to receive olaparib (300 mg twice daily) or placebo, and abiraterone (1000 mg once daily) + prednisone or prednisolone (5 mg twice daily). The primary endpoint was investigator-assessed rPFS with multiple secondary endpoints, including overall survival.

At the interim analysis, PROpel met its primary objective, demonstrating significant improvement in rPFS for olaparib + abiraterone vs placebo + abiraterone in the intent-to-treat (ITT) population (HR 0.66, 95% CI 0.54-0.81) irrespective of HRR status. An exploratory subgroup analysis in the 85 patients with BRCA-mutated disease (11% of ITT population) demonstrated a median rPFS that was NR in the olaparib with abiraterone arm compared to 8 months for those receiving placebo with abiraterone with an impressive HR of 0.24 (95% CI = 0.12–0.45). The HR of OS in these patients was 0.30 (95% CI = 0.15–0.59). In the 711 patients (89% of ITT population) without a BRCA mutation, the rPFS HR was 0.77 (95% CI = 0.63–0.96) and the OS HR was 0.92 (95% CI = 0.74–1.14), suggesting that the improvement in rPFS detected in the ITT population was chiefly attributable to patients with BRCA-mutated disease.

The most common adverse reactions (≥ 10%) in patients receiving olaparib plus abiraterone were anemia (48%), fatigue (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%), and abdominal pain (13%). Seventy-two patients (18%) required at least one blood transfusion and 46 (12%) required multiple transfusions.

The recommended olaparib dose is 300 mg taken orally twice daily with or without food; and for abiraterone dose is 1,000 mg taken orally once daily. Abiraterone should be administered with prednisone or prednisolone at 5 mg orally twice daily. Patients should also receive a GnRH analog concurrently or should have undergone a prior bilateral orchiectomy.