On 13 May 2023, the US Food and Drug Administration (FDA) approved olaparib (Lynparza, AstraZeneca Pharmaceuticals LP) with abiraterone and prednisone (or prednisolone) for adult patients with deleterious or suspected deleterious BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test.

Full prescribing information for Lynparza is available here.

Efficacy was evaluated in the PROpel study (NCT03732820) that enroled 796 patients with mCRPC, Patients were randomised (1:1) to receive either olaparib with abiraterone or placebo with abiraterone and also received prednisone or prednisolone. Patients were required to have a prior orchiectomy and, if not performed, received gonadotropin-releasing hormone analogues (GnRH). Patients with prior systemic therapy for mCRPC were excluded; however, prior docetaxel for metastatic hormone-sensitive prostate cancer was allowed. Randomisation was stratified by site of metastases and prior docetaxel.

All available clinical samples were retrospectively tested for BRCA mutational status with the FoundationOne CDx and FoundationOne Liquid CDx tests (Foundation Medicine, Inc.).

The major efficacy outcome measure was investigator-assessed radiological progression-free survival (rPFS) per RECIST v1.1 for soft tissue and Prostate Cancer Working Group criteria for bone lesions. Overall survival (OS) was an additional endpoint.

A statistically significant improvement in rPFS for olaparib with abiraterone compared to placebo with abiraterone in the intent-to-treat (ITT) population was observed. An exploratory subgroup analysis in the 85 patients with BRCA-mutated (11% of ITT population) demonstrated a median rPFS that was not reached in the olaparib with abiraterone arm compared to 8 months (95% confidence interval [CI] 6, 15) for those receiving placebo with abiraterone (hazard ratio [HR] 0.24; 95% CI 0.12, 0.45). The HR for OS in these patients was 0.30 (95% CI 0.15, 0.59). In the 711 patients (89% of ITT population) without BRCA mutation, the HR for rPFS was 0.77 (95% CI 0.63, 0.96) and the HR for OS was 0.92 (95% CI 0.74, 1.14), suggesting that the improvement in rPFS observed in the ITT population was primarily attributable to patients with BRCA mutation.

The most common adverse reactions (≥10%) in patients receiving olaparib plus abiraterone were anaemia (48%), fatigue (38%), nausea (30%), diarrhoea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%), and abdominal pain (13%). In total, 72 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. The recommended abiraterone dose is 1000 mg taken orally once daily. Abiraterone should be administered with prednisone or prednisolone 5 mg orally twice daily. Patients should also receive a GnRH analogue concurrently or should have had a prior bilateral orchiectomy.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact FDA’s Oncology Center of Excellence Project Facilitate.