FDA Approves Olaparib Plus Abiraterone and Prednisone or Prednisolone for BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer

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On May 31, the U.S. Food and Drug Administration (FDA) approved olaparib (Lynparza) in combination with abiraterone and prednisone (or prednisolone) for adult patients with deleterious or suspected deleterious BRCA-mutated metastatic castration-resistant prostate cancer, as determined by an FDA-approved companion diagnostic test.

PROpel Trial

Efficacy was evaluated in the PROpel trial ( identifier NCT03732820), which enrolled 796 patients with metastatic castration-resistant prostate cancer. Patients were randomly assigned 1:1 to receive either olaparib with abiraterone or placebo with abiraterone; they also received prednisone or prednisolone.

Patients were required to have undergone a prior orchiectomy or, if orchiectomy was not performed, to have received gonadotropin-releasing hormone (GnRH) analogs. Patients who had received prior systemic therapy for metastatic castration-resistant prostate cancer were excluded; however, prior treatment with docetaxel for metastatic hormone-sensitive prostate cancer was allowed. Random assignment was stratified by site of metastases and prior receipt of docetaxel. All available clinical samples were retrospectively tested for BRCA mutational status with the FoundationOne CDx and FoundationOne Liquid CDx tests.

The major efficacy outcome measure was investigator-assessed radiologic progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 for soft-tissue lesions, and Prostate Cancer Working Group criteria for bone lesions. Overall survival was an additional endpoint.

A statistically significant improvement in radiologic progression-free survival was observed for olaparib with abiraterone compared to placebo with abiraterone in the intent-to-treat (ITT) population. An exploratory subgroup analysis in the 85 patients with BRCA-mutated disease (11% of ITT population) demonstrated a median radiologic progression-free survival that was not reached in the olaparib with abiraterone arm compared to 8 months (95% confidence interval [CI] = 6–15 months) for those receiving placebo with abiraterone (hazard ratio [HR] = 0.24, 95% CI = 0.12–0.45). The overall survival hazard ratio 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 radiologic progression-free survival hazard ratio was 0.77 (95% CI = 0.63–0.96) and the overall survival hazard ratio was 0.92 (95% CI = 0.74–1.14), suggesting that the improvement in radiologic progression-free survival observed in the ITT population was primarily 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; the recommended 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.

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