On May 31, 2023, the FDA approved a new indication for olaparib (Lynparza; AstraZeneca), a poly (ADP-ribose) polymerase inhibitor, in combination with abiraterone (Zytiga; Astellas) and prednisone (or prednisolone) for adults with deleterious or suspected deleterious BRCA mutation–positive, metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved test.
Olaparib was previously approved as monotherapy for patients with mCRPC and deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutation–positive mCRPC whose disease progressed after previous treatment. The drug also has received various approvals for the treatment of ovarian, breast, and pancreatic cancers.
The new approval was based on results from the phase 3 PROpel clinical trial of 796 patients with mCRPC. Patients were randomized (1:1) to receive olaparib plus abiraterone or placebo plus abiraterone, and they also received prednisone or prednisolone. To be included in the trial, patients had to have a previous orchiectomy or, if not, had to have received gonadotropin-releasing hormone (GnRH) analogs. Patients were excluded if they had received systemic therapy for mCRPC, but previous treatment with docetaxel for metastatic hormone-sensitive prostate cancer was allowed. Randomization was stratified by previous docetaxel treatment and site of metastases. Retrospective testing for BRCA mutational status, with the FoundationOne CDx and FoundationOne Liquid CDx tests, was performed on all available clinical samples.
The major efficacy measure was investigator-assessed radiologic progression-free survival (PFS), with overall survival (OS) as an additional end point.
Patients treated with olaparib plus abiraterone had a significant improvement in radiologic PFS compared with those treated with placebo plus abiraterone in the intent-to-treat (ITT) population. In the 85 patients with a BRCA mutation (11% of the ITT population), an exploratory subgroup analysis revealed a median radiologic PFS that was not reached with olaparib plus abiraterone compared with 8 months (95% confidence interval [CI], 6-15) with placebo plus abiraterone (hazard ratio [HR], 0.24; 95% CI, 0.12-0.45). In this subgroup, the OS HR was 0.3 (95% CI, 0.15-0.59). The subgroup of patients without a BRCA mutation (n=711; 89% of ITT population) had a radiologic PFS HR of 0.77 (95% CI, 0.63-0.96) and an OS HR of 0.92 (95% CI, 0.74-1.14), suggesting that the radiologic PFS improvement in the ITT population was mainly attributable to patients with the BRCA mutation.
The most common (≥10%) adverse events with olaparib plus abiraterone were anemia (48%), fatigue (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%), and abdominal pain (13%). A total of 72 (18%) patients needed ≥1 blood transfusions and 46 (12%) needed several transfusions.
The recommended dose of olaparib is 300 mg taken orally twice daily, with or without food. The recommended dose of abiraterone 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 analog concurrently or should have had a bilateral orchiectomy.