FDA approves olaparib/abiraterone combination for BRCA+ metastatic castration-resistant prostate cancer

The FDA has approved olaparib (Lynparza) plus abiraterone and prednisone or prednisolone for the treatment of patients with deleterious or suspected BRCA-mutated metastatic castration-resistant prostate cancer, as determined by an accompanying FDA-approved diagnostic test.¹

The regulatory decision is supported by results from the Phase 3 PROpel study (NCT03732820) in which the olaparib regimen significantly improved radiographic progression-free survival (rPFS) compared to placebo and abiraterone alone in the intent-to-treat (ITT) population ) and in a subset of hosting patients BRCA extension mutations (n ​​= 85). In the BRCA extension-mutated, rPFS was not yet achieved in the experimental arm compared with 8 months (95% CI, 6-15) in the control arm (HR, 0.24; 95% CI, 0.12-0.45). Median overall survival (OS) has not yet been reached in the olaparib arm compared with 23 months (95% CI, 18-34) in the control arm (HR, 0.30; 95% CI, 0.15-0.59 ).

Specifically, data from an exploratory analysis of 711 patients without BRCA extension mutations showed that the hazard ratio (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), which suggests that the improvement is mainly attributed to those harboring the mutation.

PROPEL

The randomized, double-blind, placebo-controlled, multicenter study enrolled patients with histologically or cytologically confirmed prostate adenocarcinoma who had at least 1 metastatic lesion documented on bone scan or computed tomography or magnetic resonance imaging. Patients had to be at least 18 years of age and not previously treated with abiraterone. Prior docetaxel for localized or metastatic hormone-sensitive prostate cancer (mHSPC) was allowed.²

A total of 796 participants were randomly assigned 1:1 to receive olaparib 300 mg twice daily plus abiraterone 1000 mg daily (n = 399) or placebo plus abiraterone (n = 397). All patients received prednisone or prednisolone 5 mg twice daily, as well as a gonadotropin-releasing hormone analogue or a previous bilateral orchidectomy. Olaparib treatment was continued until objective radiographic progression as assessed by the investigator or intolerable toxicity.

Stratification factors included metastases (bone only vs visceral vs other) and docetaxel treatment at mHSPC stage (yes vs no).

rPFS by RECIST v1.1 and Prostate Cancer Working Group Criteria served as the primary endpoint of the study, and OS was a key secondary endpoint.

Of 796 patients, 11% had a BRCA extension mutation. Among 85 patients with BRCA extension-mutant disease, median age was 68 years (range, 43-85) and more than half (67%) were 65 years or older. The majority (72%) of patients were white and had an ECOG performance status of 0 (66%). 25% of patients had previously received docetaxel. Approximately half (53%) of the patients had bone metastases only, 15% visceral metastases, and 32% other metastases.

The most common toxicities experienced by 10% or more of patients receiving the olaparib regimen included anemia (48%), fatigue (38%), nausea (30%), diarrhea (19%), decreased appetite (16 %), lymphopenia (14%), dizziness (14%) and abdominal pain (13%).¹ Additionally, 18% of patients required at least 1 blood transfusion and 12% needed multiple transfusions.

References

1. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. FDA. May 31, 2023. Accessed May 31, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic -castration
2. Olaparib (Lynparza). Prescribing information. AstraZeneca. Updated May 2023. Accessed May 31, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/208558s025lbl.pdf