Olaparib Approved With Abiraterone and Prednisone, or Prednisolone, for BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer

Prostate cancer.

The FDA has granted approval to olaparib (Lynparza®, AstraZeneca Pharmaceuticals) with abiraterone and either prednisone or prednisolone for treatment of deleterious or suspected deleterious breast cancer gene–mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as detected by an FDA-approved companion diagnostic test.  

Why it matters: “Current treatment options in the first-line setting of mCRPC mainly comprise next-generation hormonal agents (eg, abiraterone and enzalutamide) or docetaxel chemotherapy,” wrote Noel W. Clarke, MBBS, Consultant Urologist at the Salford Royal Hospital in Manchester, the United Kingdom, and the coauthors of the PROpel trial (NCT03732820), on which approval was based. “Despite the reported activity of these agents, overall survival in clinical trial settings is approximately three years. In the real-world setting, overall survival is shorter, and approximately 50% of patients receive only one life-prolonging therapy.”

What they studied: Safety and efficacy were studied in the phase 3, double-blind trial in which approximately 796 patients were randomized 1:1 to receive either olaparib with abiraterone or placebo with abiraterone. Both arms also received prednisone or prednisolone. Key inclusion criteria required a prior orchiectomy; if not performed, those who received gonadotropin-releasing hormone (GnRH) analogs were also included. The primary end point measured was radiological progression-free survival per RECIST v1.1 for soft tissue and Prostate Cancer Working Group criteria for bone lesions, with a secondary end point of overall survival.

What they found:

  • Radiological progression-free survival saw a statistically significant improvement in those receiving olaparib with abiraterone compared with those receiving placebo with abiraterone
  • In an exploratory intent-to-treat subgroup analysis of 85 patients with BRCA mutations, median radiological progression-free survival was not reached in the olaparib with abiraterone arm compared with a median of 8 months in the placebo with abiraterone arm, for an overall survival hazard ratio of 0.30
  • In an analysis of 711 patients without BRCA mutations, the radiological progression-free survival hazard ratio was 0.77 and the overall survival hazard ratio was 0.92, which suggests that the improvement in radiographic progression-free survival seen in the intention-to-treat population was primarily driven by patients with BRCAm

Adverse events: The most common adverse events in ≥10% of 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%). Eighteen percent of patients required at least one blood transfusion and 12% required multiple transfusions.

Conclusion: “The overall results of PROpel demonstrate the clinical benefits of olaparib in combination with abiraterone in the first-line treatment of a broad, homologous recombination repair gene mutation (HRRm)–unselected population of patients with mCRPC,” concluded Dr. Clarke and colleagues in their concluding thoughts of their trial publication.

Instructions: The recommended dosage of olaparib is 300 mg, taken orally twice daily with or without food, in addition to the recommended dosage of 100 mg abiraterone, taken orally once daily. Abiraterone should be administered with the recommended dosage of prednisone or prednisolone, 5 mg orally twice daily. Patients are recommended to receive a GnRH analog concurrently or should have had a prior bilateral orchiectomy.

For More Information

Clarke N, Armstrong A, Thiery-Vuillemin A, et al (2022). abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evidence, 1(9). DOI:10.1056/EVIDoa2200043

Clinicaltrials.gov (2023). Study on olaparib plus abiraterone as first-line therapy in men with metastatic castration-resistant prostate cancer. NLM identifier: NCT03732820.

Lynparza® (olaparib) prescribing information (2023). AstraZeneca Pharmaceuticals. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/208558s025lbl.pdf

US Food and Drug Administration (2023). FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic-castration

Image credit: Nephron. Licensed under CC BY-SA 3.0


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