Niraparib and Abiraterone Acetate Plus Prednisone Approved for BRCA-Mutated Metastatic CRPC
The FDA has approved the fixed dose combination of niraparib and abiraterone acetate (Akeega™, Janssen Biotech), plus prednisone, for adult patients with deleterious or suspected deleterious BRCA-mutated metastatic castration-resistant prostate cancer (CRPC), as identified by an FDA-approved test.
Why it matters: "Metastatic CRPC remains a lethal disease, highlighting a need for new therapies," wrote Kim N. Chi, MD, Professor in the Division of Medical Oncology at the University of British Columbia, and colleagues, in their published results of the MAGNITUDE trial (NCT03748641), on which approval was based. "Deleterious gene alterations, particularly in BRCA1/2, can sensitize prostate cancer cells to inhibition of poly-ADP ribose polymerase (PARP) through a mechanism of synthetic lethality. Inhibition of androgen receptor (AR) signaling can also result in downregulated expression of DNA repair genes and sensitize prostate cancer cells to PARP inhibition. Therefore, we hypothesized that targeting both oncogenic pathways concurrently may improve outcomes in patients with and without homologous recombination repair (HRR) alterations."
What they studied: Efficacy was investigated in Cohort 1 of a double-blind, placebo-controlled trial that enrolled 423 patients with HRR gene–mutated metastatic CRPC. Patients were randomized 1:1 to receive 200 mg niraparib, 1,000 mg abiraterone acetate, and 10 mg prednisone daily, or placebo and abiraterone acetate plus prednisone daily.
Patients were eligible if they had not received prior systemic therapy for metastatic CRPC, with the exception of up to four months of prior abiraterone acetate and prednisone and ongoing androgen deprivation therapy (ADT). Prior docetaxel and AR-targeted therapies in early disease settings were allowed. Patients were required to be receiving gonadotropin-release hormone (GnRH) analogues or to have had a prior orchiectomy. Randomization was stratified based on BRCA status, prior docetaxel, prior AR-targeted therapy, and prior abiraterone acetate plus prednisone. Among the 423 patients on the trial, 53% had a prospectively determined BRCA gene mutation.
The primary end point was radiographic progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for soft tissue and Prostate Cancer Working Group 3 criteria for bone, as assessed by blinded independent central review. The secondary end point was overall survival.
What they found: Among patients with BRCA-mutated metastatic CRPC, niraparib and abiraterone acetate plus prednisone produced a statistically significant improvement in radiographic progression-free survival with a median of 16.6 months versus 10.9 months for those receiving placebo and abiraterone acetate plus prednisone. In an exploratory overall survival analysis in the BRCA-mutated population, niraparib produced a median overall survival of 30.4 months versus 28.6 months for placebo.
A statistically significant improvement in radiographic progression-free survival was observed in the overall Cohort 1 intention-to-treat (ITT) HRR population (hazard ratio 0.73). However, in the subgroup of 198 patients with non-BRCA HRR mutations, the hazard ratio for radiographic progression-free survival was 0.99, suggesting the ITT HRR gene–mutated population's improvement was attributed primarily to the results observed in the BRCA mutation subgroup.
Adverse events: The most common adverse events and laboratory abnormalities experienced by ≥20% of patients included decreased hemoglobin, decreased lymphocytes, decreased white blood cells, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, and increased aspartate aminotransferase (AST). Blood transfusions were needed by 27% of patients who received niraparib and abiraterone acetate plus prednisone in Cohort 1, and 11% required multiple transfusions.
What to know: Coadministration with strong CYP3A4 inducers and CYP2D6 substrates should be avoided for patients receiving niraparib and abiraterone acetate plus prednisone.
What's next: Detailed biomarker analyses will be reported for the combination in the future.
Conclusion: "In summary, HRR-positive patients with metastatic CRPC derived significant and clinically meaningful benefit from niraparib and abiraterone acetate plus prednisone," concluded Dr. Chi and colleagues. "The safety profile of the combination was manageable, with no new safety signals that affected the benefit-risk profile. These data underscore the need to test for HRR gene alterations for metastatic prostate cancer and support the use of niraparib and abiraterone acetate plus prednisone as first-line combination therapy for these patients with particularly poor prognoses."
Instructions: The recommended dosage is 200 mg of niraparib, 1,000 mg of abiraterone acetate, and 10 mg of prednisone taken orally once daily until disease progression or unacceptable toxicity. Patients should also receive a GnRH analog concurrently or should have had a prior bilateral orchiectomy.
For More Information
Chi KN, Rathkopf D, Smith MR, et al (2023). Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol, 41(18)3339-3351. DOI:10.1200/JCO.22.01649
Clinicaltrials.gov (2023). A study of niraparib in combination with abiraterone acetate and prednisone versus abiraterone acetate and prednisone for treatment of participants with metastatic prostate cancer (MAGNITUDE). NLM identifier: NCT03748641.
Akeega™ (niraparib and abiraterone acetate) prescribing information (2023). Janssen Biotech. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216793s000lbl.pdf
US Food & Drug Administration (2023). FDA approves niraparib and abiraterone acetate plus prednisone for BRCA-mutated metastatic castration-resistant prostate cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-and-abiraterone-acetate-plus-prednisone-brca-mutated-metastatic-castration
Image credit: Otis Brawley. Licensed under: Public Domain.