FDA Grants Regular Approval to Rucaparib for BRCA-Mutated mCRPC

The FDA has granted regular approval to rucaparib (Rubraca) for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC).¹

This regulatory decision converts the agency's May 2020 accelerated approval of the PARP inhibitor to a full approval.² The determination is based on data from the phase 3 TRITON3 trial (NCT02975934), which demonstrated a statistically significant improvement in radiographic progression-free survival (rPFS) for rucaparib compared with a physician’s choice of therapy in patients who had progressed on an androgen receptor (AR) pathway inhibitor.¹

Validation of Clinical Benefit

The multicenter, open-label, randomized TRITON3 trial served as the confirmatory study required to verify the clinical benefit of rucaparib. The trial enrolled 405 patients with mCRPC harboring BRCA1, BRCA2, or ATM alterations who had previously been treated with a second-generation AR pathway inhibitor (such as abiraterone [Zytiga], enzalutamide [Xtandi], or apalutamide [Erleada]) but had not yet received chemotherapy for metastatic disease.

Patients were randomized 2:1 to receive oral rucaparib 600 mg twice daily or a physician’s choice of control therapy, which included docetaxel, abiraterone, or enzalutamide.

Among the cohort of patients with BRCA mutations, rucaparib elicited a median rPFS of 11.2 months (95% CI, 9.2–13.8), compared with 6.4 months (95% CI, 5.4–8.3) in the control arm. This resulted in a hazard ratio (HR) of 0.50 (95% CI, 0.36–0.69; P <.001), indicating a 50% reduction in the risk of radiographic progression or death.

In the intention-to-treat population, which included patients with ATM mutations, the median rPFS was 10.2 months in the rucaparib group vs 6.4 months in the control group (HR, 0.61; 95% CI, 0.47–0.80; P <.001). However, exploratory analyses suggested the benefit was primarily driven by the BRCA subgroup, as patients with ATM mutations did not show a statistically significant improvement in rPFS compared to the control arm.

Safety Profile and Administration

The safety profile observed in TRITON3 was consistent with previous reports for rucaparib. The most common adverse events (AEs; occurring in ≥20% of patients) included fatigue (61%), nausea, anemia, decreased appetite, diarrhea, vomiting, and thrombocytopenia.

Grade 3 or higher AEs were reported, with anemia being the most frequent severe event in the experimental arm. Clinicians are advised to monitor complete blood counts at baseline and monthly thereafter, and to interrupt or reduce dosing for persistent grade 3 toxicity.

The recommended dose of rucaparib remains 600 mg taken orally twice daily with or without food. Patients must be selected for therapy based on an FDA-approved companion diagnostic for BRCA alterations.

Clinical Implications

The approval solidifies the role of PARP inhibitors in the management of mCRPC, particularly for patients with homologous recombination repair (HRR) gene deficiencies.

This approval provides a chemotherapy-free option for eligible patients in the second-line setting (post-AR pathway inhibitor), addressing a significant unmet need for personalized therapeutic strategies in advanced prostate cancer.

REFERENCES

1. FDA grants regular approval to rucaparib for metastatic castration-resistant prostate cancer. News release. US FDA. December 17, 2025. Accessed December 17, 2025. https://tinyurl.com/3x6anj2k

2. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. News release. US FDA. May 15, 2020. Accessed December 17, 2025. https://tinyurl.com/29rxz7y7