FDA Grants Full Approval to Rucaparib for BRCA Mutation–Associated mCRPC

The FDA has granted regular approval to rucaparib (Rubraca) for the treatment of adult patients with BRCA mutation–associated metastatic castration-resistant prostate cancer (mCRPC) previously treated with an androgen receptor–directed therapy.1

The decision was supported by data from the phase 3 TRITON3 trial (NCT02975934) in which rucaparib (n = 201) significantly improved radiographic progression-free survival vs physician's choice of treatment (n = 101) in those with BRCA mutations, at a median of 11.2 months (95% CI, 9.2-13.8) and 6.4 months (95% CI, 5.4-8.3), respectively (HR, 0.50; 95% CI, 0.36-0.69; P < .0001).

Moreover, the median overall survival with rucaparib was 23.2 months (95% CI, 19.1-25.2) vs 21.2 months (95% CI, 18.0-23.1) with physician's choice of treatment (HR, 0.91; 95% CI, 0.68-1.20).

Findings from an exploratory analysis revealed that in a subgroup of patients with ATM mutations, the hazard ratios for rPFS and OS were 0.95 (95% CI, 18.0-23.1) and 1.21 (95% CI, 0.77-1.90), which suggested that the overall improvement was primarily attributed to the data seen in the subset of patients whose tumors harbored BRCA mutations.

Previously, in May 2020, the FDA granted accelerated approval to rucaparib (Rubraca) for use in patients with deleterious BRCA mutation–associated mCRPC who previously received androgen receptor–directed therapy and a taxane-based chemotherapy.2 The decision was supported by findings from the phase 2 TRITON2 trial (NCT02952534), in which rucaparib elicited a confirmed ORR of 44% (95% CI, 31%-57%) with a median duration of response that was not evaluable (NE; 95% CI, 6.4-NE).

What did the TRITON3 study examine?

The open-label, randomized, phase 3 trial included patients with chemotherapy-naive mCRPC and BRCA1/2 or ATM alterations who had prior exposure to a second-generation ARPI in any setting.3 Participants were randomized in a 2:1 fashion to receive rucaparib at a twice-daily dose of 600 mg (n = 270) or physician’s choice of therapy (n = 135), which could have been docetaxel (n = 75) or a second-generation ARPI such as abiraterone acetate (Zytiga) or enzalutamide (Xtandi; n = 60).

The primary end point was rPFS by blinded independent central review (BICR), and key secondary end points included overall survival (OS) and objective response rate (ORR) by BICR.

What prior data have been reported from TRITON3?

Primary data from the study showed that at 62 months, rucaparib significantly prolonged imaging-based PFS vs physician’s choice.4 In the intention-to-treat population, the median duration of imaging-based PFS was 10.2 months (95% CI, 8.3-11.2) with rucaparib vs 6.4 months (95% CI, 5.6-8.2) with physician’s choice of therapy (HR, 0.61; 95% CI, 0.47-0.80; P < .001). In the subgroup of patients with ATM mutations, the median duration of imaging-based PFS with the respective approaches was 8.1 months (95% CI, 5.5-8.3) and 6.8 months (95% CI, 4.0-10.4; HR, 0.95; 95% CI, 0.59-1.52). Moreover, in the BRCA-mutated subgroup, the median OS with rucaparib was 24.3 months (95% CI, 19.9-25.7) vs 20.8 months (95% CI, 16.3-23.1) with physician’s choice of therapy (HR, 0.81; 95% CI, 0.58-1.12; P = .21).

Updated data shared during the 26th Annual Meeting of the Society of Urologic Oncology showed that patients younger than 65 years who were given rucaparib experienced a median rPFS of 11.2 months (95% CI, 8.7-14.2) compared with 6.3 months (95% CI, 2.3-12.0) with physician’s choice (HR, 0.60; 95% CI, 0.33-1.08).2 Those between the ages of 65 and 74 years had a median rPFS of 11.2 months (95% CI, 8.2-16.5) and 7.6 months (95% CI, 5.7-9.0), respectively (HR, 0.46; 95% CI, 0.28-0.75). In those aged 75 years or older, the median rPFS was 11.2 months (95% CI, 8.3-15.0) and 5.4 months (95% CI, 3.7-8.4), respectively (HR, 0.41; 95% CI, 0.22-0.74).

What is known about the safety profile of rucaparib?

The most frequent treatment-emergent adverse effects (TEAEs) in the rucaparib arm were asthenia/fatigue (range, 55%-67%), anemia/hemoglobin decreased (range, 31%-65%), nausea (49%-55%), decreased appetite (range, 32%-53%), and diarrhea (range, 21%-38%).

References

1. FDA grants regular approval to rucaparib for metastatic castration-resistant prostate cancer. FDA. December 17, 2025. Accessed December 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-rucaparib-metastatic-castration-resistant-prostate-cancer
2. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. FDA. May 15, 2020. Accessed December 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate
3. Bryce AH, Piulats JP, Ryan CJ, et al. Efficacy of rucaparib vs physician’s choice in patients with BRCA-mutated metastatic castration-resistant prostate cancer by age: Results from the TRITON3 study. Presented at: Society of Urologic Oncology Annual Meeting; December 2-5, 2025; Phoenix, Arizona. Poster #176.
4. Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med. 2023;388(8):719-732. doi:10.1056/NEJMoa2214676