Rucaparib Approved for Metastatic Castration-Resistant Prostate Cancer
Expert Perspectives · Keira Smith · 2025-12-30
The FDA has granted regular approval to rucaparib (Rubraca®, pharmaand GmbH) for patients with deleterious BRCA mutation–associated metastatic castration resistant prostate cancer (CRPC) who have previously received an androgen receptor–directed therapy. Rucaparib was previously granted accelerated approval for a similar indication in 2020. Patient eligibility should be determined using an FDA-approved companion diagnostic.
Why This Approval Matters
“PARP inhibitors have shown clinical efficacy in patients with metastatic CRPC associated with alterations in genes encoding DNA damage response, with the greatest efficacy observed in those with BRCA mutations,” wrote Karim Fizazi, MD, Medical Oncologist at Institut Gustave Roussy, and colleagues, in their published results of TRITON3 (NCT02975934), on which the approval was based. “In the phase 2 TRITON2 study, PARP inhibitor rucaparib showed a high level of activity in metastatic CRPC associated with a deleterious BRCA alteration in patients who had received previous treatment with a second-generation androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy. We conducted the open-label, controlled, randomized, phase 3 TRITON3 trial of rucaparib involving men with metastatic CRPC at an earlier stage of treatment to confirm and expand on data from the TRITON2 study.”
Breaking Down TRITON3
TRITON3, which was the trial required to confirm the clinical benefit of the 2020 accelerated approval, enrolled 405 patients with metastatic CRPC. Of these, 302 had BRCA mutations (BRCAm), and 103 had ATM mutations (ATMm). Patients had progressed on a previous ARPI and had not received prior chemotherapy in the castration-resistant setting.
Patients were randomized 2:1 to receive rucaparib or physician’s choice of either an ARPI (enzalutamide or abiraterone) that they had not previously received, or docetaxel. They were stratified by performance status, presence of hepatic metastases, and type of mutation. Patients maintained a castrate level of testosterone through either androgen deprivation therapy or previous surgical castration.
The primary end point was radiographic progression-free survival (rPFS) evaluated through independent radiology review, with overall survival (OS) as a secondary end point.
In both the BRCAm population and the overall population, rucaparib produced a statistically significant improvement in rPFS versus treatment of physician’s choice. Among the BRCAm group, the median rPFS was 11.2 months with rucaparib and 6.4 months for treatment of physician’s choice; median OS was 23.2 months and 21.2 months, respectively. An exploratory analysis of the ATMm patients, the rPFS hazard ratio was 0.95 and the OS hazard ratio was 1.21, suggesting that the overall improvement was primarily due to the results observed in the patients with BRCAm.
Managing Adverse Events
The prescribing information for rucaparib includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia and embryo-fetal toxicity.
Dosing and Administration
The recommended dose is rucaparib 600 mg (two 300 mg tablets) orally twice daily, with or without food, for a total daily dose of 1,200 mg until disease progression or unacceptable toxicity.
Conclusion
“The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration,” concluded Dr. Fizazi and colleagues.
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