On December 17, the U.S. Food and Drug Administration (FDA) approved the PARP inhibitor rucaparib (Rubraca) for adults with deleterious BRCA mutation (germline and/or somatic)–associated metastatic castration-resistant prostate cancer previously treated with an androgen receptor–directed therapy. Patients should be selected for therapy using an FDA-approved companion diagnostic. Rucaparib was granted accelerated approval in 2020 for a similar indication.
TRITON3
Efficacy was evaluated in TRITON3 (ClinicalTrials.gov identifier NCT02975934), a randomized, open-label trial required to confirm the clinical benefit of the 2020 accelerated approval. TRITON3 enrolled 405 patients with metastatic castration-resistant prostate cancer, of whom 302 had BRCA and 103 had ATM mutations. Patients were required to have experienced disease progression on a prior androgen receptor pathway inhibitor (ARPI) and could not have received prior chemotherapy in the castration-resistant setting.
Patients were randomly assigned 2:1 to receive either rucaparib or physician’s choice of an ARPI they had not previously received (enzalutamide or abiraterone acetate) or docetaxel. Randomization was stratified by performance status, presence of hepatic metastases, and type of mutation (BRCA1, BRCA2, or ATM). Patients maintained a castrate level of testosterone via treatment with androgen-deprivation therapy or prior surgical castration.
The major efficacy outcome was radiographic progression–free survival assessed by independent radiology review in patients with BRCA mutations and in the overall population. Overall survival was an additional efficacy outcome.
Rucaparib demonstrated a statistically significant improvement in radiographic progression–free survival compared to treatment of physician’s choice in patients with BRCA mutations and in the overall population. In patients with BRCA mutations, median radiographic progression–free survival was 11.2 months (95% confidence interval [CI] = 9.2–13.8 months) for rucaparib and 6.4 months (95% CI = 5.4–8.3 months) for treatment of physician’s choice (hazard ratio [HR] = 0.50, 95% CI = 0.36–0.69, P < .0001). Median overall survival was 23.2 months (95% CI = 19.1–25.2 months) and 21.2 months (95% CI = 18.0–23.1 months) in the respective arms (HR = 0.91, 95% CI = 0.68–1.20, P = not significant). In an exploratory analysis in the 103 (25%) patients with ATM mutations, the radiographic progression–free survival HR was 0.95 (95% CI = 0.59–1.52) and the overall survival HR was 1.21 (95% CI = 0.77–1.90), indicating that the overall improvement was primarily attributed to the results seen in patients with BRCA mutations.
The prescribing information for rucaparib includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia and embryo-fetal toxicity.
The recommended rucaparib dose is 600 mg (two 300 mg tablets) taken orally twice daily with or without food, for a total daily dose of 1,200 mg, until disease progression or unacceptable toxicity.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 1 month ahead of the FDA goal date.
