PARP Inhibitor Approved for Subtype of Advanced Prostate Cancer
The FDA has converted the accelerated approval of rucaparib to full approval for certain patients with metastatic castration-resistant prostate cancer.
The U.S. Food and Drug Administration (FDA) has granted traditional approval to rucaparib (Rubraca) for adult patients with metastatic prostate cancer that became resistant to hormone therapy and has mutations in BRCA1 or BRCA2 genes, as detected by an FDA-approved companion diagnostic.
Patients who are diagnosed with metastatic prostate cancer are often treated with androgen receptor-directed therapy to starve the cancer cells of the hormones that fuel cancer growth. When prostate cancer stops responding to this treatment, it is referred to as castration-resistant prostate cancer (CRPC).
Rucaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor—a targeted therapy that blocks the PARP enzyme, which is essential for repairing single-strand DNA damage. If left unrepaired, this type of lesion is converted into double-strand DNA damage, which is then repaired through a cellular mechanism called homologous recombination repair (HRR). The BRCA genes are critical components of the HRR pathway. Therefore, BRCA gene mutations render prostate cancer cells susceptible to PARP inhibitors, which cause selective death of HRR-mutated cancer cells through a process called synthetic lethality.
Rucaparib received accelerated approval in 2020 for patients with BRCA-mutated metastatic CRPC after prior treatment with androgen receptor-directed therapy and chemotherapy.
The conversion to traditional approval was based on results from a confirmatory trial called TRITON3. This randomized, open-label trial enrolled 405 patients with metastatic CRPC, of which 302 had mutations in BRCA and 103 had mutations in the ATM gene, which is also involved in DNA damage repair. Eligibility criteria included disease progression on a prior androgen receptor-directed therapy and not having received chemotherapy after developing resistance to androgen receptor-directed therapy.
Patients were randomly assigned (2:1) to receive either rucaparib or a physician’s choice treatment with a hormone therapy agent they had not previously received (enzalutamide or abiraterone acetate) or docetaxel. Patients also received standard androgen-deprivation therapy if they had not undergone surgical removal of both testicles.
Radiographic progression-free survival (rPFS), which measures the time from treatment initiation to the onset of radiographic evidence of disease progression or death, was used to assess the efficacy of the treatment. Overall survival (OS) was also evaluated.
Overall, study results demonstrated a significant improvement in rPFS in patients treated with rucaparib compared with those who received a physician’s choice therapy. In the 302 patients whose tumors carried BRCA mutations, median rPFS was 11.2 months with rucaparib and 6.4 months with treatment of physician’s choice, corresponding to a 50% decrease in the risk of radiographic disease progression or death. Overall survival was similar between arms. In an exploratory analysis in the 103 patients with ATM mutations, rucaparib treatment did not result in significant improvement in rPFS and OS, indicating that the overall benefit from rucaparib was to be attributed primarily to the results seen in patients with BRCA-mutant disease.
The recommended dose for rucaparib is 600 mg twice daily, for a total daily dose of 1,200 mg until disease progression or unacceptable toxicity. Rucaparib is administered orally.
Prostate cancer is the second leading cause of cancer death among men in the United States. According to federal statistics, it was estimated that 313,780 individuals would be diagnosed with prostate cancer, and 35,770 patients would die of the disease in the United States in 2025.
The FDA rendered its decision on December 17, 2025. Check this resource for updated information on all therapeutics regulated by the FDA.