The FDA has granted full (regular) approval to rucaparib (RUBRACA), an oral poly (ADP-ribose) polymerase (PARP) inhibitor, for the treatment of adult patients with deleterious BRCA1/2-mutated (germline and/or somatic) metastatic castration-resistant prostate cancer (mCRPC) who have progressed following androgen receptor-directed therapy. Rucaparib exerts its antitumor activity through inhibition of PARP1 & PARP2, leading to impaired DNA single-strand break repair and synthetic lethality in tumors with underlying homologous recombination repair deficiency, particularly BRCA-mutant disease. This decision was supported by the Phase 3 TRITON3 trial, in which rucaparib significantly improved radiographic progression-free survival (rPFS) compared with physician’s choice therapy, achieving a median rPFS of ~11.2 months versus 6.4 months in the BRCA-mutated subgroup (HR ~0.61; P < 0.001 in the overall population), with benefit driven primarily by BRCA1/2 alterations.
Rucaparib Profile & Mechanism
- Profile: Poly ADP-ribose polymerase (PARP) inhibitor, a targeted oral anticancer agent that disrupts DNA repair in tumor cells.
- Mechanism: Inhibits PARP enzymes, PARP1 & PARP2
- By blocking DNA repair pathways, rucaparib induces synthetic lethality in tumor cells with defective homologous recombination repair, leading to the accumulation of DNA damage and cancer cell death.
- Target Population: Adult patients with metastatic castration-resistant prostate cancer (mCRPC) who are deleterious BRCA mutant (germline and/or somatic) associated.
- Prior Therapy: Patients who have received prior androgen receptor-directed therapy.
- A significant benefit has been demonstrated in patients with BRCA1/2 mutations; a less clear benefit was observed in patients with other alterations.
- Delivery System: Oral tablets ingested with or without food.
- Treatment Schedule: 600 mg twice daily, 1,200 mg/day
TRITON3 Study Design (NCT02975934)
- Study Design: Phase 3, randomized, multicenter, open-label trial.
- Study Objective: Evaluate the effect of rucaparib on radiographic progression-free survival (rPFS) relative to the physician’s choice in patients with mCRPC harboring BRCA or ATM alterations.
- Participants: Adult men with mCRPC and BRCA1/2 or ATM mutations.
- 400 patients enrolled; 302 with BRCA mutations and 103 with ATM mutations
- Primary Endpoint: rPFS
- Secondary Endpoints: Overall survival (OS) & objective response rate (ORR).
Study Outcomes
- Primary Endpoint: rPFS
- BRCA-mutated subgroup
- Median rPFS with rucaparib: ~11.2 months
- Median rPFS with physician’s choice therapy (docetaxel or second-generation ARPPI): 6.4 months
- All patients (randomized):
- Median rPFS: 10.2 months with rucaparib vs 6.4 months with control (HR ~0.61; P < 0.001) in the overall population (BRCA and ATM alterations).
- BRCA-mutated subgroup
Regulatory Milestones
- Approval Date: December 17, 2025.
- Regulatory Pathway: Rucaparib initially received an accelerated approval for BRCA-mutated mCRPC based on ORR and duration of response (DOR) from the TRITON2 trial, a multicenter, single-arm study.
- Accelerated approval was converted to regular (full) approval following positive confirmatory results from the Phase 3 TRITON3 trial, which demonstrated a significant improvement in rPFS.
- Approval Review: Assessment Aid, a voluntary submission to facilitate FDA assessment, was used.
- The application was approved one month ahead of its FDA goal date, indicating an efficient review process.
Safety
- Most Common Adverse Reactions (All Grades):
- Fatigue/asthenia – present in a majority of patients (~55-67%)
- Anemia/hemoglobin decrease – (31-65% of patients)
- Nausea – (49-55%)
- Decreased appetite – (32-53%)
- Diarrhea – (21-38%)
- Grade 3 or Higher: Substantial (~60%)
- Severe anemia – most commonly reported
- Nutropenia/decreased neutrophil count and fatigue – commonly observed
- Serious Adverse Events and Discontinuations:
- Serious adverse events – reported in ~29% of patients
- Treatment discontinuation due to adverse events – ~15% of patients
- Deaths during treatment – ~2% (not considered treatment related)
- Class-Specific and Other Safety Considerations:
- Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are included in the prescribing information as warnings, although no MDS/AML cases were observed in TRITON3.
- Embryo-fetal toxicity – requires contraception and counseling for patients of reproductive potential.
- Monitoring Recommendations:
- Frequent monitoring of blood counts (baseline + monthly) is recommended to detect hematologic toxicities early.
- Clinical assessment of gastrointestinal symptoms, appetite changes, and fatigue to guide supportive care and dose adjustments is recommended.
Development Status
- Current Status: Approved by the FDA on December 17th, 2025 for the treatment of adults with deleterious BRCA1/2 mutations (germline and/or somatic)-associated mCRPC previously treated with an androgen receptor-directed therapy.
- Prescribing information: Available at Drugs@FDA
- Side Effect Reporting: Healthcare professionals are encouraged to report negative side effects to the FDA
Sources:
Rosa, Kristi. “FDA Grants Full Approval to Rucaparib for BRCA Mutation–Associated MCRPC.” OncLive, MJH Life Sciences, 17 Dec. 2025, www.onclive.com/view/fda-grants-full-approval-to-rucaparib-for-brca-mutation-associated-mcrpc?utm_content=362172738&utm_medium=social&utm_source=linkedin&hss_channel=lcp-9477517. Accessed 5 Jan. 2026.
“A Study of Rucaparib versus Physician’s Choice of Therapy in Participants with Metastatic Castration-Resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON3).” Clinicaltrials.gov, The National Library of Medicine (NLM), 25 July 2025, clinicaltrials.gov/study/NCT02975934. Accessed 5 Jan. 2026.
Fizazi, Karim, et al. “Rucaparib or Physician’s Choice in Metastatic Prostate Cancer.” New England Journal of Medicine, vol. 388, no. 8, 16 Feb. 2023, https://doi.org/10.1056/nejmoa2214676.
