What is Rucaparib?
Rucaparib is an oral poly(ADP-ribose) polymerase (PARP) inhibitor that blocks DNA repair in cancer cells, particularly those with BRCA1/2 mutations or other homologous recombination repair deficiencies, leading to cancer cell death through synthetic lethality. 1
Mechanism of Action
Rucaparib inhibits multiple PARP enzymes, including PARP-1, PARP-2, and PARP-3, which are critical for DNA repair. 1 The drug works through two key mechanisms:
- Direct enzymatic inhibition of PARP activity, preventing DNA damage repair 1
- Formation of PARP-DNA complexes that trap PARP on DNA, causing DNA damage accumulation, apoptosis, and ultimately cancer cell death 1
- Synthetic lethality occurs when rucaparib is used in tumors with deficiencies in BRCA1/2 and other DNA repair genes, as these cells cannot compensate for the loss of PARP function 1, 2
FDA-Approved Indications
Ovarian Cancer
- Treatment setting: Approved for patients with deleterious BRCA (germline and/or somatic) mutation-associated ovarian, fallopian tube, or primary peritoneal cancer who have been treated with 2 or more chemotherapy regimens 2
- Maintenance setting: Approved for platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma who achieved complete or partial response to their last platinum-based regimen after at least 2 previous platinum-based chemotherapy regimens 2
Prostate Cancer
- Approved for metastatic castration-resistant prostate cancer (mCRPC) with deleterious or suspected deleterious germline or somatic BRCA1 or BRCA2 mutations in patients who have previously received treatment with a novel hormonal agent (enzalutamide or abiraterone) and one taxane-containing chemotherapy 2
- The approval was based on the TRITON2 trial showing an objective response rate of 43.5% in BRCA1/2-mutated mCRPC 2
Clinical Efficacy Profile
Response by Mutation Status
The magnitude of benefit varies significantly by genetic profile:
- BRCA-mutated tumors: Hazard ratios of 0.18-0.3 for progression-free survival, representing the strongest benefit 2
- HRD-positive/BRCA wild-type tumors: Hazard ratios of 0.32-0.38 2
- BRCA wild-type and HRD-negative tumors: Hazard ratios of approximately 0.58 2
- RAD51C or RAD51D mutations: Small cohort data (n=5) showed 3 partial responses and 2 patients with prolonged stable disease, suggesting BRCA-like response patterns 2
Key Clinical Trial Data
- In the ARIEL3 trial, rucaparib maintenance significantly improved progression-free survival versus placebo in the BRCA-mutated, HRD cohorts, and overall intention-to-treat population 2
- The TRITON3 trial in prostate cancer showed median imaging-based progression-free survival of 10.2 months with rucaparib versus 6.4 months with control (HR 0.61) 2
- For BRCA-mutated prostate cancer specifically, progression-free survival was 11.2 months versus 6.4 months (HR 0.50) 2
Dosing and Administration
- Standard dose: 600 mg orally twice daily (1200 mg total daily dose) 2
- Can be taken with or without food, though a high-fat meal increases Cmax by 20% and AUC by 38% with a 2.5-hour delay in Tmax—this effect is not clinically significant 1
- Continuous dosing is required for optimal response; intermittent dosing schedules showed inferior efficacy 3
- Steady-state is achieved after approximately one week of continuous twice-daily dosing 1, 4
Pharmacokinetics
- Bioavailability: Mean absolute bioavailability is 36% 1
- Time to peak concentration: Median 1.9 hours at steady state 1
- Half-life: Mean terminal elimination half-life is 26 hours 1
- Accumulation: 3.5 to 6.2-fold accumulation occurs with repeated dosing 1
- Protein binding: 70% bound to human plasma proteins 1
- Metabolism: Primarily by CYP2D6, with lesser contributions from CYP1A2 and CYP3A4 1
Common Adverse Events
The most frequently reported adverse events across indications include:
- Hematologic: Anemia (71.4%), thrombocytopenia 2, 5
- Gastrointestinal: Nausea (83.3%), vomiting (54.8%) 5
- Constitutional: Asthenia/fatigue (85.7%) 5
- Hepatic: Elevated ALT/AST (57.1%) 5
- Renal: Increased creatinine 2
- Dermatologic: Rash 2
Serious Adverse Events
- Myelodysplastic syndrome or acute myeloid leukemia: Theoretical risk requiring monitoring 2
- Severe anemia requiring transfusion support 2
- Fetal teratogenicity: Contraindicated in pregnancy 2
Monitoring Requirements
Careful monitoring is essential during rucaparib therapy:
- Complete blood counts: Monitor regularly for anemia, thrombocytopenia, and neutropenia 2
- Hepatic function: Monitor liver transaminases 2
- Renal function: Monitor creatinine levels 2
- Type and screen: Maintain for potential transfusion support 2
- Dose reductions: May be necessary for severe anemia or intolerance 2
Drug Interactions
- Moderate CYP1A2 inhibitor and weak inhibitor of CYP3As, CYP2C9, and CYP2C19 4
- Weakly increases exposure of oral contraceptives, rosuvastatin, and digoxin 4
- Inhibits transporters MATE1, MATE2-K, OCT1, and OCT2 in vitro 4
- No clinically meaningful drug interactions have been observed with rucaparib as a perpetrator 4
Special Populations
No starting dose adjustments are necessary for:
- Age: 20 to 86 years 1
- Race: White, Black, and Asian populations 1
- Sex: No gender-based differences 1
- Body weight: 41 to 171 kg 1
- Mild to moderate renal impairment: CrCl ≥30 mL/min 1
- Mild hepatic impairment: Total bilirubin
ULN, or total bilirubin 1 to 1.5× ULN 1
The effect of severe hepatic or renal impairment has not been evaluated. 1
Important Clinical Considerations
Patient Selection
- Genetic testing is mandatory: Use commercially available analytically and clinically validated somatic tumor, circulating tumor DNA (ctDNA), or germline assays to identify BRCA1/2 mutations 2
- Preferred testing method for prostate cancer: Somatic analysis of BRCA1 and BRCA2 using ctDNA sample 2
- Do not use in patients with HRR gene mutations other than BRCA1/2 in prostate cancer, as minimal to no responses were observed with ATM and CDK12 mutations 2