Rucaparib — Drug Monograph

Brand names: Rubraca

Drug class: PARP Inhibitor

Mechanism of Action

Rucaparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes PARP-1, PARP-2, and PARP-3. PARP enzymes are critical for single-strand DNA break (SSB) repair via the base excision repair (BER) pathway; inhibition by rucaparib traps PARP-DNA complexes at sites of SSBs, converting them to cytotoxic double-strand breaks (DSBs) during DNA replication. Cancer cells harboring defects in homologous recombination repair (HRR) — most notably BRCA1/2 mutations — are unable to repair these DSBs via the high-fidelity HRR pathway and are selectively killed through synthetic lethality.…

FDA Indications

• BRCA1/2 mutation-associated (germline or somatic) recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who have been treated with two or more prior chemotherapies — monotherapy (treatment indication)
• Maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in adult patients who are in complete or partial response to platinum-based chemotherapy (maintenance indication)
• BRCA1/2 mutation-associated (germline or somatic) metastatic castration-resistant prostate cancer (mCRPC) in patients who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy

Common Side Effects

• Nausea (≥77%)
• Fatigue / asthenia (≥77%)
• Elevated ALT/AST (≥74%; usually Grade 1–2, transient)
• Anemia (≥44%)
• Constipation (≥40%)
• Vomiting (≥40%)
• Dysgeusia / altered taste (≥40%)
• Diarrhea (≥34%)
• Decreased appetite (≥23%)
• Dyspnea (≥21%)
• Thrombocytopenia (≥28%)
• Neutropenia (≥22%)
• Abdominal pain (≥20%)
• Stomatitis / mucositis (≥17%)
• Rash (≥13%)
• Photosensitivity (≥10%)
• Elevated creatinine (≥92%; mechanism: rucaparib inhibits creatinine tubular secretion — does not reflect true GFR change)

Clinical Pearl

Rucaparib demonstrated compelling efficacy in the ARIEL3 trial (maintenance in platinum-sensitive recurrent ovarian cancer; PFS 10.8 vs 5.4 months for BRCA-mutated cohort; HR 0.35) and in the TRITON2/3 studies for mCRPC (overall response rate ~44% in BRCA1/2-mutated patients in TRITON2). A clinically important and commonly misinterpreted laboratory finding is the rise in serum creatinine (mean increase ~0.5 mg/dL) that occurs with rucaparib — this results from inhibition of creatinine tubular…

Related Therapies & Mechanisms

• Olaparib (Lynparza) — PARP Inhibitor · Prostate
• Niraparib (Zejula) — PARP Inhibitor · Ovarian
• Talazoparib (Talzenna) — PARP Inhibitor · Prostate
• Abiraterone Acetate (Zytiga) — Prostate