Olaparib — Drug Monograph
Brand names: Lynparza
Drug class: PARP Inhibitor
Mechanism of Action
Inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes 1 and 2. PARP1/2 are required for repair of single-strand DNA breaks (base excision repair). PARP inhibition traps PARP at single-strand breaks, converting them to lethal double-strand breaks during replication. In cells with BRCA1/2 mutations (which cannot repair double-strand breaks by homologous recombination), the result is synthetic lethality — selective killing of BRCA-deficient cells with sparing of normal cells.
FDA Indications
- Germline BRCA-mutated HER2-negative metastatic breast cancer — previously treated with chemotherapy
- Germline or somatic BRCA-mutated HER2-negative early breast cancer — adjuvant treatment with residual disease after neoadjuvant chemotherapy (OlympiA trial)
- Germline or somatic BRCA-mutated metastatic castration-resistant prostate cancer — HRR-deficient, after enzalutamide or abiraterone
- BRCA-mutated ovarian cancer — maintenance after response to platinum-based chemotherapy; first-line maintenance with bevacizumab
- Germline BRCA-mutated metastatic pancreatic cancer — maintenance after platinum-based chemotherapy (POLO trial)
Common Side Effects
- Nausea (very common; anti-nausea medications help)
- Anemia
- Fatigue
- Vomiting
- Neutropenia, thrombocytopenia
- Headache
- Diarrhea
Clinical Pearl
PARP inhibitors work on the principle of synthetic lethality — BRCA1/2-mutated cells rely entirely on error-prone non-homologous end joining (NHEJ) for double-strand break repair. PARP inhibition removes the last functional repair pathway, resulting in cell death. Tumors with HRD (homologous recombination deficiency) beyond BRCA — including PALB2, RAD51C/D, BRIP1 mutations — may also benefit; genomic scar assays (HRD scores) are used to identify HRD beyond BRCA testing.
Related Therapies & Mechanisms
- Rucaparib (Rubraca) — PARP Inhibitor · Ovarian
- Talazoparib (Talzenna) — PARP Inhibitor · Breast
- Gemcitabine (Gemzar) — Breast
- Niraparib (Zejula) — PARP Inhibitor · Ovarian