Introduction
Olaparib (brand name Lynparza®) is an oral targeted cancer therapy belonging to the class of poly (ADP-ribose) polymerase (PARP) inhibitors. It represents a significant advancement in precision medicine for specific cancer types with homologous recombination repair deficiencies. Approved by the FDA in 2014, olaparib was the first PARP inhibitor to receive regulatory approval.
Mechanism of Action
Olaparib selectively inhibits PARP enzymes, particularly PARP-1 and PARP-2, which play crucial roles in DNA single-strand break repair through the base excision repair pathway. By inhibiting PARP, olaparib prevents repair of single-strand DNA breaks, which subsequently leads to double-strand DNA breaks during DNA replication. In cancer cells with homologous recombination repair deficiencies (such as those with BRCA1/2 mutations), these double-strand breaks cannot be effectively repaired, leading to synthetic lethality and cancer cell death.
Indications
- Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy
- First-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy
- Treatment of germline BRCA-mutated HER2-negative metastatic breast cancer previously treated with chemotherapy
- First-line maintenance treatment of germline BRCA-mutated metastatic pancreatic adenocarcinoma
- Maintenance treatment of homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer following response to enzalutamide or abiraterone
Dosage and Administration
Standard dosing: 300 mg orally twice daily (total daily dose 600 mg) Administration: With or without food Duration: Continue until disease progression or unacceptable toxicity Dose modifications:- Renal impairment: No adjustment needed for mild impairment (CrCl 51-80 mL/min); reduce to 200 mg twice daily for moderate impairment (CrCl 31-50 mL/min); avoid in severe impairment (CrCl ≤30 mL/min)
- Hepatic impairment: No dose adjustment for mild impairment; use caution in moderate impairment; avoid in severe impairment
- Pediatric patients: Safety and effectiveness not established
Pharmacokinetics
Absorption: Rapidly absorbed with median Tmax of 1-3 hours; bioavailability approximately 82% Distribution: Volume of distribution ~167 L; protein binding ~82% Metabolism: Primarily metabolized by CYP3A4; forms several metabolites with minimal pharmacological activity Elimination: Half-life ~11.9 hours; excreted primarily in urine (44%) and feces (42%) Special populations: Age, gender, and race do not significantly affect pharmacokineticsContraindications
- Hypersensitivity to olaparib or any component of the formulation
- Concomitant use with strong CYP3A4 inducers
- Pregnancy (based on mechanism of action and animal studies)
Warnings and Precautions
Myelodysplastic Syndrome/Acute Myeloid Leukemia: Occurs in approximately 1.5% of patients, with fatal outcomes in some cases. Monitor complete blood counts monthly. Pneumonitis: Interstitial lung disease/pneumonitis, including fatal cases, have been reported. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk and use effective contraception. Venous Thromboembolic Events: Increased risk of venous thrombosis and pulmonary embolism.Drug Interactions
Strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole): Increase olaparib exposure; reduce olaparib dose to 150 mg twice daily Strong CYP3A4 inducers (e.g., rifampin, carbamazepine): Decrease olaparib exposure; contraindicated Moderate CYP3A4 inhibitors (e.g., ciprofloxacin, diltiazem): May increase olaparib exposure; monitor for adverse reactions BCRP substrates (e.g., rosuvastatin): Olaparib may increase concentrations of these drugsAdverse Effects
Most common (≥20%):- Fatigue/asthenia (66%)
- Nausea (64%)
- Anemia (40%)
- Vomiting (38%)
- Diarrhea (28%)
- Dysgeusia (27%)
- Decreased appetite (26%)
- Constipation (23%)
- Neutropenia (22%)
- Myelodysplastic syndrome/acute myeloid leukemia (1.5%)
- Pneumonitis (<1%)
- Venous thromboembolic events
Monitoring Parameters
- Complete blood counts: Monthly and as clinically indicated
- Renal function: Baseline and periodically
- Liver function: Baseline and periodically
- Signs/symptoms of pneumonitis: Cough, fever, dyspnea, radiographic abnormalities
- Signs/symptoms of venous thromboembolism
- Pregnancy status in females of reproductive potential
Patient Education
- Take exactly as prescribed; do not change dose or stop without consulting healthcare provider
- Report any signs of infection, unusual bleeding or bruising, fatigue, or shortness of breath
- Use effective contraception during treatment and for at least 6 months after final dose
- Inform all healthcare providers about olaparib use before starting new medications
- Common side effects include nausea, fatigue, and anemia; management strategies are available
- Do not breastfeed during treatment and for at least 1 month after final dose
- Maintain regular follow-up appointments for monitoring
References
1. FDA Prescribing Information: Lynparza (olaparib). 2020 2. Pujade-Lauraine E, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274-1284 3. Robson M, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017;377(6):523-533 4. Golan T, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019;381(4):317-327 5. de Bono J, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020;382(22):2091-2102 6. National Comprehensive Cancer Network (NCCN) Guidelines. Various cancer sites. 2023