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Olaparib: Mechanism of Action, Adverse Effects, and Contraindications

Mechanism of Action of PARP Inhibitors:

The poly-ADP-ribose polymerase (PARP) enzyme participates in cellular DNA repair. Another mechanism for DNA repair is homologous recombinational repair (HRR); well-known genes involved in HRR include, among others, BRCA1 and BRCA2 (breast cancer). Inhibition of PARP by olaparib prevents DNA repair, and tumor cells, which frequently undergo division and are subject to high DNA turnover, are particularly damaged and undergo apoptosis. PARP inhibition by olaparib is especially effective when HRR is also impaired by mutations.

Indications for Olaparib

Olaparib (Lynparza) is approved as monotherapy for metastatic castration-resistant prostate cancer (mCRPC) in patients harboring BRCA1/2 mutations (de Bono et al., 2020), who have progressed under newer hormonal therapy: it has shown improved progression-free survival (7 vs. 4 months) and improved overall survival (19 vs. 15 months).

In addition, the combination of olaparib, abiraterone, and prednisone is approved for first-line therapy in mCRPC when docetaxel chemotherapy is not indicated or feasible. In Europe, the European Medicines Agency (EMA) has not restricted the approval of the olaparib/abiraterone combination to only patients with BRCA mutations (in contrast to U.S. FDA approval).

Pharmacokinetics of Olaparib

Olaparib is well absorbed orally, regardless of food intake; it has a half-life of approximately 15 hours. It is metabolized hepatically via CYP3A4 and CYP3A5, and its metabolites are excreted in roughly equal proportions via urine and feces.

Adverse Effects of Olaparib

The most common adverse events (of all grades) are anemia, neutropenia, thrombocytopenia, and nausea. Below are the frequencies of grade 3 and 4 events (very common >10%, common 1–10%, and rare <1%):

• Hematologic: anemia (14%), thrombocytopenia (2%), and neutropenia (5%).
• Gastrointestinal tract: nausea and vomiting (6%), less frequently stomatitis, diarrhea, or abdominal pain.
• Respiratory tract: rare dyspnea or cough, very rarely severe pneumonitis.
• Skin: rare rash, very rare dermatitis.
• Other adverse events: fatigue (6%) and thromboembolic events.

Drug Interactions of Olaparib

Avoid concurrent administration of CYP3A4 inhibitors (e.g., ketoconazole, azithromycin); alternatively, a substantial dose reduction is required. Avoid also concurrent use of CYP3A4 inducers (e.g., rifampicin).

Contraindications of Olaparib

• Severe hepatic impairment (Child-Pugh class C)
• Severely reduced kidney function (glomerular filtration rate < 30 mL/min)
• Persistent grade 3 or 4 adverse events despite dose reduction

Dosage of Olaparib

The recommended regimen is 300 mg Olaparib taken twice daily (150 mg tablets 2-0-2), which corresponds to a total daily dose of 600 mg. In the event of adverse effects, after a treatment pause (with weekly laboratory monitoring) and normalization, reduce the dose stepwise to daily doses of 500 mg or 400 mg. In cases of moderately reduced kidney function (GFR 30–50 mL/min), reduce the daily dose to 400 mg. If grade 3 or higher adverse events recur under reduced dosage, discontinue olaparib permanently.

Monitoring During Therapy:

During the first month, monitor the differential blood count weekly, then monthly thereafter. Monthly assessments should include electrolytes, liver function tests, creatinine, skin examination, blood pressure, and inspection of the oral cavity.

Trade Name

Lynparza

References

J. de Bono et al., “Olaparib for Metastatic Castration-Resistant Prostate Cancer.,” NEJM, 2020.

J. Mateo et al., “Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial.,” Lancet Oncol, vol. 21, no. 1, pp. 162–174, 2020.

F. Saad, N. W. Clarke, M. Oya, N. Shore, G. Procopio, and J. Guedes, “Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial.,” Lancet Oncol., vol. 24, no. 10, pp. 1094–1108, 2023.

  Deutsche Version: Mechanismus, Nebenwirkungen, Kontraindikationen und Dosierung von Olaparib

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