Olaparib

Olaparib inhibits poly (ADP-ribose) polymerase (PARP) enzymes, particularly PARP1 and PARP2, which are involved in DNA single-strand break repair. By blocking PARP activity, olaparib causes accumulation of DNA damage that leads to double-strand breaks during replication. In cells with defective homologous recombination repair, such as those with BRCA1 or BRCA2 mutations, these breaks cannot be repaired accurately, resulting in cell death—a concept known as synthetic lethality.¹ This selectivity explains its efficacy in BRCA-mutated tumors while sparing normal cells that retain functional repair pathways.

Olaparib is approved for multiple indications. It is used as maintenance therapy for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer with deleterious BRCA mutations, and for first-line maintenance in advanced ovarian cancer after response to platinum-based chemotherapy.² It is also indicated for HER2-negative metastatic breast cancer with germline BRCA mutations, for metastatic pancreatic adenocarcinoma with germline BRCA mutations, and for metastatic castration-resistant prostate cancer with BRCA or other homologous recombination repair gene mutations.³ In each case, patient selection is guided by companion diagnostic tests for BRCA or genomic instability.

Common adverse effects include fatigue, nausea, anemia, and elevated creatinine levels. More serious risks include myelodysplastic syndrome and acute myeloid leukemia, which occur rarely but are potentially fatal. Olaparib can also cause pneumonitis and embryofetal toxicity, so it is contraindicated in pregnancy. Dose adjustments are required for patients with renal impairment, and drug interactions with strong CYP3A inhibitors or inducers must be managed carefully.⁴ Long-term safety data from clinical trials have shown that the risk of secondary malignancies remains low but warrants monitoring.

Olaparib was discovered through a collaboration between scientists at the UK's Institute of Cancer Research and KuDOS Pharmaceuticals, later acquired by AstraZeneca.⁵ Its development was accelerated by the identification of PARP's role in DNA repair in the 1980s. A notable niche application is its use in patients with BRCA-mutated pancreatic cancer, where it was the first targeted therapy to show benefit in a maintenance setting.⁶ Additionally, olaparib has been studied in combination with immunotherapy agents, though results have been mixed. The drug's oral bioavailability is about 50%, and it is taken twice daily with or without food. Interestingly, olaparib has also been explored as a radiosensitizer in preclinical models, though this is not yet a clinical indication.

PARP inhibitor

A class of drugs that block poly (ADP-ribose) polymerase enzymes, used to exploit DNA repair defects in cancer cells.

BRCA mutation

A harmful change in the BRCA1 or BRCA2 genes, which normally help repair DNA damage; increases risk of certain cancers.

Synthetic lethality

A situation where simultaneous loss of function of two genes is lethal, while loss of either alone is not.