Ovarian cancer (OC) remains the eighth most common cancer among women globally and is responsible for the highest mortality rate among all gynecologic malignancies. With an incidence of 8.1 cases and a mortality rate of 5.4 deaths per 100,000 women annually, OC poses a significant global health challenge. The majority of cases are diagnosed at an advanced, metastatic stage, contributing to a five-year survival rate of only 30.8%. Platinum-based chemotherapy remains the standard first-line treatment in this setting; however, recurrence is common, with more than two-thirds of patients relapsing within two years. The introduction of poly (ADP-ribose) polymerase inhibitors (PARPis) has revolutionized the therapeutic landscape of advanced OC, offering new hope in both relapsed and newly diagnosed settings. Among these, olaparib (LYNPARZA®), developed by AstraZeneca, is the first-in-class PARPi to receive clinical approval and has since become central to the maintenance treatment strategy for this disease.
Olaparib acts by exploiting the mechanism of synthetic lethality in tumors deficient in homologous recombination repair (HRR), particularly those harboring BRCA1 and BRCA2 mutations. These tumors rely heavily on the PARP pathway for DNA repair, and inhibition leads to the accumulation of DNA damage and subsequent cancer cell death. Given that approximately 50% of high-grade epithelial ovarian cancers are homologous recombination deficient (HRD), and around 22% carry BRCA mutations, olaparib presents a highly targeted approach to treatment. Its approval has been supported by a series of pivotal clinical trials, including Study 42, Study 19, SOLO1, SOLO2, OPINION, and PAOLA-1. These studies collectively demonstrated that olaparib significantly extends progression-free survival (PFS) in both platinum-sensitive recurrent OC and newly diagnosed patients with BRCA mutations. In addition, when combined with bevacizumab, olaparib has shown efficacy in patients with HRD-positive tumors, expanding its therapeutic potential beyond BRCA mutation alone.
Currently, olaparib is approved in the United States and Europe for the maintenance treatment of women with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who exhibit a response (complete or partial) to platinum-based chemotherapy. In the first-line setting, it is approved for patients with BRCA1/2 mutations, and in combination with bevacizumab for those with HRD-positive tumors, regardless of BRCA status. These indications underscore its broad applicability in both recurrent and newly diagnosed advanced OC.
Pharmacologically, olaparib is a potent inhibitor of PARP-1, PARP-2, and PARP-3. It is rapidly absorbed following oral administration, with peak plasma concentrations occurring within 1 to 3 hours. It is metabolized primarily via CYP3A4 and is eliminated through both renal and fecal pathways. The drug has been evaluated across a range of patient populations, including the elderly and those with hepatic or renal impairment, and dosing adjustments are considered based on individual tolerability and organ function. Its safety profile is generally manageable, with the most frequently reported adverse events being nausea, fatigue, anemia, vomiting, and diarrhea. Rare but serious toxicities, such as myelodysplastic syndrome and acute myeloid leukemia, have been observed, particularly in patients receiving long-term therapy.
Looking forward, the role of olaparib continues to evolve. Ongoing research is exploring its use in combination with immune checkpoint inhibitors, potential application in earlier stages of disease, and strategies to overcome resistance. Moreover, advances in genomic profiling and the identification of broader HRD signatures may allow for more personalized and expanded use of PARPis. As the understanding of tumor biology deepens, olaparib remains a cornerstone in the management of advanced ovarian cancer, exemplifying the promise of precision oncology in gynecologic malignancies.
