Olaparib, an oral poly(ADP-ribose) polymerase (PARP) inhibitor, has emerged as a promising therapeutic agent in the management of metastatic breast cancer in patients with germline BRCA mutations. The phase 3 OlympiAD trial, published in the New England Journal of Medicine in 2017, evaluated the efficacy and safety of olaparibmonotherapy compared to standard single-agent chemotherapy in patients with HER2-negative metastatic breast cancer carrying a germline BRCA mutation. This international, randomized, open-label trial enrolled 302 patients who had received no more than two prior chemotherapy regimens for metastatic disease. Patients were randomly assigned in a 2:1 ratio to receive either olaparib tablets (300 mg twice daily) or physician’s choice of chemotherapy (capecitabine, eribulin, or vinorelbine), with treatment continuing until disease progression or unacceptable toxicity.
The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review. Olaparib significantly improved median PFS to 7.0 months, compared to 4.2 months in the standard therapy group, with a hazard ratio of 0.58 (95% CI: 0.43–0.80; P<0.001), indicating a 42% reduction in the risk of disease progression or death. The objective response rate was also markedly higher in the olaparib arm (59.9%) compared to chemotherapy (28.8%), demonstrating nearly a two-fold improvement. Furthermore, the rate of grade 3 or higher adverse events was lower in the olaparib group (36.6%) than in the standard-therapy group (50.5%), with fewer treatment discontinuations due to toxicity (4.9% vs. 7.7%).
Importantly, while overall survival did not differ significantly between groups at the time of analysis (19.3 months vs. 19.6 months), the trial was not powered to detect such differences, and post-progression therapies may have confounded results. Notably, more patients in the chemotherapy arm went on to receive PARP inhibitors or platinum-based treatments following progression. The quality-of-life outcomes favored olaparib, with patients reporting a significantly smaller decline in health-related quality of life, measured by the QLQ-C30 instrument, and a delayed time to clinically meaningful deterioration.
Mechanistically, olaparib exploits the principle of synthetic lethality by inhibiting PARP enzymes essential for DNA single-strand break repair. In BRCA1/2-mutated tumors, which already have impaired homologous recombination repair, PARP inhibition leads to unrepairable DNA damage and cancer cell death. Given that germline BRCA mutations are present in approximately 5% of unselected breast cancer cases and are particularly common in patients with triple-negative breast cancer or a strong family history, olaparib offers a targeted treatment approach for this genetically defined subgroup.
The OlympiAD trial solidifies the role of olaparib as an effective and well-tolerated therapy in HER2-negative metastatic breast cancer with germline BRCA mutations. However, the study has limitations, including its open-label design, heterogeneity in patient characteristics, and absence of platinum-based chemotherapy as a comparator. Despite these, the results underscore the clinical value of genetic testing for BRCA mutations and support the integration of PARP inhibitors into the personalized treatment paradigm for metastatic breast cancer. Further studies comparing olaparib with platinum agents and evaluating outcomes in specific subgroups (e.g., hormone receptor-positive vs. triple-negative disease) would provide additional insight into optimizing therapy for this patient population.
Reference: https://www.nejm.org/doi/full/10.1056/nejmoa1706450?utm_source
