Efficacy of Olaparib in Women With BRCA2-Mutated Breast Cancer: A Critical Review of Clinical Evidence

Abstract

Breast cancers with pathogenic BRCA2 variants exhibit impaired homologous-recombination DNA repair, increasing vulnerability to PARP inhibition. Olaparib is the best-studied PARP inhibitor in this setting, though evidence varies across disease stages, mutation types, and treatment contexts. This review synthesizes randomized trials, prospective studies, real-world cohorts, and meta-analyses.

In high-risk HER2-negative early breast cancer with germline BRCA1/2 mutations, 1-year adjuvant olaparib improved invasive disease-free, distant disease-free, and overall survival (OS), demonstrating a consistent BRCA2 subgroup effect. In HER2-negative metastatic disease, the OlympiAD trial showed progression-free survival (PFS) and response advantages over chemotherapy. The prespecified BRCA2 subgroup achieved a PFS hazard ratio of 0.49, although OS benefits were not statistically significant in the overall or BRCA2 populations.

Neoadjuvant studies show substantial activity but remain small, frequently combine BRCA1/2 carriers, and have not definitively established olaparib’s pre-surgical role alone or with chemotherapy. Evidence for somatic BRCA2 mutations is promising but relies on small, single-arm studies and pooled BRCA1/2 analyses. Real-world data reproduce clinical activity while highlighting the impact of later treatment lines, prior platinum exposure, and patient selection.

Overall, olaparib improves disease control more consistently than OS in metastatic settings. The primary limitation remains the scarcity of adequately powered BRCA2-specific analyses. Evidence supports olaparib as an effective targeted therapy for germline BRCA2-mutated, HER2-negative breast cancer, but cautions against assuming pooled BRCA1/2 results automatically represent BRCA2-specific estimates.