Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation

Background: Olaparib is an oral poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor that has shown promising antitumor effects in patients with metastatic breast cancer harboring a germline BRCA mutation.

Methods: We conducted a randomized, open-label, phase 3 trial comparing olaparib monotherapy with standard therapy in patients with HER2-negative metastatic breast cancer and a germline BRCA mutation who had previously received no more than two chemotherapy regimens for metastatic disease. Patients were randomly assigned in a 2:1 ratio to receive either olaparib tablets (300 mg twice daily) or standard therapy, which consisted of single-agent chemotherapy selected by the physician (capecitabine, eribulin, or vinorelbine, administered in 21-day cycles). The primary endpoint was progression-free survival, assessed through blinded independent central review, and analyzed on an intention-to-treat basis.

Results: Of the 302 patients randomized, 205 were assigned to receive olaparib and 97 received standard therapy. The median progression-free survival was significantly longer in the olaparib group compared to the standard-therapy group (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% confidence interval, 0.43 to 0.80; P<0.001). The response rate was 59.9% for olaparib and 28.8% for standard therapy. The incidence of grade 3 or higher adverse events was 36.6% in the olaparib group versus 50.5% in the standard-therapy group. The rate of treatment discontinuation due to adverse events was 4.9% in the olaparib group and 7.7% in the standard-therapy group.

Conclusions: In patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, olaparib monotherapy demonstrated significant improvements over standard therapy. Median progression-free survival was 2.8 months longer, and the risk of disease progression or death was reduced by 42% with olaparib compared to standard therapy.