Study Overview
Objective. To assess the efficacy and safety of olaparib as an adjuvant treatment in patients with BRCA1 or BRCA2 germline mutations who are at a high-risk for relapse.
Design. A randomized, double-blind, placebo-controlled, multicenter phase III study. The published results are from the prespecified interim analysis.
Intervention. Patients were randomized in 1:1 ratio to either receive 300 mg of olaparib orally twice daily or to receive a matching placebo. Randomization was stratified by hormone receptor status (estrogen receptor and/or progesterone receptor positive/HER2-negative vs triple negative), prior neoadjuvant vs adjuvant chemotherapy, and prior platinum use for breast cancer. Treatment was continued for 52 weeks.
Setting and participants. A total of 1836 patients were randomized in a 1:1 fashion to receive olaparib or a placebo. Eligible patients had a germline BRCA1 or BRCA1 pathogenic or likely pathogenic variant. Patients had high-risk, HER2-negative primary breast cancers and all had received definitive local therapy and neoadjuvant or adjuvant chemotherapy. Patients were enrolled between 2 to 12 weeks after completion of all local therapy. Platinum chemotherapy was allowed. Patients received adjuvant endocrine therapy for hormone receptor positive disease as well as adjuvant bisphosphonates per institutional guidelines. Patients with triple negative disease who received adjuvant chemotherapy were required to be lymph node positive or have at least 2 cm invasive disease. Patients who received neoadjuvant chemotherapy were required to have residual invasive disease to be eligible. For hormone receptor positive patients receiving adjuvant chemotherapy to be eligible they had to have at least 4 pathologically confirmed lymph nodes involved. Hormone receptor positive patients who had neoadjuvant chemotherapy were required to have had residual invasive disease.
Main outcome measures. The primary endpoint for the study was invasive disease-free survival which was defined as time from randomization to date of recurrence or death from any cause. The secondary endpoints included overall survival (OS), distant disease-free survival, safety, and tolerability of olaparib.
Main results. At the time of data cutoff, 284 events had occurred with a median follow-up of 2.5 years in the intention to treat population. A total of 81% of patients had triple negative breast cancer. Most patients (94% in the olaparib group and 92% in the placebo group) received both taxane and anthracycline based chemotherapy regimens. Platinum based chemotherapy was used in 26% of patients in each group. The groups were otherwise well balanced. Germline mutations in BRCA1 were present in 72% of patients and BRCA2 in 27% of patients. These were balanced between groups.
At the time of this analysis, adjuvant olaparib reduced the risk of invasive disease-free survival by 42% compared with placebo (P < .001). At 3 years, invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% CI, 4.5-13.0; hazard ratio [HR], 0.58; 99.5% CI, 0.41-0.82; P < .001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (HR 0.57; 99.5% CI, 0.39-0.83; P < .001). Results also showed that olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (HR, 0.68; 99% CI, 0.44-1.05; P = .02); however, there was no significant difference between treatment arms at the time of this interim analysis. Subgroup analysis showed a consistent benefit across all groups with no difference noted regarding BRCA mutation, hormone receptor status or use of neoadjuvant vs adjuvant chemotherapy.