Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer

Abstract

Background: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer.

Methods: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival.

Results: A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest.

Conclusions: Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).

Figure 1.. Kaplan–Meier Estimates of Survival.

In accordance with the standardized definitions for efficacy end points (STEEP) system, the primary end point of invasive disease–free survival (Panel A) was defined as the time from randomization until the date of one of the following events: ipsilateral invasive breast tumor, locoregional invasive disease, distant recurrence, contralateral invasive breast cancer, second primary invasive cancer, or death from any cause. Data for patients without a documented event of invasive disease or death were censored at the date they were last known to be disease-free. Distant disease–free survival (Panel B) was defined as the time from randomization until documented evidence of first distant recurrence of breast cancer or death. Distant recurrence includes the following events: distant recurrence (metastatic breast cancer that has either been biopsy confirmed or radiologically diagnosed as recurrent invasive breast cancer); death attributable to any cause, including breast cancer, nonbreast cancer, or unknown cause; and second primary nonbreast invasive cancer. Evidence of distant recurrence requires either radiologic examination or histopathological confirmation by biopsy. Overall survival (Panel C) was defined as the time from the date of randomization until death due to any cause; the P value for the boundary for significance in this prespecified event-driven interim analysis was less than 0.01. For invasive disease–free survival and distant disease–free survival, 99.5% confidence intervals are shown for the hazard ratios because a P value of less than 0.005 is required to indicate statistical significance for these end points. Similarly, the 99% confidence interval is shown for the hazard ratio for overall survival because a P value of less than 0.01 is required to indicate statistical significance for overall survival. On the basis of the pooling strategy for stratification factors described in Section 3.4 in the Supplementary Appendix, both the Cox model hazard-ratio estimation and the log-rank test were performed with hormone-receptor status as the single stratification factor. The event-free rates at 12, 24, and 36 months in each group are displayed above and below the curves.

Figure 2.. Subgroup Analysis of Invasive Disease–free Survival.

The solid vertical line indicates the overall hazard-ratio estimate, and the dashed vertical line indicates a hazard ratio of 1.00, as recommended by Cuzick. The size of the blue squares corresponds to the number of events contributing to the estimate of the treatment effect. Even without correcting for multiple comparisons, none of the tests for heterogeneity reached statistical significance. BRCA mutation data reflect central Myriad testing results only. The CPS+EG score is a staging system for disease-specific survival among patients with breast cancer treated with neoadjuvant chemotherapy (NACT). This incorporates pretreatment clinical stage, estrogen-receptor status, nuclear grade, and postneoadjuvant chemotherapy pathological stage. Patients who were enrolled had scores ranging from 2 to 6, with higher scores indicating worse prognosis. The prespecified subgroup analysis of the CPS+EG score in patients with previous NACT was performed in all the patients who had received NACT, whether they had hormone-receptor–positive (HR+) disease or triple-negative breast cancer (TNBC). ACT denotes adjuvant chemotherapy, HER2 human epidermal growth factor receptor 2, and NC not calculated.