Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer

Abstract

Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety.

Patients and methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015.

Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome.

Conclusion: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.

Keywords: BRCA1/2; PARP inhibition; adjuvant therapy; breast cancer; olaparib.

Figure 1.

Kaplan-Meier Estimates of Survival. Overall survival (OS) (A) 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 <0.015. In accordance with the standardized definitions for efficacy end points (STEEP) system, the primary end point of invasive disease-free survival (IDFS) (B) 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 (DDFS) (C) 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, non-breast cancer, or unknown cause; and second primary non-breast invasive cancer. Evidence of distant recurrence requires either radiologic examination or histopathological confirmation by biopsy. For IDFS and DDFS, 95% confidence intervals only are shown for the hazard ratios, as these results are descriptive. Similarly, the 98.5% confidence interval is shown for the hazard ratio for OS because a P value of <0.015 is required to indicate statistical significance for OS. On the basis of the pooling strategy for stratification factors described in Section 2 in the Supplementary Appendix, the primary stratified Cox proportional hazards model of IDFS, DDFS, OS, and the stratified log-rank test of OS, were based on the stratification factor of hormone receptor status only. The event-free rates at 12, 24, 36, and 48 months in each group are displayed above and below the curves. ^aDifference to 2 decimal places: 92.81–89.05 ¼ 3.76 (rounded to 3.8).

Figure 2.. Subgroup analyses by stratification factors and gBRCA1pv or gBRCA2pv groups.

(A-C) 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 (Cuzick J. Forest plots and the interpretation of subgroups. Lancet 2005; 365:1308). 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. NC, not calculated.