The second follow-up analysis of the OlympiA trial showed a statistically significant improvment in overall survival with use of adjuvant olaparib to treat germline BRCA1/2 mutation–associated breast cancer.
The pre-specified, event-driven analysis of the phase 3 OlympiA trial (NCT02032823) found an improvement in overall survival (OS) at the 3.5-year follow-up for patients with germline BRCA1/2 mutation–associated, high-risk early breast cancer who received adjuvant olaparib (Lynparza) vs placebo, according to a presentation from the European Society for Medical Oncology Virtual Plenary Session.
At the second interim analysis of OS, results meet the significance threshold for olaparib superiority in the overall population (HR, 0.68; 98.5% CI, 0.47-0.97: P = .0009). This compares favorably with the 2.5-year follow-up that was previously reported, in which a numerical OS improvement was noted, but the results did not meet the significance boundary of P <.01 (HR, 0.68; 99% CI, 0.44-1.05; P = .024).
“Treatment effect was consistent, without evidence of significant heterogeneity, across major subgroups including the BRCA1, BRCA2, hormone receptor–positive, and triple-negative breast cancer [TNBC] subtypes,” Andrew Tutt, MD, PhD, director of Breast Cancer Now Research Unit at King’s College in London, said during the presentation.
Patients were eligible for treatment if they had local genetic testing or on-study central screening, a germline pathogenic or likely pathogenic BRCA1/2 mutation, and HER2-negative disease, which could include hormone receptor–positive or triple-negative breast cancer (TNBC).
All patients were administered either neoadjuvant chemotherapy, which included those with TNBC or hormone receptor–positive disease who did not achieve a pathological complete response; or adjuvant chemotherapy if they had pT2 status or at least pN1 with TNBC, and 4 or more positive lymph nodes with hormone receptor–positive status.
A total of 1836 patients were randomized to received either olaparib at 300 mg twice daily for 1 year (n = 921) or matched placebo (n = 915) in addition to (neo)adjuvant therapy. Concurrent with local protocol, patients received either endocrine therapy, bisphosphonates, or a second adjuvant chemotherapy.
Investigators previously reported the primary and secondary end points of the trial at the 2021 American Society of Clinical Oncology Annual Meeting. Safety end points and health-related quality of life were reported at the 2021 San Antonio Breast Cancer Symposium.
Updated patient characteristics included an average age of 42 years (range, 36-49) in the olaparib group and 43 years (range, 36-50) in the placebo group. In the olaparib and placebo groups, a total of 71.3% and 73.2% had BRCA1 germline mutations, respectively, whereas 28.3% and 26.1% had germline BRCA2 mutations.Local and central BRCA results were available in 64.1% of patients in the olaparib group and 63.9% in the placebo group. Mastectomy was the most performed primary breast cancer surgery, at 75.8% in the olaparib group and 73.6% in the placebo group.
Additionally, the majority of patients had TNBC, at 81.5% vs 82.8% in the olaparib and the placebo groups, respectively.
The data cutoff for this analysis was the occurrence of 300 invasive disease-free survival (iDFS) events. Distant recurrence was observed in 9.6% of patients receiving olaparib vs 14.9% on placebo; regional recurrence was seen in 1.0% vs 2.0%; local recurrence was seen in 1.0% vs 1.3%; and contralateral invasive breast cancer was seen in 1.6% vs 2.0%, respectively. Secondary non-breast malignancies occurred in 1.2% of patients in the olaparib group and 2.5% in the placebo group and included ovarian, peritoneal, and fallopian tube tumors. Two patients in the olaparib group died without an iDFS event compared with 0 in the placebo group.
Overall, 75 patients in the olaparib group and 109 in the placebo group died, with primary causes including breast cancer recurrence (93.3% vs 94.5%, respectively), adverse effects (AE; 2.7% vs 3.7%), and other causes (4.0% vs 1.8%). There was a difference in OS rates at 3 years of 3.8% (95% CI, 0.9-6.6) and at 4 years of 3.4% (95% CI, -0.1 to 6.8), both favoring olaparib.
The updated iDFS were consistent with previous results (HR, 0.63; 95% CI, 0.50-0.78). At 3 and 4 years, the iDFS rate differences were 8.8% (95% CI, 5.0%-12.6%) and 7.3% (95% CI, 3.0%-11.5%), respectively, in favor of olaparib. The distant disease-free survival (DDFS) results were also consistent with previous estimates (HR, 0.61; 95% CI, 0.48-0.77), and 3 and 4 year rate differences were 7.0% (95% CI, 3.5%-10.6%) and 7.4% (95% CI, 3.6%-11.3%), respectively, favoring olaparib.
Between analysis follow-ups, there was no change seen in the AE profile. Overall, 91.8% of patients in the olaparib group and 83.8% in the placebo group expereinced AEs. Serious AEs were observed in 8.7% vs 8.6% of patients in the olaparib and placebo groups, respectively. AEs of special interest were myelodysplastic syndrome/acute myeloid leukemia (0.2% vs 5.6%), pneumonitis (1.0% vs 1.3%), and new primary malignancy (2.3% vs 4.0%) in the olaparib and placebo groups, respectively.
Grade 3 AEs were observed in 24.5% of patients on olaparib compared with 11.3% of patients on placebo, and grade 4 AEs were seen in 1.9% vs 0.4%, respectively. AEs leading to treatment discontinuation occurred in 10.8% and 4.6% of patients, respectively. One patient in the olaparib group and 2 in the placebo group had AEs leading to death.
“At median follow-up of 3.5 years, effect sizes and absolute differences remain consistent with the previous primary analysis, with tightening 95% confidence intervals across iDFS, DDFS, and OS end points,” Tutt concluded.
Tutt A, Garber J, Gelber R, et al. Pre-specified event driven analysis of overall survival (OS) in the OlympiA phase III trial of adjuvant olaparib (OL) in germline BRCA1/2 mutation (gBRCAm) associated Breast Cancer. Presented at the 2022 European Society of Medical Oncology Virtual Plenary Session; March 16-18, 2022.