Imlunestrant shows OS benefit in ESR1-mutated advanced breast cancer in Phase III trial

BACKGROUND: At the primary progression-free survival (PFS) analysis, the phase III EMBER-3 trial in endocrine therapy-pretreated patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) demonstrated significant PFS benefit with imlunestrant versus standard of care (SOC: fulvestrant or exemestane) in patients with ESR1 mutations (ESR1m) and with imlunestrant-abemaciclib versus imlunestrant in all patients, regardless of ESR1m. In this article, we report updated efficacy from a prespecified interim overall survival (OS) analysis. PATIENTS AND METHODS: Patients with ER-positive, HER2-negative ABC previously treated with aromatase inhibitors ± cyclin-dependent kinase 4 and 6 inhibitors were randomly assigned (1 : 1 : 1) to receive imlunestrant, SOC, and imlunestrant-abemaciclib. Primary endpoints were PFS in imlunestrant versus SOC in patients with ESR1m and all patients, and versus imlunestrant-abemaciclib in all concurrently randomized patients. OS was a key secondary endpoint (tested if the corresponding PFS was statistically significant). Due to only two of three PFS endpoints being met, a limited significance level was passed to the OS comparisons. Exploratory endpoints included time to chemotherapy, chemotherapy-free survival, and PFS2. RESULTS: A total of 874 patients were randomized (imlunestrant, n = 331; SOC, n = 330; imlunestrant-abemaciclib, n = 213). Median follow-up was 28.5 months; 10.1% of patients remained on treatment (data cut-off: 18 August 2025).In patients with ESR1m, median OS (mOS) was 34.5 months for imlunestrant versus 23.1 months for SOC [hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.43-0.86, P = 0.0043, boundary for significance not reached]. In all patients regardless of ESR1m, mOS was not reached with imlunestrant-abemaciclib versus 34.4 months with imlunestrant (HR 0.82, 95% CI 0.59-1.16, P = 0.2622). Updated PFS demonstrated sustained benefit. Notably, in all patients regardless of ESR1m, the median PFS of imlunestrant-abemaciclib versus imlunestrant was 10.9 versus 5.5 months (HR 0.59, 95% CI 0.47-0.74, nominal P < 0.0001). All prespecified exploratory endpoints favored imlunestrant-based regimens. Safety remains consistent with prior reports. CONCLUSIONS: These findings reinforce the clinical benefit of imlunestrant-based regimens as a potential all-oral, chemotherapy-free treatment option for endocrine-pretreated patients with ER-positive, HER2-negative ABC.