Abstract GS3-08: Imlunestrant with or without abemaciclib in advanced breast cancer (ABC): Updated efficacy results from the phase 3 EMBER-3 trial

Abstract Background: At the primary progression-free survival (PFS) analysis, the phase 3 EMBER-3 trial in patients (pts) with ER+, HER2- ABC demonstrated significant PFS benefit with imlunestrant (imlu) vs standard therapy (SOC: fulvestrant or exemestane) in pts with ESR1 mutations (ESR1m), and with imlunestrant+abemaciclib (imlu+abema) vs imlu in all pts, regardless of ESR1m status. Overall survival (OS) was immature. Here, we present updated efficacy from a prespecified interim OS analysis. Patients and Methods: Pts with ER+, HER2- ABC previously treated with aromatase inhibitors ± CDK4/6 inhibitors were randomized (1:1:1) to imlu, SOC, or imlu+abema. Primary endpoints were investigator-assessed PFS of imlu vs SOC in pts with ESR1m and all pts and of imlu+abema vs imlu in all concurrently randomized pts. OS was a key secondary endpoint (tested if the corresponding PFS was statistically significant). Due to only 2 of 3 PFS endpoints being met, limited significance level was passed to the OS comparisons. Exploratory endpoints included time to chemotherapy (TTC), PFS2, and efficacy analyses of imlu+abema vs SOC. Results: Between Oct2021 and Nov2023, 874 pts were randomly assigned 1:1:1 (imlu, n=331; SOC, n=330; imlu+abema, n=213). At data cut-off (18Aug2025), with a median follow-up of 28.5 months, 10.1% of pts remained on treatment (imlu, 10%; SOC, 5%; imlu+abema, 18%). In pts with ESR1m, the median OS (mOS) was 34.5 months for imlu vs 23.1 months for SOC (HR=0.60; 95% CI 0.43-0.86; p = 0.0043, boundary for significance not achieved). In all pts regardless of ESR1m, the mOS was not reached with imlu+abema vs 34.4 months with imlu (HR= 0.82, 95% CI: 0.59-1.16; p=0.2622). Updated PFS demonstrated sustained benefit from prior report (Table). Notably, in all pts regardless of ESR1m, the mPFS of imlu+abema vs imlu was 10.9 months vs 5.5 months (HR=0.59; 95% CI 0.47-0.74; nominal p<0.0001). All pre-specified exploratory endpoints favored imlu-based regimens. Safety profiles remain consistent with prior reports. Conclusions: At a median follow-up of 28.5 months, a clinically meaningful improvement in OS was observed with imlu vs SOC in pts with ESR1m (corresponding to a numeric increase in mOS of 11.4 months), however, the boundary for significance was not achieved. Also, a favorable OS trend emerged with imlu+abema vs imlu in all pts, regardless of ESR1m. Sustained benefit in PFS, with clinically meaningful improvement in TTC, and PFS2 further highlight the efficacy of imlu-based regimens. Taken together, these updated data reinforce the potential of imlu, as monotherapy or in combination with abema, as an all-oral chemotherapy-free targeted therapy option for ET-pretreated pts with ER+, HER2- ABC. Citation Format: K. L. Jhaveri, P. Neven, M. Casalnuovo, S. Kim, E. Tokunaga, P. Aftimos, C. Saura, J. O'Shaughnessy, N. Harbeck, L. A. Carey, G. Curigliano, J. Watanabe, E. Lim, J. Huang, Z. Qingyuan, A. Llombart-Cussac, C. Huang, B. Desai, X. Wang, S. Cao, F. Bidard, Y. Limay.Imlunestrant with or without abemaciclib in advanced breast cancer (ABC): Updated efficacy results from the phase 3 EMBER-3 trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS3-08.