Jhaveri, Komal L.Komal L.JhaveriNeven, PatrickPatrickNevenCasalnuovo, Monica LisMonica LisCasalnuovoKim, Sung-BaeSung-BaeKimTokunaga, ErikoErikoTokunagaAftimos, PhilippePhilippeAftimosSaura, CristinaCristinaSauraO’Shaughnessy, JoyceJoyceO’ShaughnessyHarbeck, NadiaNadiaHarbeckCarey, Lisa A.Lisa A.CareyCurigliano, GiuseppeGiuseppeCuriglianoLlombart-Cussac, AntonioAntonioLlombart-CussacLim, ElgeneElgeneLimGarcía Tinoco, María de la LuzMaría de la LuzGarcía TinocoSohn, JoohyukJoohyukSohnMattar, AndréAndréMattarZhang, QingyuanQingyuanZhangCHIUN-SHENG HUANGHung, Chih-ChiangChih-ChiangHungMartinez Rodriguez, Jorge LuisJorge LuisMartinez RodriguezRuíz Borrego, ManuelManuelRuíz BorregoNakamura, RikiyaRikiyaNakamuraPradhan, Kamnesh R.Kamnesh R.PradhanCramer von Laue, ChristophChristophCramer von LaueBarrett, EmilyEmilyBarrettCao, ShanshanShanshanCaoWang, Xuejing AimeeXuejing AimeeWangSmyth, Lillian M.Lillian M.SmythBidard, François-ClémentFrançois-ClémentBidard2025-12-162025-12-162025-03-2700284793https://scholars.lib.ntu.edu.tw/handle/123456789/734680Background: Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibition, even in cancers with mutations in the gene encoding ERα (ESR1). Methods: In a phase 3, open-label trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib. Primary end points were investigator-assessed progression-free survival with imlunestrant as compared with standard therapy among patients with ESR1 mutations and among all patients and with imlunestrant-abemaciclib as compared with imlunestrant among all patients who had undergone randomization concurrently. Results: Overall, 874 patients underwent randomization, with 331 assigned to imlunestrant, 330 to standard therapy, and 213 to imlunestrant-abemaciclib. Among 256 patients with ESR1 mutations, the median progression-free survival was 5.5 months with imlunestrant and 3.8 months with standard therapy. The estimated restricted mean survival time at 19.4 months was 7.9 months (95% confidence interval [CI], 6.8 to 9.1) with imlunestrant and 5.4 months (95% CI, 4.6 to 6.2) with standard therapy (difference, 2.6 months; 95% CI, 1.2 to 3.9; P<0.001). In the overall population, the median progression-free survival was 5.6 months with imlunestrant and 5.5 months with standard therapy (hazard ratio for progression or death, 0.87; 95% CI, 0.72 to 1.04; P = 0.12). Among 426 patients in the comparison of imlunestrant-abemaciclib with imlunestrant, the median progression-free survival was 9.4 months and 5.5 months, respectively (hazard ratio, 0.57; 95% CI, 0.44 to 0.73; P<0.001). The incidence of grade 3 or higher adverse events was 17.1% with imlunestrant, 20.7% with standard therapy, and 48.6% with imlunestrant-abemaciclib. Conclusions: Among patients with ER-positive, HER2-negative advanced breast cancer, treatment with imlunestrant led to significantly longer progression-free survival than standard therapy among those with ESR1 mutations but not in the overall population. Imlunestrant-abemaciclib significantly improved progression-free survival as compared with imlunestrant, regardless of ESR1-mutation status. (Funded by Eli Lilly; EMBER-3 ClinicalTrials.gov number, NCT04975308.).enfalse[SDGs]SDG3journal article10.1056/NEJMoa2410858396608342-s2.0-105002340093