Imlunestrant with or without Abemaciclib in Advanced Breast Cancer

Background 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 .)