Multinational phase 3 trial of imlunestrant with or without abemaciclib in advanced breast cancer

Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibiton, even in cancer with ESR1 mutations. The multinational phase 3 EMBER-3 trial included patients with ER-positive, HER2-negative advanced breast cancer (aBC) that recurred or progressed during or after aromatase inhibitor therapy with or without CDK4/6 inhibitor. Patients were randomized 1:1:1 to imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib. Among patients with ESR1 mutations, median progression-free survival was longer with imlunestrant than with standard therapy (p<0.001). This difference was not seen in the overall population (p=0.12). Among patients in the comparison imlunestrant-abemaciclib versus imlunestrant alone, the median PFS was 9.4 months and 5.5 months, respectively (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. The authors conclude that among patients with ER-positive, HER2-negative aBC, imlunestrant led to longer PFS than standard therapy among those with ESR1 mutations but not in the overall population, whereas addition of abemaciclib to imlunestrant improved PFS, regardless of ESR1-mutation status.