The phase 3 EMBER-3 trial evaluated the efficacy of imlunestrant, a novel oral endocrine therapy (ET), in patients with estrogen receptor (ER)-positive/HER2-negative advanced breast cancer previously treated with aromatase inhibitors with or without CDK4/6 inhibitors. The trial’s primary progression-free survival (PFS) analysis demonstrated a significant benefit with imlunestrant compared with standard-of-care (SOC) ET (fulvestrant or exemestane) in patients with ESR1 mutations. Additionally, the combination of imlunestrant and abemaciclib showed improved PFS compared with imlunestrant alone in all patients, irrespective of ESR1 mutation status. However, overall survival (OS) results were immature at the time of the initial analysis. This article presents updated efficacy data from a prespecified interim OS analysis with 14 months of additional follow-up.

Between October 2021 and November 2023, a total of 874 patients with ER-positive/HER2-negative advanced breast cancer were randomized (1:1:1) to receive imlunestrant (n=331), SOC ET (n=330), or imlunestrant plus abemaciclib (n=213). The trial’s primary endpoints were investigator-assessed PFS of imlunestrant versus the SOC in patients with an ESR1 mutation and in all concurrently randomized patients for imlunestrant plus abemaciclib versus imlunestrant. OS was a key secondary endpoint, assessed only if the corresponding PFS results were statistically significant. Exploratory endpoints included time to chemotherapy (TTC), second progression-free survival (PFS2), and chemotherapy-free survival comparing imlunestrant plus abemaciclib versus the SOC.

At the data cutoff (August 18, 2025) and a median follow-up of 28.5 months, 10.1% of patients remained on treatment (imlunestrant, 10%; SOC, 5%; imlunestrant plus abemaciclib, 18%). Among patients with an ESR1 mutation, the median OS (mOS) was 34.5 months with imlunestrant compared with 23.1 months with the SOC (hazard ratio, 0.60; 95% CI, 0.43-0.86; P=.0043), although this did not meet the boundary for statistical significance. In all patients, mOS was not reached with imlunestrant plus abemaciclib and was 34.4 months with imlunestrant (hazard ratio, 0.82; 95% CI, 0.59-1.16; P=.2622). Updated PFS results reinforced the sustained benefit of imlunestrant-based regimens. In all patients, regardless of ESR1 mutation status, the median PFS for imlunestrant plus abemaciclib was 10.9 months compared with 5.5 months for imlunestrant alone (hazard ratio, 0.59; 95% CI, 0.47-0.74; nominal P<.0001). There was consistent benefit of imlunestrant plus abemaciclib versus imlunestrant alone across all subgroups. All prespecified exploratory endpoints, including TTC and PFS2, favored imlunestrant-based regimens. Safety profiles remained consistent with previous analyses.

With a median follow-up of 28.5 months, imlunestrant demonstrated a clinically meaningful improvement in OS compared with the SOC in patients with an ESR1 mutation, with an 11.4-month increase in mOS, although statistical significance was not achieved. A favorable OS trend was also observed with imlunestrant plus abemaciclib compared with imlunestrant in all patients, irrespective of ESR1 mutation status. Sustained PFS benefit and meaningful improvements in TTC and PFS2 further underscore the efficacy of imlunestrant-based regimens. These updated findings highlight the potential of imlunestrant, as monotherapy or in combination with abemaciclib, as a promising all-oral, chemotherapy-free targeted therapy option for patients with ER-positive/HER2-negative advanced breast cancer who have been previously treated with ET.

Source: Jhaveri KL, Neven P, Casalnuovo M, et al. Imlunestrant with or without abemaciclib in advanced breast cancer (ABC): updated efficacy results from the phase 3 EMBER-3 trial. Presented at: San Antonio Breast Cancer Symposium 2025. December 12, 2025; San Antonio, TX. Presentation GS3-08.