The EMBER-3 trial evaluated imlunestrant, a novel endocrine therapy (ET) in patients with estrogen receptor (ER)-positive/HER2-negative advanced breast cancer previously treated with ET. The study demonstrated a significant improvement in progression-free survival (PFS) with imlunestrant compared with standard ET (standard-of-care [SOC] ET: fulvestrant or exemestane) in patients with an ESR1 mutation. Additionally, imlunestrant combined with abemaciclib showed superior PFS outcomes compared with imlunestrant alone, regardless of ESR1 mutation status. Circulating tumor DNA (ctDNA), a surrogate marker for early clinical response, was analyzed to assess treatment impact. This article presents exploratory analyses of ctDNA dynamics from baseline to 4 weeks after treatment.

The study included 874 patients randomized into 3 treatment arms: SOC ET (n=330), imlunestrant (n=331), and imlunestrant plus abemaciclib (n=213). Plasma samples collected at baseline and 4 weeks after treatment (cycle 2, day 1 [C2D1]) were analyzed using the Guardant360 assay, which sequences 74 genes. ctDNA dynamics were measured as mean variant allele frequency (VAF) change, and median PFS (mPFS) was assessed based on whether patients achieved a ≥50% reduction in ctDNA from baseline to C2D1.

Among the intent-to-treat population, 635 patients (73%) had evaluable ctDNA samples at baseline and C2D1: SOC ET (n=241), imlunestrant (n=240), and imlunestrant plus abemaciclib (n=154). In patients with an ESR1 mutation (n=223), imlunestrant resulted in a greater overall decline in ctDNA (–74% vs –40%) and reduction of ESR1 mutations (–98% vs –75%) compared with SOC ET. Among all patients randomized to imlunestrant plus abemaciclib or imlunestrant (n=311), imlunestrant plus abemaciclib demonstrated a higher overall decline in ctDNA (–58% vs –37%) regardless of baseline ESR1 mutation status. Across all treatment arms, patients achieving a ≥50% reduction in mean VAF from baseline to C2D1 had a longer mPFS compared with patients who did not, with variability observed between treatment groups. In the SOC ET arm, the median PFS in the no molecular response (MR) versus MR group was 3.7 versus 7.4 (hazard ratio, 0.56; CI, 0.41-0.75).

Exploratory analyses of ctDNA dynamics in the EMBER-3 trial revealed greater early ctDNA reduction with imlunestrant compared with SOC ET in patients with an ESR1 mutation. The addition of abemaciclib to imlunestrant further enhanced ctDNA decline across all patients, aligning with the trial’s primary outcomes. Importantly, a ≥50% reduction in ctDNA at C2D1 was associated with improved PFS, although the assigned treatment remained the key determinant of patient outcomes. These findings highlight the potential of ctDNA dynamics as an early marker of treatment efficacy, and support the clinical benefits of imlunestrant, particularly in combination with abemaciclib, in ER-positive/HER2-negative advanced breast cancer.

Source: Bidard F, Jhaveri K, Kim S, et al. Circulating tumour DNA (ctDNA) dynamics from patients with ER+, HER2- advanced breast cancer in the phase 3 EMBER-3 trial. Presented at: San Antonio Breast Cancer Symposium 2025. December 11, 2025; San Antonio, TX. Presentation PD5-08.