Abstract PD5-08: Circulating Tumour DNA (ctDNA) Dynamics From Patients With ER+, HER2- Advanced Breast Cancer in the Phase 3 EMBER-3 Trial

Abstract Background: The EMBER-3 trial, which included patients with ER+/HER2- advanced breast cancer previously treated with endocrine therapy (ET), demonstrated a significant improvement in progression-free survival (PFS) with imlunestrant (imlu) over standard ET (SOC ET, fulvestrant or exemestane) in patients with ESR1 mutations (ESR1m). This improvement was also seen with imlu+abemaciclib (abema) over imlu alone in all patients regardless of ESR1m. ctDNA is a surrogate marker for early clinical response. Here, we present exploratory analyses of ctDNA dynamics from baseline to 4 weeks after treatment. Methods: A total of 874 patients were randomized across 3 treatment arms: SOC ET (n=330), imlu (n=331), and combination imlu+abema (n=213). Plasma samples from baseline and after 4 weeks of treatment (cycle 2 day 1 C2D1) were sequenced using the Guardant360 assay, covering 74 genes. ctDNA dynamics were assessed as a continuous measure (mean variant allele frequency VAF change). Median PFS (mPFS) was assessed in patients who achieved or did not achieve a ≥50% reduction in ctDNA from baseline to C2D1. Results: A total of 635 patients (73%) from the intention-to-treat population had evaluable ctDNA samples at baseline and C2D1: SOC ET (n=241), imlu (n=240), and imlu+abema (n=154). In patients with ESR1m (n=223), imlu led to a higher overall decline in ctDNA (-74% vs -40%) and a reduction of ESR1m (-98% vs -75%), compared with SOC ET. Among all patients randomized to imlu or imlu+abema (n=311), imlu+abema led to higher overall decline in ctDNA compared with imlu alone (-58% vs -37%), regardless of baseline ESR1m status. Across all treatment arms, patients who achieved a ≥50% reduction in mean VAF from baseline to C2D1 had a longer mPFS compared with those who did not ( Table 1 ), with variability between treatment groups. Conclusions: Analyses of early ctDNA dynamics from EMBER-3 demonstrated greater early ctDNA reduction with imlunestrant compared with SOC ET in patients with ESR1m. The addition of abemaciclib to imlunestrant enhanced ctDNA decline in all patients, consistent with the primary study outcomes. Furthermore, while a ≥50% decline in ctDNA at C2D21 was associated with improved PFS, the allocated treatment remained a key determinant of patient outcomes. Citation Format: F. BIDARD, K. Jhaveri, S. Kim, E. Tokunaga, P. Aftimos, C. Saura, J. O’Shaughnessy, N. Harbeck, G. Curigliano, A. Llombart-Cussac, E. Lim, S. Im, H. Bando, P. Neven, S. T. Estrem, B. Nguyen, S. Cao, M. Makena, B. Desai, L. A. Carey. Circulating Tumour DNA (ctDNA) Dynamics From Patients With ER+, HER2- Advanced Breast Cancer in the Phase 3 EMBER-3 Trial abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD5-08.