Abstract P1-01-25: Elacestrant vs SOC in ER+, HER2- advanced or metastatic breast cancer (mBC) with ESR1-mutated tumors: ESR1 allelic frequencies and clinical activity from the phase 3 EMERALD trial

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Abstract Background: The EMERALD trial (NCT03778931) reported significantly prolonged progression-free survival (PFS) and a manageable safety profile with single-agent elacestrant vs standard of care (SOC) endocrine therapy (ET) in patients with ER+/HER2− mBC and tumors harboring ESR1 mutation following progression on prior ET+CDK4/6i; mPFS 3.8 months with elacestrant vs 1.9 months with SOC (HR=0.55; 95% CI, 0.39-0.77; P = 0.0005) (Bidard 2022). In those patients with prior ET + CDK4/6i ≥12 months and ESR1-mutated tumors, median PFS with elacestrant was 8.6 vs 1.9 months with SOC ET (HR = 0.41; 95% CI, 0.26-0.63) (Bardia 2022). The PFS benefit associated with elacestrant was maintained across ESR1 mutation variants D538G, Y537S, and Y537N, which represent nearly 90% of ESR1-mutated tumors. Variant allele frequency in circulating tumor DNA correlates with tumor disease burden and predicts outcomes in patients with advanced breast cancer. This new analysis evaluates the clinical benefit of single-agent elacestrant in patients with high vs low ESR1 variant allele frequency (VAF). Methods: Patients with ER+/HER2- advanced or mBC who previously had 1-2 lines of ET, mandatory CDK4/6i, and ≤1 chemotherapy were randomized 1:1 to receive oral elacestrant or SOC (investigator’s choice of AI or fulvestrant). A post-hoc subgroup analysis was performed in patients with ESR1-mutated endocrine-sensitive tumors (prior exposure to ET+CDK4/6i ≥12 months) detected in plasma ctDNA using Guardant Health360 gene panel to evaluate the benefit of elacestrant vs SOC by ESR1 VAF. Median VAF was 1.2% (95% CI 0.04-56.1). High and low VAF were defined as ≥1.2% and <1.2%, respectively. Results: In patients with low ESR1 VAF (n=79) who received prior ET+CDK4/6i ≥12 months, a clinically meaningful improvement in mPFS favoring elacestrant compared with SOC was observed, 8.6 with elacestrant vs 1.9 with SOC (HR = 0.51, 95% CI 0.26-0.99, P = 0.049). In patients with high ESR1 VAF (n=79), mPFS with elacestrant was 9.1 vs 1.9 for SOC (HR=0.36, 95% CI 0.19-0.69, P = 0.001). Baseline characteristics and additional data will be presented at the meeting. Conclusions: Elacestrant demonstrated a significant improvement in mPFS vs SOC in patients with both high and low ESR1 VAF. The clinical benefit and activity of elacestrant vs SOC was maintained regardless of type of ESR1 mutation variant and the abundance/quantity of ESR1 mutations in patients with ER+/HER2- mBC. In all patients with ER+/HER2, ESR1-mut mBC, elacestrant may replace fulvestrant-based combinations, and delay chemotherapy or ADC-based regimens. Citation Format: Aditya Bardia, Javier Cortés, Francois Clement-Bidard, Guillermo Streich, José García-Sáenz, Janice Lu, Giulia Tonini, Simona Scartoni, Alessandro Paoli, Alessio Fiascarelli, Alessandro Bressan, Monica Binaschi, Tomer Wasserman, Virginia Kaklamani. Elacestrant vs SOC in ER+, HER2- advanced or metastatic breast cancer (mBC) with ESR1-mutated tumors: ESR1 allelic frequencies and clinical activity from the phase 3 EMERALD trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-01-25.

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