As reported in the Journal of Clinical Oncology by François-Clément Bidard, MD, PhD, of the Institut Curie, Paris and Saint Cloud, and colleagues, the phase III EMERALD trial has shown prolonged progression-free survival with the oral selective estrogen receptor degrader elacestrant vs standard endocrine therapy among patients with previously treated estrogen receptor–positive, HER2-negative advanced breast cancer, including those with ESR1 mutations.1 Elacestrant is a nonsteroidal combined selective estrogen receptor modulator and selective estrogen receptor degrader.
In the open-label trial, 477 patients from sites in 17 countries who had received one to two lines of endocrine therapy, a CDK4/6 inhibitor, and up to one line of chemotherapy were randomly assigned between February 2019 and October 2020 to receive elacestrant at 400 mg once daily (n = 239) or standard-of-care endocrine monotherapy (n = 238). Standard-of-care therapy consisted of investigator’s choice of fulvestrant, anastrozole, letrozole, or exemestane dosed according to product labeling; a total of 165 patients received fulvestrant, and 73 received an aromatase inhibitor. The primary endpoints were progression-free survival on blinded independent committee review among all patients and among those with detectable ESR1 mutations.
François-Clément Bidard, MD, PhD
In total, 110 patients (46.0%) in the elacestrant group and 97 (40.8%) in the standard-of-care group received two prior endocrine therapies in the advanced or metastatic setting. An ESR1 mutation was detected in 115 patients (48.1%) in the elacestrant group and 113 patients (47.5%) in the standard-of-care group. Among those with ESR1 mutations, 36.5% of those in the elacestrant group and 38.9% of those in the standard-of-care group had received two prior endocrine therapies.
Median follow-up was 15.1 months. Progression-free survival was significantly prolonged with elacestrant vs the standard of care among all patients (hazard ratio [HR] = 0.70, 95% confidence interval [CI] = 0.55–0.88, P = .002) and among patients with ESR1 mutations (HR = 0.55, 95% CI = 0.39–0.77, P = .0005).
Kaplan-Meier curves showed an initial precipitous decline during the first 2 months of treatment in both groups, indicative of potential endocrine resistance in the second-/third-line setting, followed by a clear separation favoring the elacestrant group. As noted by the investigators, median progression-free survival values can be misleading in such cases, warranting landmark analysis. For the elacestrant group vs the standard-of-care group, progression-free survival rate was 34.3% (95% CI = 27.2%–41.5%) vs 20.4% (95% CI = 14.1%–26.7%) among all patients and 40.8% (95% CI = 30.1%–51.4%) vs 19.1% (95% CI = 10.5%–27.8%) among patients with ESR1 mutations at 6 months; at 12 months, the rates were 22.3% (95% CI = 15.2%–29.4%) vs 9.4% (95% CI = 4.0%–14.8%) among all patients and 26.8% (95% CI = 16.2%–37.4%) vs 8.2% (95% CI = 1.3%–15.1%) among those with ESR1 mutations.
Comparison of the elacestrant group vs the 165 patients receiving fulvestrant as standard of care showed a hazard ratio of 0.68 (95% CI = 0.52–0.90, P = .0049), with 6- and 12-month rates of 34.3% vs 22.9% and 22.3% vs 10.2%. Among those with ESR1 mutations (n = 83 among those receiving fulvestrant), the hazard ratio was 0.50 (95% CI = 0.34–0.74, P = .0005), with 6- and 12-month rates among fulvestrant patients of 20.8% and 8.4%.
In a subgroup analysis by the number of lines of prior endocrine therapy, hazard ratios favored elacestrant among patients with one prior line (HR = 0.71, 95% CI = 0.52–0.96) and among those with two prior lines (HR = 0.60, 95% CI = 0.42–0.84).
At interim analysis of overall survival (n = 149 events), hazard ratios favored elacestrant at 0.75 (95% CI = 0.54–1.04, P = .08) among all patients (6- and 12-month rates of 93.0% vs 85.2% and 79.3% vs 73.3%) and 0.59 (95% CI = 0.36–0.96, P = .03, nonsignificant according to a predefined significance level) in patients with ESR1 mutations (6- and 12- month rates of 92.8% vs 84.4% and 82.6% vs 72.6%).
The most common adverse events of any grade in the elacestrant group were nausea (35.0% vs 18.8% in the standard-of-care group), fatigue (19.0% vs 18.8%), and vomiting (19.0% vs 8.3%). Grade 3 or 4 adverse events occurred in 27.0% of patients (most commonly nausea and back pain, in 2.5% each) vs 20.5% of patients (no single event in ≥ 1%) and were considered related to treatment in 7.2% vs 3.1%. Adverse events led to treatment discontinuation in 6.3% vs 4.4% of patients, with discontinuations considered related to treatment occurring in 3.4% vs 0.9%. Adverse events led to death in four patients (1.7%) vs six patients (2.6%); no deaths were considered related to treatment.
The investigators concluded; “Elacestrant is the first oral selective [estrogen receptor] degrader demonstrating a significant [progression-free survival] improvement versus [standard of care] both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with [estrogen receptor]-positive/HER2-negative advanced breast cancer.”
DISCLOSURE: The study was supported by Radius Health, Inc. Dr. Bidard has served as a consultant or advisor to Pfizer, AstraZeneca, Lilly, Novartis, Radius Health, Menarini, and Sanofi (institutional); has served on speakers bureaus for Pfizer, Novartis, AstraZeneca, Roche, Lilly, and Rain Therapeutics; has received institutional research funding from Novartis, Pfizer, Menarini Silicon Biosystems, and Prolynx; holds institutional patents for ESR1 and microsatellite instability detection techniques; and has received travel, accommodations, or expenses from Roche, Pfizer, AstraZeneca, and Novartis.
1. Bidard FC, Kaklamani VG, Neven P, et al: Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: Results from the randomized phase III EMERALD trial. J Clin Oncol 40:3246-3256, 2022.
Endocrine therapy is the foundation of first-line therapy in most patients with hormone receptor–positive, HER2-negative metastatic breast cancer. Many of these patients respond to endocrine therapy but eventually become resistant to it through both intrinsic and acquired resistance mechanisms....