As reported in the Journal of Clinical Oncology by François-Clément Bidard, MD, PhD, and colleagues, the phase III EMERALD trial has shown prolonged progression-free survival with the oral selective estrogen receptor (ER) degrader elacestrant vs standard endocrine therapy among patients with previously treated ER-positive, HER2-negative advanced breast cancer, including those with an ESR1 mutation.
Elacestrant is a nonsteroidal combined selective estrogen receptor modulator and selective estrogen receptor degrader.
François-Clément Bidard, MD, PhD
The open-label trial included 477 patients from sites in 17 countries who had received one or two lines of endocrine therapy, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, and no more than one previous line of chemotherapy. They 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 a detectable ESR1 mutation.
In total, 110 patients in the elacestrant group and 97 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 an ESR1 mutation, 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 standard-of-care therapy among all patients (hazard ratio [HR] = 0.70, 95% confidence interval [CI] = 0.55–0.88, P = .002) and among patients with an ESR1 mutation (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- or 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 standard-of-care group, progression-free survival 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 an ESR1 mutation at 6 months; at 12 months, 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%–5.1%) among those with an ESR1 mutation.
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 an ESR1 mutation (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 of 20.8% and 8.4% among patients receiving fulvestrant.
At interim analysis of overall survival, 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%). The hazard ratio was 0.59 (95% CI = 0.36–0.96, P = .03, nonsignificant according to predefined significance level) in patients with an ESR1 mutation (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 ER degrader demonstrating a significant progression-free survival improvement vs 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 ER-positive/HER2-negative advanced breast cancer.”
Aditya Bardia, MD, of Massachusetts General Hospital Cancer Center, Harvard Medical School, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Radius Health, Inc. For full disclosures of the study authors, visit ascopubs.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.