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

Study Details

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.

Progression-Free Survival

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%).

Adverse Events

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.