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

Abstract

Purpose: Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies.

Methods: This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations.

Results: Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively).

Conclusion: Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC 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.

Trial registration: ClinicalTrials.gov NCT03778931.

FIG 1.

Kaplan-Meier estimates of PFS assessed by blinded independent central review are shown for (A) elacestrant versus SOC in all patients, (B) elacestrant versus SOC in patients with detectable ESR1 mutation, (C) elacestrant versus fulvestrant in all patients, and (D) elacestrant versus fulvestrant in patients with detectable ESR1 mutation. Analyses were performed on the intention-to-treat population. HR, hazard ratio; PFS, progression-free survival; SOC, standard of care.

FIG 2.

Subgroup analysis of PFS in all patients. PFS, as assessed by blinded independent central review, in clinically relevant subgroups of patients with ER-positive/HER2-negative advanced breast cancer. Interaction P values were all nonsignificant indicating that elacestrant benefit on PFS is independent of subgroup. ^aNonstratified analysis. ^bIn the advanced setting. ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; PFS, progression-free survival; SOC, standard of care.

FIG 3.

Interim analysis of OS. Kaplan-Meier estimates of overall survival at the interim analysis are (A) shown for all patients and (B) patients with detectable ESR1 mutation. The differences in overall survival in this interim analysis were not statistically significant on the basis of the allocated two-sided alpha level of .0001. Analysis was performed on the intention-to-treat population. HR, hazard ratio; NS, nonsignificant; OS, overall survival; SOC, standard of care.