Elacestrant in ER+, HER2- MBC with ESR1-mutated tumors: Subgroup Analyses from the Phase III EMERALD Trial by Prior Duration of Endocrine Therapy Plus CDK4/6 Inhibitor and in Clinical Subgroups.

PURPOSE: Elacestrant significantly prolonged progression-free survival (PFS) with manageable safety versus standard-of-care (SOC) endocrine therapy (ET) in patients with ER+, HER2- mBC and tumors harboring ESR1 mutation following ET plus a cyclin-dependent kinase 4/6 inhibitor (ET+CDK4/6i). In patients with ESR1-mutated tumors, we evaluated the efficacy and safety of elacestrant versus SOC based on prior ET+CDK4/6i duration, and in clinical subgroups with prior ET+CDK4/6i ≥12 months. METHODS: EMERALD, an open-label phase III trial, randomized patients with ER+, HER2- mBC, 1-2 prior lines of ET, mandatory CDK4/6i, and ≤1 chemotherapy to elacestrant (345 mg daily) or SOC (aromatase inhibitor or fulvestrant). PFS was assessed across subgroups in post-hoc exploratory analyses without adjustment for multiple testing. RESULTS: In patients with ESR1-mutated tumors and prior ET+CDK4/6i ≥12 months, median PFS (mPFS) for elacestrant versus SOC was 8.6 versus 1.9 months (HR, 0.41; 95% CI, 0.26-0.63). In this population, mPFS (in months) for elacestrant versus SOC was 9.1 versus 1.9 (bone metastases), 7.3 versus 1.9 (liver and/or lung metastases), 9.0 versus 1.9 (<3 metastatic sites), 10.8 versus 1.8 (≥3 metastatic sites), 5.5 versus 1.9 (PIK3CA mutation), 8.6 versus 1.9 (TP53 mutation), 9.0 versus 1.9 (HER2-low), 9.0 versus 1.9 (ESR1 D538G-mutated tumors), and 9.0 versus 1.9 (ESR1 Y537S/N-mutated tumors). Subgroup safety was consistent with the overall population. CONCLUSIONS: Duration of prior ET+CDK4/6i ≥12 months in mBC was associated with a clinically meaningful improvement in PFS for elacestrant compared to SOC and was consistent across all subgroups evaluated in patients with ER+, HER2-, ESR1-mutated tumors.