Giuliano Borges

Purpose: Treatment options for progression on first-line endocrine therapy (ET) + cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) for estrogen receptor–positive/human epidermal growth factor receptor 2–negative (ER+/HER2−) advanced breast cancer (ABC) include ET plus targeted agents [CDK4/6i or phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin (PAM) pathway inhibitors]. Elacestrant is the first single-agent oral selective ER degrader that significantly improved progression-free survival (PFS) versus standard-of-care (SOC) ET in ESR1-mutated and overall ER+/HER2− ABC populations. Patients and Methods: This phase Ib/II umbrella trial enrolled patients with ER+/HER2− ABC who received 1 to 2 lines of ET + CDK4/6i (including prior fulvestrant and primary endocrine resistance) and no prior chemotherapy for ABC. Patients received elacestrant with everolimus, alpelisib, capivasertib, abemaciclib, ribociclib, or palbociclib. We evaluated PFS of elacestrant plus everolimus. Results: In phase Ib (N = 23), the optimal recommended phase II dose was determined as elacestrant 345 mg plus everolimus 7.5 mg. The phase II patient population (N = 50) included 100% prior CDK4/6i, 50% prior fulvestrant, 72% visceral metastasis, 20% primary endocrine resistance, 42% ESR1-mutated, and 50% PIK3CA-mutated. Median PFS was 8.3 months [95% confidence interval (CI), 4–10.2] in all patients; 8.3 months (95% CI, 3.5–12.9) in ESR1-mutated, 9 months (95% CI, 4.2–12.7) in ESR1 wild-type, 8.3 months (95% CI, 3.6–10.2) in PIK3CA-mutated, and 9.4 months (95% CI, 4–not reached) in PIK3CA wild-type. Adverse events (AEs) were consistent with the known safety of everolimus plus SOC ET. The most common AEs were grades 1 to 2. Any AE leading to drug withdrawal or dose reduction was 6% and 2%, respectively. Conclusions: Elacestrant plus everolimus showed a clinically meaningful PFS benefit across clinical/genomic subgroups, irrespective of ESR1 or PIK3CA mutation status. Elacestrant has the potential to become an ET backbone for combinations to inhibit the PAM pathway with everolimus as a promising all-oral treatment.