Elacestrant in Combination with Everolimus for Estrogen Receptor-Positive, HER2-Negative Previously Treated Advanced Breast Cancer: Results from ELEVATE

PURPOSE: Treatment options for progression on first-line endocrine therapy (ET)+CDK4/6i for ER-positive/HER2-negative (ER+/HER2-) advanced breast cancer (ABC) include ET plus targeted agents (CDK4/6i or PI3K/AKT/mTOR-pathway inhibitors). Elacestrant is the first single-agent oral SERD that significantly improved progression-free survival (PFS) versus standard-of-care ET in ESR1-mutated and overall ER+/HER2- ABC populations. PATIENTS AND METHODS: This phase 1b/2, umbrella trial enrolled patients with ER+/HER2- ABC who received 1-2 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 1b (n=23), the optimal RP2D was determined as elacestrant 345 mg plus everolimus 7.5 mg. The phase 2 patient population (n=50) included: 100% prior CDK4/6i, 50% prior fulvestrant, 72% visceral metastasis, 20% primary endocrine resistance, 42% ESR1mut, 50% PIK3CAmut. Median PFS was 8.3 months (95% CI:4.0-10.2) in all patients; 8.3 months (95% CI:3.5-12.9) in ESR1mut, 9.0 months (95% CI:4.2-12.7) in ESR1wt, 8.3 months (95% CI:3.6-10.2) in PIK3CAmut, and 9.4 months (95% CI:4.0-NR) in PIK3CAwt. Adverse events (AEs) were consistent with known safety of everolimus plus SOC ET. Most common AEs were grade 1-2. 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 PI3K/AKT/mTOR-pathway with everolimus as a promising all-oral treatment.

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Journal
Clinical Cancer Research
Published
2026-08-24
DOI
https://doi.org/10.1158/1078-0432.ccr-26-1816
Primary Topic
Advanced Breast Cancer Therapies
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article
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article

Elacestrant in Combination with Everolimus for Estrogen Receptor-Positive, HER2-Negative Previously Treated Advanced Breast Cancer: Results from ELEVATE

Erika Hamilton, J. Thaddeus Beck, Giuseppe Curigliano, Pablo Tolosa et al.
Clinical Cancer Research
Advanced Breast Cancer Therapies
article

Elacestrant in Combination with Everolimus for Estrogen Receptor-Positive, HER2-Negative Previously Treated Advanced Breast Cancer: Results from ELEVATE

Erika Hamilton, J. Thaddeus Beck, Giuseppe Curigliano, Pablo Tolosa, Begoña Bermejo, Faten Koraïchi, Marla Lipsyc-Sharf, Neelima Vidula, Joyce O’Shaughnessy, Virginia Kaklamani, Kristine Rinn, Marina N. Sharifi, Javier Cortés, Isabel García-Fructuoso, Sara M. Tolaney, Rinat Yerushalmi, Philippe Aftimos, Vicente Valero, Nancy Chan, Hope S. Rugo, Alessandro Paoli, Yuan Yuan, Paula Muñoz Romero, Tomer Wasserman, Wassim McHayleh, Jennifer A. Crozier, G. Borges
article en

Abstract

PURPOSE: Treatment options for progression on first-line endocrine therapy (ET)+CDK4/6i for ER-positive/HER2-negative (ER+/HER2-) advanced breast cancer (ABC) include ET plus targeted agents (CDK4/6i or PI3K/AKT/mTOR-pathway inhibitors). Elacestrant is the first single-agent oral SERD that significantly improved progression-free survival (PFS) versus standard-of-care ET in ESR1-mutated and overall ER+/HER2- ABC populations. PATIENTS AND METHODS: This phase 1b/2, umbrella trial enrolled patients with ER+/HER2- ABC who received 1-2 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 1b (n=23), the optimal RP2D was determined as elacestrant 345 mg plus everolimus 7.5 mg. The phase 2 patient population (n=50) included: 100% prior CDK4/6i, 50% prior fulvestrant, 72% visceral metastasis, 20% primary endocrine resistance, 42% ESR1mut, 50% PIK3CAmut. Median PFS was 8.3 months (95% CI:4.0-10.2) in all patients; 8.3 months (95% CI:3.5-12.9) in ESR1mut, 9.0 months (95% CI:4.2-12.7) in ESR1wt, 8.3 months (95% CI:3.6-10.2) in PIK3CAmut, and 9.4 months (95% CI:4.0-NR) in PIK3CAwt. Adverse events (AEs) were consistent with known safety of everolimus plus SOC ET. Most common AEs were grade 1-2. 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 PI3K/AKT/mTOR-pathway with everolimus as a promising all-oral treatment.

Clinical Cancer Research
Cedars-Sinai Medical Center (US), City Of Hope National Medical Center (US), The University of Texas MD Anderson Cancer Center (US), University of Wisconsin–Madison (US), The University of Texas at San Antonio Health Science Center (US), Rabin Medical Center (IL), Institut Jules Bordet (BE), Baylor University Medical Center (US), Florida Hospital Cancer Institute (US), Research Institute Hospital 12 de Octubre (ES), NYU Langone Health (US), Massachusetts General Hospital (US), Empresa de Pesquisa Agropecuária e Extensão Rural de Santa Catarina (BR), Hospital Quirón Teknon (ES), Hospital Clínico Universitario de Valencia (ES), Sarah Cannon (US), Cancer Care Northwest (US), Highlands Oncology Group (US), Menarini Group (Italy) (IT), Dana-Farber Cancer Institute (US), Comprehensive Blood & Cancer Center (US), Center for Cancer Research (US), Fundació Clínic per a la Recerca Biomèdica (ES), Menarini Group (Germany) (DE), European Institute of Oncology (IT)
Good health and well-being
Openalex Percentile: Top 10%
Advanced Breast Cancer Therapies
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