Menarini Group and MEDSIR presented findings from the ADELA phase III clinical trial at the San Antonio Breast Cancer Symposium (SABCS) 2024, evaluating a novel therapeutic strategy for advanced ER+/HER2- breast cancer. The study focuses on overcoming therapeutic resistance in patients with ESR1 mutations through a combination of elacestrant and everolimus.
Addressing Endocrine Resistance in Breast Cancer
Standard first-line treatment for advanced ER+/HER2- breast cancer typically involves endocrine therapy combined with CDK4/6 inhibitors. However, resistance often develops due to ESR1 mutations, which can affect up to 50% of patients with ER+, HER2- advanced or metastatic breast cancer after prior endocrine therapy exposure. These mutations lead to estrogen-independent estrogen receptor activation, rendering tumors less responsive to endocrine treatments. The ADELA trial seeks to address this critical unmet need.
ADELA Trial Design and Objectives
The ADELA trial is a phase III, international, randomized, double-blind study designed to assess the efficacy of combining elacestrant, a next-generation oral selective estrogen receptor degrader (SERD), with everolimus, an mTORC1 inhibitor. This combination is being evaluated in patients with advanced ER+/HER2- breast cancer harboring ESR1 mutations who have experienced disease progression following standard first-line treatment.
The primary objective is to determine whether the elacestrant and everolimus combination provides superior efficacy in delaying disease progression compared to elacestrant monotherapy. Secondary endpoints include overall survival, assessment of the toxicity profile, and evaluation of the impact on patients' quality of life.
Rationale for Elacestrant and Everolimus Combination
Elacestrant's approval was based on the phase III EMERALD study results, which demonstrated its efficacy in treating ER+/HER2- advanced or metastatic breast cancer with ESR1 mutations. Everolimus has shown promise in overcoming other resistance mechanisms in this type of cancer. Preliminary data from the phase 1b/2 ELEVATE study (NCT05563220) indicated that the combination of elacestrant and everolimus has manageable safety profile and preliminary efficacy.
Expert Commentary
"We at Menarini Stemline are delighted to announce the collaboration with MEDSIR to continue advancing the clinical research to explore the combination therapy with elacestrant," said Nassir Habboubi, MD, Chief Medical Officer of Stemline Therapeutics. "We are committed to driving innovation in cancer treatment by delivering transformational therapies aiming to extend the lives of people living with cancer."
Dr. Antonio Llombart-Cussac, Senior Scientific Leader at MEDSIR, added, "At MEDSIR, we understand innovation not only as achieving clinical results but as the ability to transform patients' lives on a global scale. With ADELA, we take a decisive step toward accomplishing less invasive and more accessible treatments, aiming to offer new hope to those facing the most complex forms of the disease."
Potential Impact and Future Directions
The ADELA study has the potential to support regulatory approval of the elacestrant and everolimus combination, expanding treatment options for patients with advanced breast cancer. The trial includes participation from multiple countries, including Spain, Italy, France, Austria, the Czech Republic, Greece, Germany, and the United Kingdom, highlighting its global relevance.
The ADELA study is currently active and recruiting patients, marking a significant step forward in addressing unmet needs in breast cancer treatment and reinforcing the importance of personalized medicine in oncology.
About Elacestrant
Elacestrant is indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.
Common adverse reactions (≥10%) include musculoskeletal pain (41%), nausea (35%), increased cholesterol (30%), increased AST (29%), increased triglycerides (27%), fatigue (26%), decreased hemoglobin (26%), vomiting (19%), increased ALT (17%), decreased sodium (16%), increased creatinine (16%), decreased appetite(15%), diarrhea(13%), headache (12%), constipation (12%), abdominal pain (11%), hot flush (11%), and dyspepsia (10%).
