A Real-World Study on the Effectiveness and Safety of Elacestrant in Patients with ESR1-Mutated Metastatic Breast Cancer Progressing After CDK4/6 Inhibitors and Endocrine Therapy.

Background/Objectives: Advanced hormone receptor-positive (HR+), epidermal growth factor 2-negative (HER2-) breast carcinoma (BC) patients receive frontline therapy with cyclin-dependent tyrosine kinase 4/6 inhibitors + endocrine therapy (ET). At progression, the best management includes mutational analysis for ESR-1, allowing second-line therapy with elacestrant. The aim of this study was to evaluate the efficacy and safety of elacestrant in an Italian real-world setting. Methods: A multicenter, observational study with a mixed retrospective and prospective design was conducted in 13 medical oncology units across Italy. The study population included adult patients with HR+/HER2- locally advanced or metastatic breast cancer with an activating ESR1 mutation documented by liquid biopsy and progressing after at least one line of endocrine therapy containing a CDK4/6 inhibitor. Mutational analysis of plasma was performed using next-generation sequencing with a multigene panel that included ESR1, PIK3CA, AKT, and PTEN. The sample size was calculated according to the two-stage Simon design. Toxicity was classified according to CTCAE version 5.0 criteria. Survival analyses were conducted using the Kaplan-Meier method. Results: At the time of analysis, 39 evaluable patients were enrolled, all female and Caucasian, with a median age of 67 years (range 41-89). The efficacy analysis documented an overall ORR of 28% and a disease control rate of 56%. The median duration of response was 6+ months (95% CL: 3.5-10.6 m). Median overall survival was not reached with a median follow-up of 10 months. The toxicity profile was overall favorable: grade ≥2 asthenia was the most frequent adverse event (23%), followed by gastrointestinal toxicity, which was generally mild. No treatment-related toxicity was reported in 64% of patients. Dose reductions were necessary in 15% of cases, while permanent treatment discontinuation due to toxicity occurred in only 4%. Conclusions: The results of this Italian multicenter observational study confirm the efficacy and tolerability of elacestrant in HR+/HER2- metastatic breast cancer with ESR1 mutation, in a real-world context consistent with the data from the pivotal EMERALD study and with real-world data present in the literature.