Real-world survival benefit of glucagon-like peptide-1 receptor agonists (GLP-1 Ras) concomitant with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy in hormone receptor-positive (HR+)/HER2− metastatic breast cancer: A large propensity-matched analysis.

1070 Background: Obesity increases hormone receptor-positive (HR+) breast cancer risk through adipose-derived estrogens and inflammation. In metastatic HR+/HER2- disease, endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is standard first-line therapy, improving survival. The widespread use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for diabetes and obesity management induces meaningful weight loss and may enhance ET efficacy by reducing body fat mass, which modulates estrogen levels and cancer-related inflammation, albeit their impact on mBC survival in patients receiving ET plus CDK4/6i remains unclear. Methods: Using the TriNetX Global Collaborative Network, we retrospectively identified two cohorts of patients with mBC receiving endocrine therapy (ET) plus a CDK4/6i: 26,689 patients treated with ET+CDK4/6i alone and 604 patients who also received a GLP-1 RA initiated within 3 months of CDK4/6i start. Propensity score matching (PSM) was applied to balance cohorts for age, race, body mass index, heart failure, hypertension, diabetes mellitus, fulvestrant use, and type of CDK4/6i. Overall survival (OS) was estimated using the Kaplan–Meier method, and hazard ratios (HRs) were calculated to compare OS between cohorts. Results: After PSM, 604 matched pairs of patients were identified in the ET plus CDK4/6i and GLP-1 RA groups, respectively (mean age +/- standard deviation:61.4 ±11.3 and 61.8 ±11.8 years), with well-balanced baseline characteristics. After a median follow-up of 18.8 months (interquartile range, IQR 27.9) in the non-exposed cohort and 15.8 months (IQR 24.5) in the non-exposure and in the exposure cohorts, median OS was 67,9 months among patients receiving GLP-1 RA compared with 49 months in those not receiving GLP-1 RA (HR 0.70; 95% CI,0.56–0.89; P=0.003), corresponding to a 30% reduction in the risk of death mortality risk. Conclusions: This is the largest real-world, propensity-matched analysis demonstrating a significant OS benefit with GLP-1 RAs added to ET+CDK4/6i in HR+/HER2− mBC. These provocative findings warrant prospective validation to elucidate underlying mechanisms—such as metabolic reprogramming or immune modulation—and explore GLP-1 RAs as a novel therapeutic strategy in this setting.