Incretin-Based Therapies in Prostate Cancer: From Metabolic Protection to Potential Antitumour Activity - A Narrative Review

This narrative review evaluates the clinical rationale for integrating incretin-based therapies as therapeutic adjuncts for men with advanced prostate cancer undergoing androgen axis suppression. Androgen deprivation therapy combined with potent androgen receptor pathway inhibitors significantly prolongs survival but induces severe, progressive metabolic toxicities, including sarcopenic obesity, profound insulin resistance, dyslipidemia, and heightened cardiovascular mortality. To address this unmet need, this study reviews published preclinical mechanisms, epidemiological data, and emerging clinical datasets examining glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists. The compiled evidence indicates that these agents provide robust metabolic protection by counteracting treatment-induced metabolic syndrome and cardiovascular risk. Furthermore, incretins may exert indirect antitumor effects by attenuating systemic hyperinsulinemia and visceral adiposity-driven chronic inflammation. Direct antitumor activity is also supported by preclinical evidence demonstrating that receptor engagement on malignant cells downregulates oncogenic signaling pathways, which correlates with recent retrospective clinical database trends showing a numerical reduction in metastatic stage migration among men with localized disease. However, dual receptor agonism introduces mechanistic uncertainty due to potential proliferative signaling cascades in neuroendocrine tumor phenotypes. In conclusion, incretin-based therapies offer a highly rational dual-action strategy for metabolic rescue and potential tumor suppression in advanced prostate cancer. Although several early-phase prospective clinical trials are currently underway to evaluate safety and metabolic efficacy, routine clinical implementation cannot be recommended until rigorously designed randomized controlled trials definitively establish long-term safety, optimal patient selection, and durable oncological outcomes.