Emerging therapies to overcome antiandrogen resistance and beyond in lethal prostate cancer

Abstract

Prostate cancer remains the second most common malignancy among men worldwide, with treatment paradigms evolving dramatically over the last two decades. Despite the longstanding efficacy of androgen deprivation therapy (ADT) and its combination with next-generation androgen receptor (AR) signaling inhibitors or chemotherapy in metastatic hormone-sensitive settings, most tumors ultimately develop resistance and progress to lethal castration-resistant prostate cancer (CRPC). This resistance often stems from a range of molecular alterations, including AR mutations, amplifications, splice variants, and tumor suppressor gene lesions (e.g., TP53, RB1). Recent advances in genomic and translational research underscore the importance of biomarker-guided patient stratification to optimize therapeutic choices. Novel strategies to circumvent resistance include non–ligand-binding-domain AR inhibitors, potent AR degraders (e.g., proteolysis-targeting chimeras [PROTACs]), bipolar androgen therapy, and combination regimens incorporating PARP inhibitors or immunotherapies for selected subsets of patients. Additionally, gene-editing approaches targeting “undruggable” genetic lesions offer promise in preclinical models. Moving forward, clinical development of these emerging agents and personalized treatment approaches, supported by robust genomic profiling, is poised to enhance tumor control, extend survival, and improve quality of life for patients with advanced prostate cancer.