Evolving Treatments and Resistance Mechanisms in Prostate Cancer Therapeutics

Prostate cancer remains a leading cause of cancer-related morbidity and mortality among men, fundamentally driven by gain-of-function alterations in the androgen receptor (AR) signaling axis. Although major therapeutic advances from androgen deprivation therapy to next-generation antiandrogens have significantly improved clinical outcomes, disease progression and the emergence of therapeutic resistance continue to pose substantial clinical challenges. This review provides a comprehensive overview of historical and contemporary treatment strategies in prostate cancer with particular emphasis on the molecular mechanisms underlying therapeutic resistance and disease evolution. To support the narrative presented in this review, we incorporate selected in silico analyses, such as molecular docking studies of antiandrogen AR interactions, which are intended to complement published structural and functional studies and provide a mechanistic context to the reviewed literature. In addition, we highlight emerging and evolving therapeutic modalities, including adoptive cell therapy, nanomedicine-based drug delivery, poly(ADP ribose) polymerase (PARP) inhibition, proteolysis-targeting chimera (PROTAC) technologies, and RNA-based approaches, with emphasis on their translational potential and current limitations. By integrating the existing literature with targeted in silico insights, this perspective presents a forward-looking perspective on overcoming resistance and advancing precision therapeutics in prostate cancer.