Prostate cancer (PC), including castration-resistant disease (CRPC), remains largely driven by dysregulated androgen receptor (AR) signaling. While androgen deprivation therapy (ADT) combined with next-generation AR inhibitors improves survival, resistance inevitably arises through mechanisms such as AR amplification, mutations, and splice variants. Additionally, chronic AR suppression induces significant metabolic, musculoskeletal, and cardiovascular toxicities, highlighting the need for novel therapies that overcome resistance while minimizing systemic adverse effects. This review outlines the pivotal role of AR signaling in PC pathogenesis and evaluates the clinical impact and limitations of current AR-targeted therapies. In addition, it examines emerging therapeutic strategies aimed at modulating AR activity, disrupting androgen biosynthesis, and degrading the AR protein itself. Finally, we explore novel approaches targeting alternative oncogenic pathways involved in resistance and lineage plasticity, with the goal of advancing more effective and durable treatment paradigms. Novel strategies such as bipolar androgen therapy (BAT), selective androgen receptor modulators (SARMs), and AR degraders like PROTACs offer context-specific or mechanistically distinct ways to overcome resistance to traditional AR antagonism in prostate cancer. These approaches, along with CYP11A1 inhibitors and resistance pathway targeting (e.g. PI3K/AKT, EZH2), mark a shift toward more personalized therapies aimed at improving efficacy while minimizing toxicity.
Bleve et al. (2025) studied this question.