Abstract
Prostate cancer remains one of the most prevalent cancers in men, and while current hormone therapies aim to block androgen receptor activity, many patients eventually develop resistance, leading to advanced disease. This review explores emerging therapeutic strategies designed to overcome this resistance by targeting the androgen receptor through both direct and indirect mechanisms. Direct inhibitors block specific regions of the receptor to prevent its activation, whereas indirect inhibitors disrupt related signalling pathways that sustain its activity. By summarising these novel approaches, including compounds that degrade or silence the receptor and those that interfere with its supporting networks, this review aims to provide insight into how these treatments could improve outcomes for patients with advanced, treatment-resistant prostate cancer and guide future research directions. Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, with disease progression frequently occurring despite the use of potent androgen receptor (AR)-targeted therapies. As AR signalling continues to drive tumour growth in this setting, new therapeutic strategies are being developed to disrupt the AR axis through both direct and indirect mechanisms. This review highlights a selection of promising agents in preclinical or clinical development that represent the next generation of therapies targeting AR signalling. Direct approaches include novel agents that degrade the AR or target domains beyond the conventional ligand-binding domain, aiming to overcome resistance to existing anti-androgens. Indirect strategies are designed to interfere with AR function by modulating AR-associated transcriptional co-regulators, chromatin accessibility, and other regulatory proteins, such as splicing factors, that are critical for sustaining AR-driven gene expression in prostate cancer. Together, these therapies form the basis of emerging strategies to more effectively suppress AR activity in CRPC. This review discusses AR-activating mechanisms, the mechanisms of action of these agents, their clinical development status, and their potential to reshape future treatment paradigms in CRPC.