Targeting Androgen Receptor Alterations in Metastatic Prostate Cancer

Androgen receptor (AR) alterations are frequent in castration-resistant prostate cancer and are often correlated with resistance to treatment, including novel systemic therapies. Ongoing trials are investigating the predictive role of these alterations in efforts to identify targeted therapies to overcome AR-driven resistance. There have been significant advances in our understanding of the biology of metastatic prostate cancer (mPCa) and its response to therapy. Androgen receptor (AR) alterations, including mutations, amplifications, splice variants, and alternative activations, play a significant role in mPCa resistance to treatment. Recent studies indicate that AR alterations detected via genomic testing can be considered predictive biomarkers in men with castration-resistant PCa and can guide treatment strategies. Novel therapeutic approaches, including AR antagonists and inhibitors of ACK1, the AR N-terminal domain, or cytochrome P450 11A1, have shown promise in overcoming treatment resistance. Ongoing clinical trials are exploring the efficacy of these treatments in relation to AR mutation status and could potentially transform the treatment landscape for mPCa. Our mini review highlights advances in the treatment of metastatic prostate cancer, with a focus on drugs that target genetic alterations affecting a protein called the androgen receptor. Some promising results have been obtained and clinical trials are ongoing.