Targeting the androgen receptor in metastatic castrate-resistant prostate cancer: A review

•The following mechanisms by which AR signaling is maintained in mCRPC are reviewed:○AR overexpression/overamplification.○Intracrine androgen synthesis.○AR mutations.○AR splice variants.•Current treatments targeting persistent AR signaling in mCRPC.•Role of AR-CAG repeats and AR splice variants as potential biomarkers.

Despite recent advances in the treatment of advanced prostate cancer (PCa), metastatic castrate-resistant PCa remains incurable at this time. The androgen receptor (AR) plays a key role in the development and progression of PCa, continuing to be active in most patients even after the development of castration resistance. Here, we aim to more closely review the mechanisms by which AR signaling is maintained, including AR overexpression/overamplification, intracrine androgen synthesis, AR mutations, and the development of AR splice variants. We also review therapies targeting each of these mechanisms. We also discuss the potential role of AR-CAG repeats and AR splice variants as potential biomarkers of response to hormonal manipulation therapies.