Prostate cancer is heavily influenced by the activation of the androgen receptor (AR) and its associated transcriptional programs. While targeting AR has shown promise, therapeutic resistance often develops due to changes in the androgen signaling axis. The success of next-generation AR-directed therapies for castration-resistant prostate cancer has validated the importance of AR signaling and provided new treatment options. However, metastatic prostate cancer remains largely incurable, underscoring the need to understand the various ways tumors resist AR-directed therapies. This review explores current understandings of AR signaling-dependent resistance mechanisms and highlights the next frontier of AR targeting in prostate cancer. By gaining insights into these resistance mechanisms, new therapeutic avenues can be explored to improve patient outcomes.

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