Investigational therapies targeting the androgen signaling axis and the androgen receptor and in prostate cancer - recent developments and future directions.

INTRODUCTION: Despite the heterogeneity of prostate cancer (PCa), androgen stimulation is fundamental to its development, growth, and lethality. Therefore, the blockade of androgen receptor (AR) signaling is critical to controlling the disease, even after progression with castrate levels of androgens.

AREAS COVERED: We review the current understanding of new ways to block the AR, using novel antiandrogen inhibitors, which act on different parts of the AR signaling pathway in PCa. We also review new approaches, such as the use of poly(ADP-ribose) polymerase (PARP) inhibitors, targeting both the AR and the DNA repair pathway, potentially adding synergy and improving efficacy and the combination of AR inhibitors and immunotherapy. Bipolar androgen therapy (BAT), an innovative strategy to target the AR, has shown early evidence of efficacy in PCa is also discussed in detail. We highlight some of the key ongoing studies of greatest relevance to this topic.

EXPERT OPINION: Clinical trials investigating new AR-targeted therapies should be encouraged in patients with PCa. While it is unlikely that one AR inhibitor will produce long-lasting responses in a substantial proportion of patients, there is evidence that some strategies, such as the BAT could resensitize the AR to antiandrogens, alternating therapies and delaying time to progression, maximizing benefit to patients.