Androgen Receptor Signaling Inhibition in Advanced Castration Resistance Prostate Cancer: What Is Expected for the Near Future?

SIMPLE SUMMARY: Prostate cancer progression is mainly driven by the androgen receptor (AR) signaling pathway and its inhibition has been the cornerstone in the treatment of patients harboring this disease. However, during the course of prostate cancer, various resistance mechanisms have been defined as responsible for tumor progression and the lack of response to current antiandrogen drugs. These resistance mechanisms act directly over the AR signaling pathway, but also over other bypassing pathways that could potentially be targetable. Therefore, the improvement in the molecular knowledge of prostate cancer progression and the development of new active therapies may overcome the current limits in prolonging the survival of patients with prostate cancer. ABSTRACT: The androgen signaling pathway is the cornerstone in the treatment of high risk or advanced prostate cancer patients. However, in recent years, different mechanisms of resistance have been defined in this field, limiting the efficacy of the currently approved antiandrogen drugs. Different therapeutic approaches are under research to assess the role of combination therapies against escape signaling pathways or the development of novel antiandrogen drugs to try to solve the primary or acquired resistance against androgen dependent or independent pathways. The present review aims to summarize the current state of androgen inhibition in the therapeutic algorithm of patients with advanced prostate cancer and the mechanisms of resistance to those available drugs. In addition, this review conducted a comprehensive overview of the main present and future research approaches in the field of androgen receptor inhibition to overcome these resistances and the potential new drugs under research coming into this setting.