Beyond androgen deprivation therapy: Next-generation hormonal therapies and emerging combination approaches in...

Multiple phase 3 studies have shown that early use of androgen receptor (AR) pathway inhibitors (ARPIs) results in marked improvement in overall survival for men with metastatic androgen pathway modulation-sensitive (APMS) prostate cancer (formerly castration-sensitive prostate cancer). However, resistance to these agents and progression to androgen pathway modulation-resistant (APMR) prostate cancer (formerly castration-resistant prostate cancer) inevitably occurs. As such, patients previously treated with an ARPI for APMS prostate cancer have inherently more resistant disease. In spite of this, AR still remains a relevant therapeutic target in most patients with APMR prostate cancer and several novel therapies targeting both AR-dependent and -independent mechanisms of resistance are under clinical development. These include hormonal therapies that appear effective in the setting of well-characterized ARPI resistance mutations (e.g., AR ligand binding domain mutations), and include non-ligand binding domain inhibitors, AR degraders and next-generation extra-gonadal androgen biosynthesis inhibitors. This review will also discuss combinatorial approaches utilizing ARPIs and newer agents designed to suppress key resistance mechanisms (e.g., epigenetic therapies) and emerging data on the use of supraphysiological testosterone to both exert an antitumor effect and "re-sensitize" APMR prostate cancer to downstream ARPIs. Herein, we summarize the next wave of AR-directed therapies being developed for advanced prostate cancer, with a focus on agents being evaluated in ongoing clinical trials.