Current Status and Future Perspectives of Androgen Receptor Inhibition Therapy for Prostate Cancer: A Comprehensive Review.

Tae Jin Kim,Young Hwa Lee,Kyo Chul Koo

doi:10.3390/biom11040492

Abstract

The androgen receptor (AR) is one of the main components in the development and progression of prostate cancer (PCa), and treatment strategies are mostly directed toward manipulation of the AR pathway. In the metastatic setting, androgen deprivation therapy (ADT) is the foundation of treatment in patients with hormone-sensitive prostate cancer (HSPC). However, treatment response is short-lived, and the majority of patients ultimately progress to castration-resistant prostate cancer (CRPC). Surmountable data from clinical trials have shown that the maintenance of AR signaling in the castration environment is accountable for disease progression. Study results indicate multiple factors and survival pathways involved in PCa. Based on these findings, the alternative molecular pathways involved in PCa progression can be manipulated to improve current regimens and develop novel treatment modalities in the management of CRPC. In this review, the interaction between AR signaling and other molecular pathways involved in tumor pathogenesis and its clinical implications in metastasis and advanced disease will be discussed, along with a thorough overview of current and ongoing novel treatments for AR signaling inhibition.

Highlights

Prostate cancer (PCa) is the most frequently diagnosed neoplasm in developed countries and is accountable for the second-highest rate of cancer-related deaths [1]
The need to understand the intricate relationship between androgen receptor (AR) signaling and other molecular cascades involved with the pathogenesis of PCa and its therapeutic implications in advanced disease is of utmost importance, along with the familiarity of current and novel therapeutic approaches utilizing the AR signaling pathway for the treatment and management for patients with PCa in the advanced setting
The results showed that combining enzalutamide with androgen deprivation therapy (ADT) improved median overall survival (OS) to 67.0 months compared with the placebo plus ADT group, which was 56.3 months (HR 0.73, 95% CI 0.61–0.89; p = 0.001)

Summary

Introduction

Prostate cancer (PCa) is the most frequently diagnosed neoplasm in developed countries and is accountable for the second-highest rate of cancer-related deaths [1]. Results from recent clinical trials support the additional use of docetaxel, abiraterone, enzalutamide, or apalutamide with ADT in the treatment of metastatic hormone-sensitive PCa (mHSPC) [2,3,4,5,6,7,8] This transient hormone-sensitive phase lasts for a median of 18 to 36 months, and the majority of patients will progress to metastatic castration-resistant PCa (mCRPC) [9]. Treatment modalities for mCRPC patients include chemotherapy agents, such as docetaxel and cabazitazel, androgen receptor axis targeted (ARAT) agents, such as abiraterone acetate and enzalutamide, radiotherapy with radium-223, and immunotherapeutic approaches using sipuleucel-T [5,8,10,11,12,13,14,15] Even with these improvements and novel therapeutic strategies, mCRPC has a poor clinical prognosis and outcome [16]. The need to understand the intricate relationship between AR signaling and other molecular cascades involved with the pathogenesis of PCa and its therapeutic implications in advanced disease is of utmost importance, along with the familiarity of current and novel therapeutic approaches utilizing the AR signaling pathway for the treatment and management for patients with PCa in the advanced setting

The Androgen Receptor and Tumor Microenvironment in Prostate Cancer

Novel Androgen Receptor Inhibitors in the Treatment of Non-Metastatic

Androgen Receptor Inhibition in Metastatic Hormone-Sensitive Prostate Cancer

Selective Androgen Receptor Degraders and Proteolysis Targeting Chimeras

Future Directions and Perspectives in Androgen Receptor Inhibitor Therapy

Conclusions