Perspectives on the current and emerging chemical androgen receptor antagonists for the treatment of prostate cancer

ABSTRACT

Introduction: Prostate cancer is the most common cancer in men. Regardless of the initial treatment of localized disease, almost all patients develop castration resistant prostate cancer (CRPC). A better understanding of the molecular mechanisms behind castration resistance has led to the approval of novel oral androgen receptor (AR) antagonists, such as enzalutamide and apalutamide. Indeed, research has accelerated with numerous agents being studied for the management of CRPC.

Areas covered: Herein, the authors present currently used and emerging AR antagonists for the treatment of CRPC. Emerging agents include darolutamide, EZN-4176, AZD-3514, and AZD-5312, apatorsen, galeterone, ODM-2014, TRC-253, BMS-641988, and proxalutamide.

Expert opinion: Further understanding of the mechanisms leading to castration resistance in prostate cancer can reveal potential targets for the development of novel AR antagonists. Current novel agents are associated with modest clinical and survival benefit, while acquired resistance and safety issues are under continuous evaluation. The combination of AR antagonists used and ideal sequencing strategies are key tasks ahead, along with the investigation of molecular biomarkers for future personalized targeted therapies. In the future, the challenge will be to determine an AR antagonist with the best combination of outcome and tolerability

KEYWORDS:

• Prostate cancer
• androgen receptor
• antagonist
• enzalutamide
• apalutamide
• darolutamide
• apatorsen
• proxalutamide
• galeterone

Article highlights

• Further in-depth understanding of the molecular mechanisms behind castration resistance in prostate cancer will enable the development of novel AR antagonists.

• Enzalutamide and most recently apalutamide are established AR antagonists; nowadays tested even earlier in the progression of the disease.

• Emerging AR antagonists include darolutamide, EZN-4176, AZD-3514, and AZD-5312, apatorsen, galeterone, ODM-2014, TRC-253, BMS-641988, and proxalutamide.

• Until now the novel agents are associated with modest clinical and survival benefit, while acquired resistance and safety issues are under constant evaluation.

• The combination of novel AR antagonists with established medication and the ideal sequencing are key questions lying ahead.

This box summarizes key points contained in the article.

Acknowledgments

We acknowledge that many of the current anti-cancer agents under development seem unlikely to add value to the current treatment arsenal of AA or ENZ and apalutamide, due to the likelihood of cross-resistance. The better understanding of the heterogeneity of resistance mechanisms in PCa is of utmost importance. Future clinical trials with appropriate endpoints are critical in order to provide insights and address key points, such as resistance (primary, acquired after initial response and cross-resistance), optimal timing and drug sequencing, treatment combinations in order to improve outcome and reduce toxicity, as well as predictive molecular biomarkers for the shake of PCa patient.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.