Phase I and II therapies targeting the androgen receptor for the treatment of castration resistant prostate cancer

ABSTRACT

Introduction: Prostate cancer is the most common cancer in elderly males. Regardless of the initial hormonal treatment in metastatic disease, a significant proportion of patients develop castration resistant prostate cancer (CRPC). A better understanding of the molecular mechanisms behind castration resistance has led to the approval of oral medications such as abiraterone acetate and enzalutamide. Relevant research is accelerated with numerous agents being tested for the management of CRPC.

Areas covered: The authors present Phase I and II studies targeting the androgen receptor for the treatment of CRPC. Three groups of agents are identified according to the mechanism of action. These include the CYP-17 modulators (Orteronel, Galeterone, VT-464 and CFG-920), novel antiandrogens (Apatorsen, ARN-509, ODM-201, EZN-4176, AZD-3514) and bipolar androgen therapy.

Expert opinion: Further understanding of the mechanisms leading to castration resistance in prostate cancer can reveal potential targets for the development of novel anti-cancer agents. Except for the development of novel antiandrogens and CYP-17 modulators, bipolar androgen therapy is an interesting therapeutic approach. The combinations of the novel agents tested in Phase I and II studies with established agents is another field of interest. The real challenge is to distinguish a novel anti-cancer agent with acceptable tolerability and the best outcome.

KEYWORDS:

• Prostate
• cancer
• androgen receptor
• castration resistance
• antiandrogens
• CYP-17
• bipolar androgen therapy

Article highlights

• Novel CYP-17 modulators are highly selective and act as androgen receptor antagonist.

• ARN-509 and ODM-201 are novel antiandrogens demonstrating promising oncological results.

• Bipolar androgen therapy presents an alternative treatment approach in castration-resistant prostate cancer.

• Combination therapies with abiraterone acetate and enzalutamide as well as docetaxel seem efficient.

• The development of biomarkers predicting resistance and response to targeted therapies is warranted.

This box summarizes key points contained in the article.

Acknowledgements

The authors thank Mrs. Melpomeni Troumpi for editing this manuscript.

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.