Investigational therapies targeting the androgen signaling axis and the androgen receptor and in prostate cancer – recent developments and future directions

ABSTRACT

Introduction: Despite the heterogeneity of prostate cancer (PCa), androgen stimulation is fundamental to its development, growth, and lethality. Therefore, the blockade of androgen receptor (AR) signaling is critical to controlling the disease, even after progression with castrate levels of androgens.

Areas covered: We review the current understanding of new ways to block the AR, using novel antiandrogen inhibitors, which act on different parts of the AR signaling pathway in PCa. We also review new approaches, such as the use of poly(ADP–ribose) polymerase (PARP) inhibitors, targeting both the AR and the DNA repair pathway, potentially adding synergy and improving efficacy and the combination of AR inhibitors and immunotherapy. Bipolar androgen therapy (BAT), an innovative strategy to target the AR, has shown early evidence of efficacy in PCa is also discussed in detail. We highlight some of the key ongoing studies of greatest relevance to this topic.

Expert commentary: Clinical trials investigating new AR-targeted therapies should be encouraged in patients with PCa. While it is unlikely that one AR inhibitor will produce long-lasting responses in a substantial proportion of patients, there is evidence that some strategies, such as the BAT could resensitize the AR to antiandrogens, alternating therapies and delaying time to progression, maximizing benefit to patients.

KEYWORDS:

• Prostate
• cancer
• androgen
• receptor
• hormone

Article highlights

• Despite the heterogeneity of prostate cancer (PCa), androgen stimulation is fundamental to its development, growth, and lethality.

• Even after PCa becomes resistant to castration, the blockade of the androgen receptor (AR) signaling is critical in controlling the disease.

• New generation AR-targeted agents have demonstrated promising results in preclinical and clinical trials, and some of them are being tested in phase III trials now.

• New approaches to inhibit the AR signaling pathway, such as the use of poly (ADP-ribose) polymerase (PARP) inhibitors in combination strategies, immunotherapy and the bipolar androgen therapy (BAT), are promising in some subgroups of patients.

• BAT induces clinical responses, including radiologic responses, and can resensitize tumors after acquired resistance to hormone blockade, maybe representing a therapeutic vulnerability which should be explored in next studies.

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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 paper was not funded.