Metastatic castration-resistant prostate cancer: targeting the mechanisms of resistance to abiraterone acetate and enzalutamide

Abstract

Persistent androgen receptor (AR) axis is a functionally important pathway for prostate cancer cells and it is currently regarded as a critical therapeutic target. Although the impressive clinical activity of new hormonal agents, such as the second-generation AR antagonist enzalutamide (formerly MDV3100) and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone acetate (AA), in patients with metastatic castration-resistant prostate cancer (mCRPC), innate or acquired resistance invariably arises. To date, emerging hypotheses are different, but the mechanisms of resistance to these drugs have not yet been clarified. The aim of this review is to summarize the main data available on the evaluation of the multiple levels of development of resistance to next-generation AR-directed therapies. Understanding how the AR is activated may have clinical implications in defining which patients will respond to existing therapeutic agents and provide a proof for making novel strategies.

Keywords:

• abiraterone acetate
• drug resistance
• enzalutamide
• metastatic castration-resistant prostate cancer
• prostate cancer

Financial & competing interests disclosure

This work was supported by Italian Association for Cancer Research (AIRC-IG 11930, AIRC 5 per mille 12214). F Massari has consultancies for Pfizer, Novartis, speaker’s fee from Pfizer, GSK, Novartis, Janssen, Sanofi-Aventis, Pierre Fabre; G Tortora has consultancy role for Novartis, Pfizer and GSK. The authors have no other 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 apart from those disclosed.

Key issues

• The maintenance of androgen receptor (AR) axis is a core mechanism in mCRPC and it is actually considered a critical therapeutic target.

• Although the recent impressive clinical activity of abiraterone and enzalutamide in mCRPC, it has been evident that not all patients in either therapy have the same successful outcome, developing innate or acquired resistance, with a widely variable duration of response.

• The main data currently available on the potential mechanisms of resistance to these two drugs include ectopic androgen synthesis, persistent AR signaling (AR amplification or overexpression, genetic mutations in the AR gene, AR splice variants), activation of compensatory AR-independent pathways and modulation of AR coregulators.

• There is increasing and emerging evidence of cross-resistance among abiraterone and enzalutamide, which may complicate the prognostic and predictive implications.

• Understanding how the AR is exactly activated and evaluating the multiple levels of development of resistance to next-generation AR-directed therapies may have clinical implications for determining which patients will most benefit from existing drugs and provide a foundation for making new strategies.

• The identification of the best timing, setting and sequence for novel agents to maximize clinical benefit and minimize the risk of cross-resistance represents a further step toward understanding the molecular complexity behind the universe of the mCRPC.

• Overall, in terms of prognostic and predictive implications, the heterogeneity of the different genetic abnormalities represents one of the major research issues, together with the development of resistance to the targeted agents.

Notes