Sequential Androgen Receptor Pathway Inhibitor in Prostate Cancer: Piling-Up The Benefits or a Case for Cross-Resistance?

*Bertrand Tombal

Cliniques universitaires Saint-Luc, Brussels, Belgium
*Correspondance to

Disclosure: Paid investigator or advisor for Amgen, Astellas, Ferring, Bayer, Medivation, Janssen, and Sanofi-Aventis.
Support: The author would like to thank Dr Caroline Charles for medical writing assistance with this manuscript.
Received: 13.10.14 Accepted: 27.10.14
Citation: EMJ Oncol. 2014;2:40-47.


In the last 10 years, there has been accumulating evidence that, even in a low serum testosterone environment, the androgen receptor (AR) remains the main driver of prostate cancer progression. This has led to the discovery and clinical development of new anti-androgens and androgen biosynthesis inhibitors. Enzalutamide and abiraterone acetate are the lead compounds of this new generation of agents, but multiple other agents are on their way. Because they both target the ligand-dependent regulation of AR activity, it is plausible that cross-resistance may exist when both drugs are used sequentially, and that the benefit of these agents may fade away when sequencing them. As the exact mechanisms for cross- resistance between AR-targeted agents remain unclear at this point, additional clinical studies are crucial to define the exact combination or sequencing order that could yield highest clinical benefits. Moreover, new molecular targets are needed in order to address these resistances, as well as establishing biomarkers to improve patient selection that could most benefit from AR-targeted therapies, but also help develop novel agents to improve and optimise the management of castration-resistant prostate cancer and metastatic, castration-resistant prostate cancer.

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