• Theodoros Karantanos, Christopher P Evans, Bertrand Tombal, Timothy C Thompson, Rodolfo Montironi, and William B Isaacs.
• Department of Genitourinary Medical Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: theodoroskarantanosmd@gmail.com.
• Eur. Urol. 2015 Mar 1; 67 (3): 470-9.

ContextVarious molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC).ObjectiveTo understand the mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC.Evidence AcquisitionPubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants, and AR alterations. Papers published before 1990 were excluded from the review, and only English-language papers were included.Evidence SynthesisThis review summarizes the current literature regarding the mechanisms implicated in the development of CRPC and the acquisition of resistance to novel antiandrogen axis agents. The review focuses on androgen biosynthesis in the tumor microenvironment, androgen receptor (AR) alterations and post-transcriptional modifications, the role of glucocorticoid receptor, and alternative oncogenic signaling that is derepressed on maximum AR inhibition and thus promotes cancer survival and progression.ConclusionsThe mechanisms implicated in the development of resistance to AR inhibition in PCa are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses. Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with CRPC.Patient SummaryWe looked for mechanisms related to the progression of PCa in patients undergoing hormonal therapy and treatment with novel drugs targeting the AR. Based on recent data, combining maximal AR inhibition with novel agents targeting other tumor-compensatory, non-AR-related pathways may improve the survival and quality of life of patients with castration-resistant PCa.Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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