Treatment options for metastatic castration-resistant prostate cancer (CRPC) have evolved with the established benefit of the novel androgen receptor (AR)-targeted agents abiraterone and enzalutamide in the prechemotherapy setting. However, concerns regarding cross-resistance between the taxanes docetaxel and cabazitaxel and these AR-targeted agents have arisen, and the optimal drug treatment sequence is unknown. We investigated the in vivo efficacy of docetaxel and cabazitaxel in enzalutamide-resistant CRPC, and mechanisms of cross-resistance between these agents. Castrated mice harboring enzalutamide-resistant tumors and enzalutamide-naïve tumors were treated with docetaxel and cabazitaxel. Tumor growth kinetics, AR nuclear localization, AR-regulated gene expression, Ki67 expression, and serum levels of prostate-specific antigen, docetaxel, and cabazitaxel were analyzed. Docetaxel inhibited tumor growth, AR nuclear localization, and AR-regulated gene expression in enzalutamide-naïve tumors, but did not in enzalutamide-resistant tumors, demonstrating in vivo cross-resistance. By contrast, cabazitaxel remained highly effective in enzalutamide-resistant tumors and demonstrated superior antitumor activity compared to docetaxel, independent of the AR pathway. These findings demonstrate that the AR pathway is able to confer in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in CRPC. Patient summary We found reduced efficacy of docetaxel, but not cabazitaxel, in enzalutamide-resistant prostate cancer.

Androgen receptor, Cabazitaxel, Castration-resistant prostate cancer, Cross-resistance, Docetaxel, Enzalutamide, Taxanes
dx.doi.org/10.1016/j.eururo.2014.11.033, hdl.handle.net/1765/91481
European Urology : Official Journal of the European Association of Urology
Department of Medical Oncology

van Soest, R.J, de Morrée, E.S, Kweldam, C.F, de Ridder, C.M.A, Wiemer, E.A.C, Mathijssen, A.H.J, … van Weerden, W.M. (2015). Targeting the androgen receptor confers in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in castration-resistant prostate cancer. European Urology : Official Journal of the European Association of Urology, 67(6), 981–985. doi:10.1016/j.eururo.2014.11.033