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.
Written by:
van Soest RJ, de Morrée ES, Kweldam CF, de Ridder CM, Wiemer EA, Mathijssen RH, de Wit R, van Weerden WM. Are you the author?
Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; Department of Pathology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; Department of Medical Oncology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Reference: Eur Urol. 2014 Dec 4. pii: S0302-2838(14)01216-0.
doi: 10.1016/j.eururo.2014.11.033
PubMed Abstract
PMID: 25484141