Targeting the Mechanisms of Progression in Castration-resistant Prostate Cancer

Until recently, few treatment options were available for metastatic castration-resistant prostate cancer (mCRPC). However, in recent years, there has been a rapid increase in the number of therapeutic options in addition to docetaxel. Novel therapies include the androgen synthesis inhibitor abiraterone, the antiandrogen enzalutamide, the taxane cabazitaxel, immunotherapeutic sipuleucel-T, and bonetargeting radium 223. Although these new therapies have shown an improvement in overall survival for patients with mCRPC, and although clinical trials optimising their sequence with one another may further increase survival values, death from mCRPC is invariably due to resistance to contemporary treatment modalities. Understanding the biology behind mCRPC is of crucial importance if we are to develop new and better treatment regimens for this patient group. In this month’s issue of European Urology, Karantanos et al provide an updated and in-depth review of issues pertaining to mechanisms behind development of resistance in mCRPC [1]. While the molecular basis implicated in the development of CRPC is complex and varied, it is clear that androgen receptor (AR) signalling remains an important driver of mCRPC despite systemic androgen deprivation and the new therapeutic options available today. Schweizer et al recently showed that docetaxel has only limited antitumor activity in CRPC patients previously treated with abiraterone [2], and this cross-resistance is likely due to interference of taxanes with the AR pathway [3]. Likewise, it has been reported that there is crossresistance between abiraterone and enzalutamide therapy, although a proportion of patients benefit from sequential treatment therapy [4]. Such resistance may be associated