Androgen stimulation is fundamental to prostate cancer growth and ultimately to its lethality. Although interest in impeding androgen and androgen receptor (AR) interactions in the disease has been the foundation of its systemic treatment for over six decades, interest has been accelerated by the development of active secondary hormonal therapies that are reaching the clinic concurrent with an understanding of the mechanisms of resistance to androgen deprivation therapy (ADT). These developments not only promise to change the standard therapies in use clinically but are likely to change entirely our perspective on the biology of the disease.

As conventionally described, ADT involves the use of leutinizing hormone releasing hormone (LHRH) drugs (agonists or antagonists) that consistently result in an 90-95% reduction in circulating levels of testosterone, as measured by commercially available immunoassays. Selection pressure induced by this treatment ultimately leads to the emergence of a tumor phenotype characterized by disease progression despite castrate levels of testosterone, which, coupled with metastatic spread, renders the disease lethal. Although the importance of treatment-mediated selection pressure has been appreciated for some time, it is unclear whether the emergence of the lethal phenotype is a function of the ADT itself (eg that, given time, all tumors will develop castration resistance) or that it is a function of factors initiated at the time of carcinogenesis. Interestingly metastasis and castration resistant prostate cancer (CRPC) growth may occur separately, resulting the development of “non-metastatic CPRC” a clinical state that is now the target of a therapeutic approach, which aims to simultaneously