Gonadal androgen suppression (castration via orchiectomy or gonadotropin-releasing hormone analogues) suppresses circulating testosterone levels but does not achieve adequate androgen ablation within the prostate cancer microenvironment because it does not address adrenal and intratumoral steroid contributions. These residual extragonadal sources of androgens allow prostate cancer cells to survive, adapt, and evolve into castration-resistant prostate cancer (CRPC). The persistent significance of the androgen receptor (AR) axis in CRPC was recently validated by the clinical efficacy of androgen synthesis inhibitors (abiraterone) and novel, second-generation AR antagonists (enzalutamide). The appreciation that conventional therapeutic approaches achieve a suboptimal ablation of intratumoral androgens and AR axis signaling output opens transformative therapeutic opportunities. A treatment paradigm of comprehensive AR axis targeting at multiple levels (androgen synthesis, metabolism, and action) and at all relevant sites (gonadal, adrenal, intratumoral) simultaneously at the time of initiation of endocrine therapy (instead of the current approach of sequentially adding one agent at a time and only after disease progression) deserves examination in clinical trials to explore whether maximal first-line AR axis suppression via combination therapy can achieve maximal induction of cancer cell apoptosis (before they have the chance to adapt and evolve into CRPC) and thus, improve patient outcomes. Cancer Res; 73(15); 4599-605. ©2013 AACR.