Purpose: The hypothesis of this study is that EPI-001 that targets the AR NTD will inhibit AR-driven recurrence of prostate cancer resistant to current methods of androgen deprivation or blockade. Scope: Aim 1 will determine the impact of EPI-001 on castration sensitive tumor regression and re-growth in LuCaP xenografts and on growth of their castration resistant forms. Aim 2 will examine the impact of EPI-001 on castration sensitive and castration resistant growth of tumors with differing tumor androgen levels and differing ratios of ARv567es to full-length AR. Aim 3 will elucidate the specific molecular mechanisms by which EPI-001 inhibits the activity of full-length AR and truncated ARv567es variants using in vitro models. Progress: This is the final report on this award. The SOW has been completed and the EPI compound had transitioned to Phase 1 clinical trial. Findings: We have clearly shown that EPI-001 and -002 can suppress the growth of AR-variant driven prostate cancers. We have also shown that Intratumoral androgens play a major role in determining response to N-terminal inhibition. We have shown in this reporting year that EPI combined with MDV is additive on suppressing the growth of castrate-resistant xenografts. Further, we show that the expression of stimulatory co-regulators of the AR do not blunt the activity of EPI on suppression of AR activity. Significance: Based on these studies to this point EPI has entered Phase 1 clinical trials.