Background: Neoadjuvant androgen deprivation therapy (nADT) with abiraterone and prednisone for localized disease leads to pathological complete response (pCR) rates of up to 10%. In this study we tested the efficacy of nADT with enzalutamide for patients with high risk, localized disease. We also tested the ability of post-treatment multiparametric MRI (mpMRI) to evaluate response. Methods: A single institution trial (NCT02430480) evaluated nADT (goserelin) and enzalutamide 160 mg daily in patients with high risk non-metastatic prostate cancer. Patients underwent MRI-TRUS-guided fusion biopsy at screening and repeat mpMRI followed by radical prostatectomy (RP) after completing six months of therapy. Results: Twenty-two patients have completed therapy and undergone radical prostatectomy. Baseline clinical characteristics were typical of those with high risk disease: median PSA 10.3 ng/ml (range 2.1-985.9) and clinical stage by mpMRI cT2-cT4. Following 6 months of therapy, median pre-RP PSA was 0.02 ng/ml (range < 0.02 – 0.35). On final pathology, 0 patients were upstaged, 5 (23%) were unchanged, and 15 (77%) were downstaged, including 4 (18%) with pCR or near pCR (Residual Cancer Burden < 0.001 cc). Five of 9 patients with bulky nodes at baseline were downstaged to pN0. Of 9 patients with pT3 disease at prostatectomy, 6 were cT3 on post-treatment mpMRI. Of 4 patients with pCR or near pCR, 1 was cT0, 1 was cT2, and 2 were cT3 on post-treatment mpMRI. One additional patient had radiographic complete response but was pT3a on pathological review. Conclusions: Six months of nADT with enzalutamide has activity in high risk, localized prostate cancer, with a small number of patients having exceptional responses. Standard analysis of mpMRI identifies most patients with persistent T3 disease but does not reliably identify exceptional responses. Evaluation of molecular characteristics that predict exceptional response or intrinsic resistance is on-going. Clinical trial information: NCT02430480