Background: Neoadjuvant therapy with novel androgen receptor inhibitors, like enza, offer an opportunity to improve cure rates in men with high risk PC but also emphasizes the need for improved imaging techniques and genomic studies to evaluate treatment (trt) responses. We conducted a feasibility study using mpMRI to evaluate tumor responses and resistance in newly diagnosed, high-risk PC. Methods: Patients (pts) were treated with androgen deprivation therapy (ADT) + enza 160 mg po qdaily for 6 months (mos). Pts underwent 2 mpMRI: baseline and post 6 mos of therapy. Post-trt mpMRI was followed by radical prostatectomy (RP). Primary endpoint was feasibility of mpMRI for localization and detection of PC before and after therapy with ADT + enza. Results: 31 out of 33 pts completed 6 mos of therapy and underwent RP. Median on-study PSA was 9.58 (1.18-984.72 ng/dL). Median PSA post 6 mos of ADT + enza was <0.02 (0.02-0.35 ng/mL). No pt was taken off-trt for adverse events. Median residual cancer burden (RCB) defined as volume of tumor corrected by tumor cellularity was 0.1584 (0.0001-12.32 cc). Using RCB of <0.05 cc, 12 patients had minimal residual disease of which 4 pts were pathologic complete responses. Post-trt mpMRI volume correlated with final pathology in all cases. Conclusions: Neoadjuvant enza + ADT is tolerable and shows activity in a newly-diagnosed, high-risk population. mpMRI can be utilized to assess responses to trt. Analysis of genomic characteristics and resistance mechanisms is on-going. Clinical trial information: NCT02430480