Background: PCa is driven by androgen receptor (AR) signaling and neoadjuvant therapy with AR inhibitors offer an opportunity to improve cure rates in high-risk PCa particularly with utilization of multiparametric MRI (mpMRI). A loss of AR-regulated lineage characteristics and genomic loss of tumor suppressors RB1 and TP53 or mutations in DNA damage repair (DDR) genes can represent aggressive prostate variants. We conducted a feasibility study using mpMRI to evaluate tumor responses and resistance in newly diagnosed, high-risk PCa (NCT02430480). Methods: Pts were treated with androgen deprivation therapy (ADT) + enzalutamide (enza) 160 mg daily for 6 months (mos). Pts underwent 2 mpMRIs: baseline and post 6 mos treatment (trt). Post-trt mpMRI was followed by radical prostatectomy (RP). Primary endpoint: feasibility of mpMRI for localization and detection of PCa before and after ADT + enza. Results: 39 pts were enrolled on-study with 36 pts completing 6 mos trt and undergoing RP. Of 39 pts, 3 had disease progression. Conclusions: Neoadjuvant intense testosterone lowering therapy shows activity in PCa but a subset of pts not respond to AR-targeted therapies through lineage plasticity enabled by characteristic loss of RB1 and TP53 or due to genetic alterations. Identification of this high-risk patient population, along with development of treatment options, needs further investigation. Clinical trial information: NCT02430480