Background: Current data suggests RB function is often attenuated in tumors through hyperphosphorylation; thus, RB activity can be “re-awakened” in RB+ tumors by suppressing key kinases that phosphorylate RB (CDK4/6). Recent findings identified perturbations of the RB tumor suppressor as a major mechanism of androgen receptor (AR) deregulation and castration-resistant prostate cancer (CRPC) formation. Our preclinical studies indicate RB+ tumors are exquisitely responsive to CDK4/6 inhibitors, revealing tumor-specific cytostatic and cytotoxic effects. These analyses strongly support the use of CDK4/6 inhibitors to activate the RB pathway, and impede the transition to CRPC. We hypothesize the CDK4/6 inhibitor ribociclib (ribo) in combination with enzalutamide (enz) in patients (pts) with progressive metastatic CRPC (mCRPC) that retains RB expression will significantly increase the efficacy of enz.Methods: This is a phase IB/II study of pts with mCRPC with RB+ tumors who have not received chemotherapy. Since ribo and enz have not been combined together in pts, the standard doses of enz and a traditional 3x3 dose escalation schema will be used in phase I to establish the safe dose of the combination; this dose will be used in phase II. Since both drugs are metabolized via the liver, plasma concentrations of ribo and enz will be monitored. To determine if ribo will improve the clinical activity in pts treated with enz, a randomized (1:1) phase II study using enz as the control arm vs. the combination will follow. This study will evaluate an early clinical activity readout, thus the primary phase II endpoint will be a proportion of pts with ≥ 50% PSA decline at 12 weeks. Secondary endpoints are rPFS, PSA PFS, OS and safety. If there is clinical activity noted, further randomized testing will be required to establish ribo clinical benefit in combination with enz. 5 sites are participating, managed by the Prostate Cancer Clinical Trials Consortium. Dose Levels 1 and 2 have been completed without any DLTs in the phase I portion of the study. A review of Dose Level 3 is planned for October 2017. Clinical trial information: NCT02555189