Background: Palbociclib, a CDK4/6 inhibitor, blocked proliferation and promoted G1 arrest in an Rb and Cyclin D dependent manner in preclinical models of HSPC. Alterations in this pathway contribute to the development of CRPC. We hypothesized that co-targeting AR (ADT) and cell cycle (palbociclib) would improve outcomes including PSA RR at 28 weeks in mHSPC pts. Methods: mHSPC pts with Rb intact tumors based on IHC of metastatic biopsy were stratified and randomized (1:2) to Arm A: ADT or Arm B: ADT+ palbociclib (125mg 3 weeks on, 1 week off). Primary endpoint is confirmed PSA RR (≤ 4 ng/mL) after 28 weeks of therapy. With 20 patients randomized to ADT and 40 to ADT + palbociclib there is a 64.2% power to detect a 20% difference in proportions with a one-sided type I error of 0.10 using the mid p-value method of the Fisher’s exact test. Secondary endpoints include safety/tolerability, biochemical and clinical PFS, PSA and radiographic RR and exploratory biomarkers (circulating DNA, tumor cells and transcriptome). Results: 72 eligible pts (median age 67, PSA 73ng/mL) with newly diagnosed mHSPC were registered and underwent biopsy (41 soft tissue, 31 bone). 64/72 (90%) had adequate tissue for RB assessment and 62/64 (97%) retained RB expression (IHC). 62 pts were stratified by disease extent and early initiation of ADT, and randomized. 60 pts initiated therapy (Arm A: 20; Arm B: 40). Neutropenia was the most common G3/4 AE (Arm A: 0% Arm B: 33%). 80% of pts (Arm A: 16/20, Arm B: 32/40; p = 0.87) on both arms met primary PSA endpoint (≤4ng/mL at 28 weeks). PSA undetectable rate at 28 weeks was Arm A: 50% (10/20) and Arm B: 43% (17/40; p = 0.5). Measurable disease RR: Arm A: 78% and Arm B: 74%. 12-month biochemical PFS was Arm A 69% (95%CI: 43-85%), Arm B 74% (95%CI: 56-85%). Clinical PFS is not mature and correlative biomarker studies are ongoing. Conclusions: Co-targeting of AR signaling and cell cycle in a tissue biomarker preselected trial is feasible in mHSPC. RB loss was rare in this population. PSA RR at 28 weeks was not impacted by addition of palbociclib to ADT. Important clinical PFS data will be reported when mature. Clinical trial information: NCT02059213