Background: Androgens drive proliferation of prostate cancer cells via upregulation of cyclin D which complexes with the CDK4/6 kinases, resulting in phosphorylation of Rb and G1/S progression. Perturbations in this pathway (loss of Rb, upregulation of cyclin D) are felt to promote castration-resistance. PD0332991 (palbociclib) is a novel specific inhibitor of CDK4 and 6. Preclinically PD0332991 inhibited proliferation and promoted G1 arrest in an RB and Cyclin D-dependent manner. 80-90% of early metastatic hormone-sensitive prostate cancers are estimated to retain wild-type RB expression. Addition of PD0332991 to hormonal therapy in ER+ breast tumors demonstrated statistically significant improvements in progression-free survival. Hypothesis: Addition of PD0332991 to initial ADT in patients with newly metastatic RB-positive prostate cancer will significantly increase the efficacy of ADT. Methods: A multicenter randomized phase II study of PD0332991 was initiated (NCT02059213) in which patients (n = 60) with new metastatic hormone sensitive prostate cancer and RB intact tumors based on metastatic biopsy are stratified by disease extent and randomized (1:2) to ADT or ADT plus PD0332991. Primary endpoint is PSA response ( < 4 ng/mL) after 7 months of therapy. With 20 patients randomized to ADT and 40 randomized to ADT plus PD0332991 there will be 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: safety and tolerability of ADT + PD0332991, rate of undetectable PSA ( < 0.2ng/mL), biochemical and clinical progression-free survival, overall PSA and radiographic response rates, assessment of biomarkers which predict therapy response (circulating DNA and tumor cells, tumor protein and transcriptome analysis) and to establish a repository of metastatic hormone sensitive prostate tumor samples. Support: Movember-PCF Challenge Award, Pfizer. Clinical trial information: NCT02059213