Genomic studies in clinical castration resistant prostate cancer have highlighted alterations in the cell cycle including RB1 deletion and CDK4 and CCND1 amplifications as critical drivers of prostate cancer (PCa) progression. This finding, together with the success of CDK4/6 cell cycle inhibitors in breast cancer has led to the initiation of phase-II trials for these agents in PCa. Despite CDK4/6 inhibitors palbociclib and ribociclib entering clinical trials, there has been little pre-clinical characterisation of their efficacy in PCa. In this study we aimed to characterise the anti-tumour activity of ribociclib in PCa cell lines, and in a patient derived explant (PDE) model of PCa.