Despite the early approval of Sipuleucel-T for metastatic castration-resistant prostate cancer, subsequent progress in prostate cancer immunotherapy development has been limited. It is now generally accepted that we need to tackle prostate cancer by combinatiorial approaches, requiring highly relevant preclinical models for proof of principle efficacy evaluation. PTEN loss of function in the prostate epithelium is one of the central events in human prostate cancer, and activation of the MAPK pathway is often observed in advanced tumors. Our prostate homograft models feature these and other clinically-relevant mutations while retaining morphological similarity to human prostate cancer, thus ideally positioned to test novel combination regimens.