Men who develop metastatic castration-resistant prostate cancer (mCRPC) will invariably succumb to their disease. Thus there remains a pressing need for preclinical testing of new drugs and drug combinations for late-stage prostate cancer (PCa). Insights from the mCRPC genomic landscape have revealed that, in addition to sustained androgen receptor (AR) signaling, there are other actionable molecular alterations and distinct molecular subclasses of PCa; however, the rate at which this knowledge translates into patient care via current preclinical testing is painfully slow and inefficient. Here, we will highlight the issues involved and discuss a new translational platform, "the co-clinical trial project," to expedite current preclinical studies and optimize clinical trial and experimental drug testing. With this platform, in vivo preclinical and early clinical studies are closely aligned, enabling in vivo testing of drugs using genetically engineered mouse models (GEMMs) in defined genetic contexts to personalize individual therapies. We will discuss the principles and essential components of this novel paradigm, representative success stories and future therapeutic options for mCRPC that should be explored.