Advances in genomic sequencing and molecular characterization are improving our understanding of the biology of prostate cancer and challenging us to translate emerging data into meaningful clinical outcomes. Several recently approved treatments for advanced prostate cancer extend survival; however, these therapies are not personalized based on predictive biomarkers. Innovative strategies for early phase drug testing that harness our growing knowledge of important prognostic markers and emerging predictive biomarkers are needed. In this review we discuss new strategies to assess drug response in early phase clinical trial testing.