It is well recognized men with metastatic hormone sensitive prostate cancer (mHSPC) managed with testosterone suppression alone have varied overall survival (OS). “First-generation radiomics” with conventional imaging using CT and Technetium bone scan revealed men with liver metastases and/or 4 or more bone metastases have poorer overall survival (OS) managed with testosterone suppression alone but are more likely to benefit from the addition of the cytotoxic chemotherapy, docetaxel. In contrast, there is clear evidence of an OS benefit from addition of new potent androgen receptor inhibitors to testosterone suppression for patients regardless of distribution and number of metastases. In the presentation, details will be provided regarding the strategic and orthogonal multi-omic approaches being used to define biomarkers associated with varied prognoses and benefits from chemotherapy, hormonal therapy, PARP inhibition and AKT inhibitors.