The AR pathway inhibitors (ARPI) abiraterone (ABI) and enzalutamide (ENZ) prolong survival of patients with metastatic CRPC. However, resistance rapidly occurs in patients, and targeting the AR with novel inhibitors is merely palliative. This lack of durable control of AR inhibition in drug resistant CRPC may reflect a shift in the natural history of this classically “AR-driven” disease to a “AR non-driven” phenotype, characterized in patients by low circulating levels of PSA despite high metastatic burden in soft tissues, and resistance to AR inhibitors. This hypothesis is supported by recent data from the Stand up to Cancer-Prostate Cancer Foundation East Coast and West Coast Dream Team (SU2C) indicating up to 27% of CRPC patients resistant to ARPI, including ENZ or ABI, develop an AR non-driven disease resulting in poor survival. Notably, our pre-clinical model of ENZ-R also reflects this clinical distribution of disease heterogeneity, as we have shown that while 75% of ENZ-R tumors recur in vivo with AR re-activation and rising PSA, 25% of tumors show downregulation of canonical AR target genes, including PSA, and maintain an AR non-driven phenotype. Dr Zoubeidi will discuss how cell plasticity including cancer stem cells and neuroendocrine are mechanisms of ENZ resistance.