The present invention describes a method for detecting NEPC in a patient afflicted with prostate cancer comprising (a) performing a direct analysis comprising immunofluorescent staining and morphological characterization of nucleated cells in a blood sample obtained from the patient to detect circulating tumor cells (CTC), and (b) determining presence or absence of a CTC subpopulation associated with NEPC comprising detecting a measurable feature of each biomarker in a panel of morphological and protein biomarkers, wherein the presence of the CTC subpopulation associated with NEPC is indicative of NEPC. In other embodiments, the biomarkers for the CTC subpopulation associated with NEPC comprise small size, absence of Androgen Receptor (AR−), and presence of nucleoli (nucleoli+). In additional embodiments, the methods of the invention further comprise molecular analysis of the CTCs.
