132 Background: Numerous resistance mechanisms have been postulated in progressive mCRPC. Determining the presence of putative predictive biomarkers in patients requires a real-time tumor assessment because the biology changes under the influence of the specific therapy(ies) that a patient (Pt) has received. We examined CTC and CTC subpopulation incidence and molecular characterization of tumors from Pts with progressive mCRPC to assess if determinants of resistance can be assessed through a CTC test. Methods: 48 samples from 21 unique progressive mCRPC pts treated with androgen receptor targeted (AR tx) therapies, 9 (43%) on Abiraterone plus Prednisone (AA+P) and 12 (57%) on Enzalutamide (E). Samples were collected and shipped to Epic Sciences, where cells were stained and CTC identified by fluorescent scanners and algorithmic analysis. CTCs, defined as classic (CK+ CD45- w/intact DAPI nuclei and distinct), apopotic (CK+, CD45-, non-intact nuclei) and CK- (CK-, CD45-, intact and distinct) were identified. CTCs reported per mL of blood and were examined for AR, PTEN & ERG. CTC data were analyzed in context of PSA, Veridex CTC (reported per 7.5mL of blood), and clinical history. Results: With Epic, all 21 pts had detectable CTCs (mdn 23 cells/ml, range 2 to 249), whereas with Veridex, 14 (67%) pts had > 5 CTC/7.5 ml (mdn 5 cells/7.5 ml, range 0 to >200). 0/7 (0%) with high AR responded to AA+P or E, 8/14 (53%) with low AR had a PSA decline and stable radiographic disease (median follow-up 12 wks). Variations in AR protein expression and localization heterogeneity was seen in all pts to varying degrees. 6/21 (29%) Pts demonstrated CK- CTC/CTC ratio >50% (mdn 9 cells/ml, range 5-38). ERG rearrangement and PTEN loss were correlated. Conclusions: Epic CTC analysis provides higher detection rates, while enabling individual cell analyses for predictive biomarkers of sensitivity to AR directed therapies. Notable was the marked heterogeneity of detection of AR, ERG, and PTEN of individual CTCs. Studies are ongoing to further explore associations with outcomes. [Table: see text]