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Background: With the advent of secondary androgen receptor (AR)-targeted therapies in metastatic castration resistant prostate cancer (PC), nonadenocarcinoma PCs are becoming more prevalent. Many of these cancers express neuroendocrine markers, which may provide biomarkers for emergence of this disease state. We aimed to quantify the expression of synaptophysin (Syp) on circulating tumor cells (CTCs) from serial samples of patients being treated with abiraterone acetate or enzalutamide.Methods: CTCs were isolated from 44 patients with castration resistant PC before starting abiraterone or enzalutamide, at 4, 8, and 12 weeks on therapy, and at progression. Patients were stratified into 3 groups: de novo resistance, short response, and long response. CTCs were enumerated on the CellSearch platform and Syp expression was quantified using the open fluorescent channel on the platform. Correlative analyses were performed.Results: A baseline CTC count of 5 or greater was associated with a more rapid time to progression and increasing CTC counts correlated with emergence of drug resistance. Syp was readily detectable on the surface of CTCs, and baseline percentage CTC Syp expression was significantly associated with time to progression. Furthermore, in evaluable patients, percent CTC Syp expression increased with the emergence of drug resistance. We also found that prior exposure to AR-targeted therapies was inversely associated with progression free survival.Conclusions: We have demonstrated that Syp can be quantified on CTCs and that Syp expression correlates with resistance to abiraterone and enzalutamide. Larger studies testing Syp as a biomarker of emergence of nonadenocarcinoma disease and as a marker of response to AR-targeted therapies are warranted. [ABSTRACT FROM AUTHOR]