Circulating tumor cell chromosomal instability and neuroendocrine phenotype by immunomorphology and poor outcomes in men with mCRPC treated with abiraterone or enzalutamide.

Background: While the detection of the AR-V7 in CTCs is associated with resistance to abiraterone or enzalutamide (abi/enza) in men with metastatic castration resistant prostate cancer (mCRPC), it only accounts for a minority of this resistance. Neuroendocrine (NE) differentiation or chromosomal instability (CIN) may be additional mechanisms that mediate resistance. Methods: PROPHECY was a multicenter prospective study of men with poor risk mCRPC starting abi/enza. A secondary objective was to assess Epic CTC CIN and NE phenotypes before abi/enza and at progression. The proportional hazards (PH) model was used to investigate the prognostic importance of CIN and NE in predicting progression free survival (PFS) and overall survival (OS) adjusting for CTC number (CellSearch), AR-V7, prior therapy, and clinical risk score. The PH model was utilized to validate this association of NE with OS in an external dataset of patients treated similarly at MSKCC. Results: We enrolled 118 men with mCRPC starting on abi/enza; 107 were evaluable on the Epic platform. Of these, 36.4% and 8.4% were CIN positive and NE positive, respectively. CIN and NE were independently associated with worse OS (HR 2.2, 95% CI 1.2-4.0 and HR 3.8, 95% CI 1.2-12.3, respectively) when treated with abi/enza. The prognostic significance of NE positivity for worse OS was confirmed in the MSKCC dataset (n=173, HR 5.7, 95% CI 2.6-12.7). Conclusions: A high chromosomal instability and neuroendocrine CTC phenotype is independently associated with worse survival in men with mCRPC treated with abi/enza, warranting further prospective controlled predictive studies to inform treatment decisions.