Background: Men with CTC AR-V7 + mCRPC have very poor outcomes when treated with enzalutamide/abiraterone. However, many men lack AR-V7. Here, we determined whether baseline or post-treatment DNA alterations in CTCs from AR-V7 negative mCRPC men could provide clinical utility in predicting outcomes with these hormonal therapies. Methods: We analyzed whole-genome copy number alterations (CNA) using array-comparative genomic hybridization (aCGH) in CTCs from 48 men (45 baseline and 28 progression), and whole-exome sequencing (WES) from 11 mCRPC men treated with abi/enza, longitudinally, and focused exclusively on AR-V7 negative men (N = 40) by the Epic-AR-V7 nuclear protein assay, and comparing those men who benefit from therapy vs. who do not. Results: We observed broad heterogeneity of CNAs between patients; common genomic alterations included gain in KDM6A (44%), FOXA1 (44%), MYCN (32%), and AR (38%), and loss in BRCA1 (30%) and PTEN (25%). Men who had the clinical benefit to abi/enza (n = 23, median PFS 10 mo) were more likely to have CTCs with genomic gains of ATM, HSD17B4, or PTEN, and loss of BRAF, ABL1, or NKX3-1. Likewise, men who did not benefit from abi/enza (n = 14, median PFS 2.6 mo) had CTCs with more copy number alterations than men who had clinical benefit (median 19.5 vs. 14, p = 0.01), and were enriched for gain of BRCA2, APC, KDM5D, SPARC, MYCN, AR, and CYP11B1, and loss of PTEN, CHD1, PHLPP1, and NCOR2. After progression on abi/enza, we observed clonal evolution of CTCs harboring gain of ATM, FOXA1, KDM6A, CYP11B1, MYC, APC, and NCOR2, and loss of NCOR1, ERG, and RUNX2. Several COSMIC-validated non-synonymous pathogenic exome mutations were detected in progressed or non-responding patients’ CTC DNA; TP53 (55 vs 27% at baseline), AKAP9 (36 vs 9%), CDK12, KMT2D, and BRAF (each 36 vs 18%), and BRD4 and SPOP (each 18 vs 0%). Conclusions: We demonstrate that specific CTC genomic profiles associated with TP53, PTEN, WNT, DNA repair, epigenetic, and AR signaling, as well as lineage plasticity pathways are associated with worse clinical outcomes in AR-V7 negative men with mCRPC treated with abi/enza. Further mechanistic and validation studies are warranted. Clinical trial information: NCT02269982