Background: Androgen receptor signaling inhibitors (ARSi) are a mainstay for patients with metastatic castration-resistant prostate cancer (mCRPC). However, patient response is heterogeneous and the molecular underpinnings of ARSi resistance are not well elucidated. Methods: We performed transcriptome analysis of circulating tumor cells (CTCs) and peripheral blood mononuclear cells (PBMC) in the context of PROPHECY, a prospective clinical trial of men (n = 118) with mCRPC treated with abiraterone (Abi) or enzalutamide (Enza). We obtained CTCs at baseline (before treatment) and at the time of progression on Abi/Enza, performed a comprehensive transcriptomic analysis of CTC patient samples (n = 40) and correlated with clinical outcomes to identify mechanisms of ARSi resistance. In addition, we also performed a transcriptomic analysis of matching peripheral blood mononuclear cells (PBMCs) in order to uncover potential involvement of the circulating immune macroenvironment (CIME) in ARSi resistance. The proportional hazard model was used to determine the prognostic significance of these signatures in predicting overall survival (OS) and progression-free survival (PFS). Results: CTC RNA-sequencing identified that RB loss concurrently with enhanced E2F signaling transcriptional networks were associated with intrinsic ARSi resistance. Using single sample GSEA (ssGSEA) score, we identified that the RB/E2F common signature at baseline was associated with short PFS (median PFS = 6.5 months) and OS (median OS = 24.5 months) (hazard ratio (HR) = 3.5; 95% CI 1.5-8.2) in men with mCRPC. We further developed a BRCA loss transcriptional signature which we validated in the SU2C mCRPC patient cohort, by showing that BRCA loss transcriptional network reflected BRCA genomic alterations as it was significantly enriched in the SU2C BRCA-altered patients vs unaltered patients. Generating BRCA loss ssGSEA scores in the PROPHECY cohort we observed that patients with high BRCA loss scores at baseline experienced shorter OS (HR = 2.42; 95% CI = 1-5.9). Through the comparison of CTC transcriptomic profiles at progression with baseline, we identified an inflammatory response signature in CTCs which was significantly associated with acquired ARSi resistance. Transcriptomic analysis of matching PBMCs identified enrichment of inflammasome gene signatures indicative of activated innate immunity at progression, with concurrent downregulation of CD8 T and NK cells. Importantly, CTC gene signatures of RB loss/E2F signaling had a significant positive association with this CIME signatures. Conclusions: Taken together, these data demonstrate that liquid biopsy transcriptomics of both tumor cells and immune cells can identify molecular pathways associated with clinical ARSi resistance paving the way for treatment optimization and the development of novel precision therapies in patients with mCRPC.