Background: IL-6 is an upstream regulator of various moieties, including STAT3, that are associated with a poor prognosis in mCRPC. The specific association between these moieties and outcomes with enza and abi are as yet undefined. Methods: Pts receiving abi or enza in the course of routine clinical care were consented for blood collection at weeks 0, 4, 8, and 12 of therapy, and at the time of progression (based on PCWG3 criteria). PBMCs were isolated within 4 hours of blood collection and plasma samples were assessed for 30 soluble immune mediators using Luminex analysis. Flow cytometric analysis was used for characterization of CD3, CD4, CD8 and PD-1. CellSearch was used for CTC enumeration. Results: Of 36 patients consented, 21 received abi and 15 received enza. Median age in the cohort was 71 (range, 54-84). Median PSA was 21.9 ng/dL (range, 0-918.3) and mean CTC count was 158 (range, 0-2126). Median duration of therapy (DOT) with abi or enza was 10.5 mos (range, 1-53); pts were divided into two groups around median DOT. Median DOT in Group A and B were 4 mos (range, 1-10) and 49 mos (range, 11-53), respectively. Patients in Group A had higher levels of pre-treatment levels of IL-6, IL-10, GM-CSF, MIG and FGF, and higher expression of PD1 and FoxP3 on CD4+ T cells (P < 0.05 for each). In an exploratory analysis, patients with > 5 CTCs/7.5 mL of blood at baseline had higher levels of IL-6, although this was not statistically significant (P = 0.08). Conclusions: Elevated levels of IL-6 and several other cytokines are seen in patients with relative resistance to abi/enza for mCRPC. Surface expression of PD-1 and FoxP3 on CD4+ T-cells is also higher in the setting of resistance. The dual combination of elevated pro-inflammatory cytokines along with elevated immunosuppressive signals supports ongoing trials assessing checkpoint inhibition with abi/enza, as well as efforts by the current investigators to develop therapies antagonizing STAT3 (Moreira D et al CCR 2018).