Background: Allostatic load (AL)/chronic toxic stress is linked to a higher risk of adverse cancer-specific and cardiac events in prostate cancer (PC) patients especially non-Hispanic Blacks (NHBs). We hypothesize that NHBs experience more adverse social determinants of health (SDOH) that increases this AL. Methods: We included men≥18 years diagnosed with PC (2010-2022). Individual-level SDOH with 19 covariates across 4 domains was obtained. Pre-PC diagnosis AL was calculated as an ordinal measure (0-11). Components and cutoffs for the AL score: Each measure above the cutoff add 1 point to AL. Systolic blood pressure (BP) ≥140 mmHg, diastolic BP ≥90 mmHg, heart rate >100 bpm, total cholesterol (chol) ≥240 mg/dl, high-density lipoprotein chol ≤50 mg/dl, triglycerides ≥150 mg/dl, glycated hemoglobin ≥6.5, body mass index ≥30 kg/m2, glucose ≥110 mg/dl, C-reactive protein >3 mg/L and interleukin-6 >1.8 pg/ml. A gradient-boosting Machine Learning model ranked AL predictors using SHAP scores (SS). Cubic splined from logistic regressions defined SDOH adversity cutoffs. Results: Among 4,258 patients (886 NHB), the median age was 69 (IQR 63-77). Most were former smokers (44.2%), and the median Charlson comorbidity score was 4 (IQR 2-7). In NHBs, the SDOH variables among the top 5 overall predictors of AL were annual income (SS=0.10), neighborhood murder index (SS=0.07), neighborhood median income (SS=0.06), and neighborhood car theft index (SS=0.05). Considering all the SDOH features analyzed, NHBs faced adversity in 12 of 19 SDOH features (63%; Table). Conclusions: SDOH related to the neighborhood, built environment, and economic stability, are crucial predictors of pre-PC diagnosis AL in NHBs.

*<0.001.