Urinary Creatine Riboside Complements PSA to Improve Disease Detection in the Diagnostic Gray Zone of Prostate Cancer

Circulating prostate-specific antigen (PSA) discriminates poorly in the diagnostic gray zone (3.0–9.99 ng/mL), where ~75% of biopsies yield no clinically significant prostate cancer (PCa). We evaluated whether urinary creatine riboside (CR), a tumor-derived metabolite excreted through the prostatic urethra, complements PSA for gray-zone detection and independently predicts prostate-cancer-specific mortality (PCSM). In the NCI-Maryland PCa Case-Control Study (951 cases, 962 controls; 47.6% African American men; median follow-up 11.5 years), urinary CR was quantified by UPLC-MS/MS. Within the PSA gray zone ( n = 668), urinary CR was complementary to PSA, with markedly higher single-marker discrimination than PSA (AUC 0.93, 95% CI 0.88–0.98 vs 0.77, 0.66–0.89) and additive when combined (ΔAUC +0.17, p < 0.001; 91.4% sensitivity at 80% specificity). After adjustment for 11 clinical and sociodemographic covariates, urinary CR independently predicted PCSM complementary to PSA (Fine–Gray SHR 1.72, 1.35–2.19 for CR; 1.35, 1.08–1.68 for PSA; Harrell’s C 0.85 for CR + PSA vs 0.77 for PSA alone), with strongest signal in African American men (SHR 2.43, 1.57– 3.75 for CR). We conclude that urinary CR is a candidate non-invasive biomarker complementary to PSA — improving gray-zone triage and predicting PCSM; prospective validation in biopsy-referred cohorts is warranted.