BACKGROUND: Commercial biomarkers and multiparametric MRI (mpMRI) have been utilized to triage men with elevated prostate specific antigen (PSA) and determine patients most likely to harbor clinically-significant prostate cancer (csPCa). We studied combinations of mpMRI, PSA-based and novel extracellular vesicle (EV)-based biomarkers to determine the optimal pre-biopsy testing to predict csPCa at biopsy. METHODS: Men presenting with elevated PSA (≥ 2 ng/mL) were prospectively enrolled and all men underwent clinically indicated mpMRI and blinded study blood draws to determine PSA, prostate health index (PHI) scoring, and EV serum levels. MRI-fusion transperineal prostate biopsy was performed in all patients. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and receiver operator characteristic (ROC) curves were constructed. Bootstrapping analysis was performed to provide more accurate assessment of predictive abilities. RESULTS: Ultimately, 175 consecutive men were prospectively enrolled. Median age in the study population was 65 years. Combinations of biomarkers and MRI demonstrated better predictive ability for csPCa on biopsy than individual modalities. Predictive ability was greatest for PHI density (PHID)-mpMRI with an AUC of 0.86 (95% CI: 0.80-0.92) while combinations of PSA density -mpMRI (AUC: 0.81
95% CI: 0.73-0.89) and STEAP1-mpMRI (AUC: 0.77
95% CI: 0.70-0.86) demonstrated similar ability to predict csPCa. The study is limited by small, predominantly white patient cohort and requires external validation. CONCLUSIONS: Inclusion of prostate density with biomarkers increases prognostic ability for detecting csPCa. EV density can refine prediction of csPCa and in combination with PHID-mpMRI leads to superior specificity, thereby decreasing unnecessary biopsies.