Risk-stratified Prostate Cancer Screening in 2026: Blood- and Urine-based Biomarkers

Prostate cancer (PCa) encompasses a broad biological spectrum ranging from indolent to aggressive disease. Although early randomized trials generated controversy regarding the benefits versus harms of screening, contemporary evidence supports screening and early detection strategies that focus on men at the highest risk of clinically significant PCa (csPCa) or International Society of Urological Pathology grade group ≥2. Current guidelines from major urological associations emphasize shared decision-making, with earlier screening considerations for high-risk populations. Prostate-specific antigen (PSA) testing is important in PCa screening, but its limited specificity necessitates adjunctive tools to reduce unnecessary biopsies and overdiagnosis. Risk calculators/nomograms, magnetic resonance imaging (MRI), blood-based assays (including PSA derivatives and multivariable tests such as the Prostate Health Index, 4Kscore, Stockholm3, and Proclarix), and urine-based assays (including SelectMDx, MyProstateScore 2.0, ExoDx, and miR Sentinel) further refine detection. The integration of MRI and biomarkers represents modern risk-adapted screening and early detection pathways. Ongoing large-scale trials are evaluating multimodal biomarker and MRI strategies to optimize csPCa detection while minimizing harm. Overall, risk-stratified, imaging- and biomarker-driven approaches offer pragmatic and evidence-based pathways to enhance early detection of csPCa while reducing overdiagnosis and overtreatment. PATIENT SUMMARY: This short review discusses how blood and urine tests, alongside genetic risk information, can help identify the men most likely to harbor aggressive prostate cancer-enabling early detection and intervention while avoiding unnecessary biopsies and potential harm in men at low risk.