Emerging serum and urine biomarkers for non-invasive detection, risk stratification and prognostic assessment of prostate cancer: a systematic review

Abstract

This review synthesised current evidence on emerging serum and urine protein biomarkers with diagnostic, prognostic, and predictive relevance for non-invasive PCa detection and risk stratification. A systematic search of PubMed, Scopus, and ScienceDirect was conducted for studies published between January 2006 and December 2025. Study selection was performed independently by two reviewers, with disagreements resolved by an additional reviewer. Eligible cohort, case-control, and cross-sectional studies reporting diagnostic performance were included. Study quality was assessed using the QUADAS-2 tool, and findings were synthesized narratively. Out of 1,543 records identified, sixteen studies met the inclusion criteria with moderate-to-low overall risk of bias. Our analysis highlights several biomarkers that demonstrate superior diagnostic performance compared to PSA models. These key serum-based potential markers include the PSA derivatives, particularly Prostate Health Index (PHI), which consistently improves prediction of significant PCa and tumor volume; the GDF15 propeptide, which reliably detects bone metastasis in castration-resistant PCa; and the MiCheck panel (IL-7, VEGF, GPC-1), which effectively differentiates aggressive from non-aggressive PCa. Furthermore, the serum PSP94/PSA ratio shows strong potential to distinguish PCa from benign prostatic hyperplasia (BPH). Notable urine-based markers include ANXA3, which significantly enhances diagnostic performance in the PSA “gray zone” (4–10 ng/mL), and panels of uromodulin peptides, which demonstrate high specificity in differentiating PCa from controls. The integration of these novel markers into multivariable models significantly increases diagnostic accuracy, with some combinations achieving AUCs as high as 0.979. Exosomal PSA demonstrated good diagnostic performance compared with conventional serum PSA; however, these findings should be interpreted with caution, given the small sample size and lack of external validation. Serum and urine protein biomarkers may complement PSA-based testing to improve non-invasive PCa detection and risk stratification, thereby minimising PSA-associated overdiagnosis and avoiding unnecessary biopsies.