BackgroundPSA is central to referrals for prostate biopsy but has low specificity for aggressive prostate cancer. This study evaluates the 4Kscore (OPKO Diagnostics) versus total PSA in predicting short- and long-term risks of aggressive prostate cancer.MethodsBaseline blood samples from 1,658 men diagnosed with prostate cancer (median diagnosis time = 8.6 years) and 1,658 matched controls in the European Prospective Investigation into Cancer and Nutrition were analyzed. Discrimination for the 4Kscore and total PSA was assessed using the AUC with 95% confidence intervals (CI) via bootstrapping.ResultsFor high-grade tumors, AUCs were 0.69 (95% CI, 0.66-0.72) for the 4Kscore and 0.75 (95% CI, 0.73-0.78) for total PSA. For advanced-stage disease, AUCs were 0.71 (95% CI, 0.66-0.75) for the 4Kscore and 0.77 (95% CI, 0.73-0.80) for total PSA. Similar findings were observed for other aggressive cancer endpoints. Among men with PSA >2 ng/mL, the 4Kscore had better discrimination than PSA for overall prostate cancer, high-grade disease, and prostate cancer death but only in men <60 years at recruitment.ConclusionsIn this large European study, the 4Kscore did not significantly improve the prediction of clinically significant prostate cancer compared with total PSA, except in younger men with elevated PSA.ImpactThe findings underscore the limited utility of the 4Kscore in improving medium- to longer-term risk prediction over PSA, with potential benefits restricted to younger men with elevated PSA.