The evolving role of PSA in prostate cancer screening: revisiting the evidence in the era of personalized medicine

Prostate-specific antigen (PSA) is a widely available and analytically robust biomarker, but its role in prostate cancer (PCa) screening remains controversial due to concerns regarding limited specificity, overdiagnosis of indolent tumors, and the downstream risk of overtreatment. This review provides a critical analysis of the main randomized trials, systematic reviews, and meta-analyses that have shaped current recommendations against PSA-based screening, highlighting the substantial methodological heterogeneity that complicates interpretation of aggregated outcomes. Key limitations identified across studies include variability in PSA thresholds and screening intensity, insufficient follow-up in some cases to detect long-term mortality benefits, non-comparability of PSA assays, and extensive contamination of control groups - particularly in the PLCO trial - which undermines estimates of screening efficacy. Recent updates from the ERSPC and CAP trials show that mortality reductions associated with screening increase with longer follow-up, supporting the need to reassess earlier conclusions. Parallel to the evolving evidence base, European initiatives such as the PRAISE-U consortium and several regional pilot programs following the European Council's recommendations are implementing risk-adapted pathways that combine baseline PSA stratification with multiparametric MRI triage and selective biopsy. These programs aim to minimize overdiagnosis while improving detection of clinically significant PCa and generating real-world evidence for organized screening. Additionally, the variability among PSA assays underscores the need for greater harmonization and standardized reporting. Overall, emerging data suggest that intelligently targeted, risk-stratified PSA screening may offer a more balanced approach than the traditional dichotomy of screening vs. no screening.