Effect of Prostate Cancer Screening with Prostate-specific Antigen Testing on Long-term Prostate Cancer-specific Mortality: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

CONTEXT: Earlier evidence syntheses reached uncertain conclusions about the effect of prostate-specific antigen (PSA)-based screening on prostate cancer (PCa)-specific mortality (PCSM). Extended follow-up from major trials has provided an opportunity to re-evaluate the evidence.

OBJECTIVE

To estimate the effect of PSA-based screening versus no screening or usual care on PCSM in individuals engaging in screening.

EVIDENCE ACQUISITION: We systematically searched PubMed, MEDLINE, EMBASE, and CENTRAL through October 2025 for randomized controlled trials (RCTs) comparing PSA-based screening with no screening or usual care among adults with prostates. The primary outcome was PCSM at the longest available follow-up. Secondary outcomes were PCSM beyond 12 yr and PCSM closest to 10 yr of follow-up. Risk of bias was assessed using the Risk Of Bias instrument for Use in SysTematic reviews-for RCTs (ROBUST-RCT). Incidence rate ratios were pooled using fixed-effect models. Certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.

EVIDENCE SYNTHESIS: We included 5 RCTs analyzing 721,607 participants aged 45-80 yr of age with 11-23 yr of follow-up. PSA-based screening, with a high certainty in the evidence, demonstrated a reduced risk of PCSM at the longest follow-up (p < 0.001). Secondary analyses suggested greater relative PCSM reduction with longer follow-up. The overall effect was observed despite limitations including differing screening protocols and control-arm contamination, which likely underestimated benefit.

CONCLUSIONS

With 11-23 yr of follow-up, high-certainty evidence demonstrates that PSA-based PCa screening is associated with reduced PCSM among individuals who engage in screening-a finding that contrasts with earlier evidence syntheses. This finding does not in itself justify population-based screening or imply that every well-informed individual would elect to undergo screening. This PCSM benefit should be weighed against known harms and consider emerging approaches under study that may mitigate these harms.