Background Previous recommendations on screening for prostate cancer relied on ongoing trials of screening with prostate-specific antigen (PSA), which may have lacked sufficient follow-up duration to fully examine effects on mortality and overdiagnosis. Findings which consider absolute effects by age and screening intensity, along with newer guidance for assessing evidence certainty, may lead to different interpretations. Adding magnetic resonance imaging (MRI) to PSA-based screening has been raised as a way to reduce false positives (FPs) and overdiagnosis.

Methods We systematically searched MEDLINE, Embase, and Central from 2014 to January 28, 2026, for randomized controlled trials (RCTs) and prospective observational studies of: (i) screening versus no screening and (ii) sequential screening with MRI for those with a positive PSA test versus PSA alone among men not known to be at high risk for prostate cancer. Studies on screening with PSA or digital rectal examination (DRE) published pre-2014 were identified from existing systematic reviews and reference lists. Studies on FPs and complications from biopsies after PSA screening did not require a control group. Paired reviewers screened titles/abstracts (assisted with artificial intelligence) and full texts, assessed risk of bias, and extracted data, by age when available. We pooled data when suitable using random-effects models, investigated heterogeneity, and assessed the certainty of evidence using GRADE with conclusions of effects based on decision thresholds based on absolute effect sizes.

Results Across both questions, we included 15 RCTs (N=856,000; 8 sites of ERSPC considered separate trials) and 8 observational studies (N=56,122). At 20 years, among 1000 men who underwent repeated PSA-based screening every 2-4 years starting from age 55-69 (mean 62), there is likely a reduction in prostate-cancer mortality (≥2 fewer) and metastatic cancer incidence (≥6 fewer), at the expense of prostate-cancer overdiagnosis (≥24 cases) and FPs (≥150 cases) (all moderate certainty). If screening starts at age 50-54 or age 55, the benefits are probably smaller (e.g., 1 vs. 2 fewer prostate-cancer related deaths) with similar harms. Adding DRE or screening with PSA annually does not add benefit. One round of PSA screening or starting screening later at age 70-74 may not offer any important benefit or harm (low to moderate certainty), and any benefit from screening primarily with DRE was not shown. Compared with PSA alone, sequential screening with PSA followed by MRI reduces FPs (≥33 fewer) and overdiagnosis (via ≥10 fewer diagnoses of clinically insignificant [e.g., Gleason 6] cancers without impacting detection of clinically significant cancers) (moderate to high certainty), though findings were limited to one round of screening without long-term follow-up or measurement of mortality.

Interpretation This review provides clinicians and other interest holders with anticipated absolute effects by age, and assessments of certainty across critical and important outcomes and with approximately two decades of follow-up. Findings apply to a general population and may differ for specific groups. Results for most critical outcomes, both benefits and harms, exceeded thresholds for clinically important effect sizes, thereby demonstrating the complexity of guideline developers’ and patients’ decision-making regarding screening trade-offs. Findings about adding MRI for those with a positive PSA test were limited and would require additional consideration of costs, infrastructure, expertise, and equity.

Protocol registration PROSPERO - CRD420250651056.

The authors have declared no competing interest.

This review was conducted with funding provided by the Public Health Agency of Canada (PHAC). The views expressed in this article do not necessarily represent those of PHAC or the Government of Canada.

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