Clinical and Liquid Biomarkers of 20-Year Prostate Cancer Risk in Men Aged 45 to 70 Years.

[IMPORTANCE] Prostate cancer incidence is projected to double by 2040, yet optimal risk stratification approaches for screening remain unclear despite recent international endorsements of organized programs that call for risk-adapted algorithms using readily available biomarkers.

[OBJECTIVE] To identify biomarkers for risk-adapted prostate cancer screening in men without prostate cancer.

[DESIGN, SETTING, AND PARTICIPANTS] This cohort study used data from the Study of Health in Pomerania (SHIP), a prospective population-based research initiative in Germany that randomly invited participants aged 20 to 79 years who underwent comprehensive examinations with structured 20-year follow-up. Data were collected from October 17, 1997, through September 14, 2021, with final analysis completed November 16, 2025.

[EXPOSURES] Baseline clinical and liquid biomarkers, including body mass index, waist-to-hip ratio, and glycated hemoglobin, together with prostate cancer-specific biomarkers of serum prostate-specific antigen (PSA) and magnetic resonance imaging-derived prostate volume and PSA density.

[MAIN OUTCOMES AND MEASURES] The primary outcome was long-term prostate cancer incidence. Cumulative incidence functions for prostate cancer and death were treated as competing risks. Cause-specific Cox models were used to estimate risk and assess the association between baseline biomarkers and long-term incidence.

[RESULTS] Among 2651 men included in the study (median [IQR] age, 54.0 [48.0-62.0] years), 1482 (55.9%) had low baseline PSA levels (<1.00 ng/mL), with a cumulative prostate cancer incidence of 0.1% (95% CI, 0.0%-0.4%), 0.6% (95% CI, 0.3%-1.2%), and 3.3% (95% CI, 2.1%-4.8%) at 5, 10, and 20 years, respectively. In 958 men (36.1%) with intermediate PSA levels (1.00-3.00 ng/mL), prostate cancer incidence was 1.4% (95% CI, 0.7%-2.3%), 5.0% (95% CI, 3.6%-6.6%), and 11.8% (95% CI, 9.2%-14.8%) at 5, 10, and 20 years, respectively. In 211 men (8.0%) with high PSA levels (>3.00 ng/mL), prostate cancer incidence was 14.5% (95% CI, 10.1%-19.7%), 28.3% (95% CI, 22.2%-34.8%), and 34.8% (95% CI, 27.5%-42.2%) at 5, 10, and 20 years, respectively. Cumulative prostate cancer incidence differed significantly among the PSA groups (P < .001). In univariable and multivariable Cox regression, age (hazard ratio [HR], 1.04; 95% CI, 1.02-1.07), PSA (HR, 1.06; 95% CI, 1.04-1.07), and PSA density (HR, 1.41; 95% CI, 1.30-1.52) remained consistently associated with prostate cancer risk, whereas other variables showed either no association or inconsistent results across models.

[CONCLUSIONS AND RELEVANCE] This cohort study found that a low baseline PSA level was associated with low long-term prostate cancer risk among men aged 45 to 70 years, supporting risk-adapted screening with extended intervals for men with low PSA levels.