INTRODUCTION: Overdiagnosis in PSA-based prostate cancer (PCa) screening is primarily studied in younger, healthier populations from clinical trials. This study aimed to evaluate the probability of overdiagnosis in PCa screening within a clinical practice context, focusing on its relationship with PSA levels, Gleason scores, and subsequent clinical procedures. METHODS: We conducted a retrospective cohort analysis of 1,070 asymptomatic men over 40 years old diagnosed with PCa between 2004 and 2022, following a positive PSA test. The patients were followed until December 31, 2022, with a median follow-up time of 5.7 years (IQR 3.2-8.6). The primary outcome was the probability of overdiagnosis, assessed through life expectancy and the Charlson Comorbidity Index, considering lead times of 5, 10, and 15 years. RESULTS: We found that patients with PSA levels >
10 ng/dL and/or Gleason scores ≥8 were generally older and had more comorbidities than those with PSA levels 4-10 ng/dL and/or Gleason scores ≤7. The probability of overdiagnosis was significantly higher in patients with PSA levels >
10 ng/dL (41.4%, IQR 21.5-73.9) and Gleason scores ≥8 (42.6%, IQR 14.9-38.9), compared to those with PSA levels 4-10 ng/dL (20.1%, IQR 12.8-30.4) and Gleason scores ≤7 (26.6%, IQR 23.6-68.6). Notably, 71.7% of patients did not receive pharmacological treatment. Patients with higher PSA levels also experienced greater radiation exposure from diagnostic imaging (median 19.9 mSv vs. 14.7 mSv, p = 0.004). CONCLUSIONS: These findings underscore the high likelihood of overdiagnosis in older patients with elevated PSA levels and significant comorbidities, highlighting the need for careful consideration of patient comorbidities before PSA testing.