Prostate-Specific Antigen Levels Among Participants Receiving Annual Testing.

Importance: Repeating a prostate-specific antigen (PSA) test after an elevated measurement is a guideline-recommended component of the prebiopsy workup. However, it is unclear whether certain patients can be exempted from repeat PSA testing and proceed directly to further workup. Objective: To determine yearly PSA variability and implications of repeating an elevated PSA in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Design, Setting, and Participants: This retrospective multicenter cohort study used data from men aged 54 to 75 years participating in the screening arm of the randomized PLCO trial who received PSA testing annually over 6 years (between 1995 and 2006) without a prostate cancer diagnosis. Data were analyzed from February 10, 2023, to May 23, 2025. Main Outcomes and Measures: The primary outcome was the proportion of PSA measurements above 1 of the 3 biopsy thresholds of interest (2.5, 3.0, and 4.0 ng/mL) that decreased below the threshold at the subsequent yearly measurement. Analyses were conducted at both the PSA test and patient levels. Results: Among 11 176 eligible patients (median age 60 years, IQR, 57-65 years), 2700 patients were included at a threshold of 2.5 ng/mL, 1928 patients at 3.0 ng/mL, and 952 patients at 4.0 ng/mL at least once. Among PSA measurements greater than or equal to 2.5 ng/mL, 22% (95% CI, 21%-23%) decreased below 2.5 ng/mL the following year; rates were similar for thresholds of 3.0 ng/mL and 4.0 ng/mL. At the patient level, 54% (95% CI, 53%-56%) of men with at least 1 PSA greater than or equal to 2.5 ng/mL had a subsequent level below this threshold, with slightly greater rates for the higher thresholds. A predictive scoring system incorporating current and prior PSA levels showed that patients with PSA levels persistently above thresholds had a low (<10%) probability of PSA decreasing below the threshold. Conclusions and Relevance: In this study, significant intra-individual variability in PSA levels was observed in this large screening cohort, with many elevated values falling below the threshold at the next yearly measurement. These findings suggest the utility of guideline recommendations to confirm elevated PSA results in most patients before performing further diagnostic evaluation and that patients with a prior PSA score above a given biopsy threshold, and no recent PSA scores below that threshold, could proceed to further diagnostic evaluation without repeat testing.