Can Prostate Cancer Screening Reduce Mortality in Men Aged 75-79 Years? A Protocol for Target-trial Emulation

Opportunistic testing using the prostate-specific antigen (PSA) test is common among men aged 75-79 yr. American and European guidelines consider PSA-based screening through joint decision-making if men have at least 10 yr of life expectancy. The age threshold for PSA-based screening was previously described in these guidelines as 70-74 yr. However, Swedish men, similar to their global counterparts, are experiencing increased life expectancy. As of 2024, Swedish men aged 75-79 yr have on average >10 yr of life expectancy. To date, there are no randomized controlled trials on prostate cancer screening for men aged 75-79 yr at baseline. With a lack of randomized data, we plan on leveraging the population-based Stockholm Prostate Cancer Diagnostics Register from 2007 to 2023, to explore the effect of PSA-based screening on all-cause and prostate cancer-specific mortality. In this target-trial emulation study protocol, our aim is to evaluate whether PSA-based screening in men aged 75-79 yr with no previous prostate cancer diagnosis would have survival benefits from PSA-based screening. We will conduct sequential and clone-censor-weight target-trial emulations based on the age at enrollment, assigning men to screened or unscreened arms based on the observational analog of an intention-to-screen analysis of PSA test records. Men will be followed until death or December 31, 2023. The statistical analysis involves survival models, reporting of the cumulative incidence functions (CIF), and differences in CIFs. Sensitivity analyses aim to evaluate whether similar findings can be observed if we restrict enrollment to those who have a minimum of 5 and 10 yr of follow-up, consider calendar year instead of age at enrollment, and consider enrollment of younger men. This study aims to provide evidence on the survival benefits of PSA-based screening in this age group, and clarify whether extending screening guidelines to men aged 75-79 yr would reduce mortality without exacerbating the risk of overdiagnosis. Findings will guide clinical recommendations and inform the design of future randomized controlled trials. The study is registered at ClinicalTrials.gov (NCT07206693).