ABSTRACT Screening for prostate cancer (PCa) is highly controversial, as accumulated evidence indicates that widespread, routine prostate-specific antigen (PSA)-based screening reduces PCa mortality but at the cost of significant over- diagnosis and over-treatment. PSA-based risk-stratified screening could capture much of the benefit of screening while greatly reducing over-diagnosis. This promising approach uses men’s baseline PSA values to inform their risk of future aggressive and/or fatal PCa and determine their frequency of further screening. Under this approach, men with high baseline age-specific total PSA levels receive more frequent screening and men with lower levels receive less frequent screening. This efficient approach is currently supported by at least three US advisory agencies, but not by several others, including most notably, the US Preventive Services Task Force. This agency recommends additional “validation studies” with “longer-term follow-up” before considering PSA- based risk-stratified screening. Additional data are also needed to optimize each of the components of PSA- based risk-stratified screening, including the: (1) age at which baseline PSA values should be obtained, (2) length of tailored re-screening intervals, (3) tailored age at screening cessation, (4) tailored strategies for Black men, as these men are at higher risk of aggressive and fatal PCa, yet remarkably under-represented in the screening literature, and (5) prostate-specific kallikreins used for screening, as kallikreins beyond total PSA have also been found to predict PCa risk and mortality and thus might help to optimize PSA-based risk-stratified screening. Therefore, to address each of these gaps, we propose to leverage data and serum specimens collected in the large racially-diverse Kaiser Permanente Northern California integrated health system, along with its long- running (over 5 decades), embedded Multiphasic Health Checkups cohort and nested case-cohort to: (1) evaluate the utility of initiating baseline PSA screening before age 50, (2) determine the optimal re-screening interval after a baseline PSA test, (3) identify populations of men at age 60 who might consider stopping screening, (4) explore whether Black men should initiate screening earlier and be screened more frequently than White men, and (5) evaluate whether adding other prostate-specific kallikreins to total PSA enhances prediction of clinically-relevant PCa. Our overall goal is to provide evidence for “smarter” or more nuanced PSA screening strategies to preserve or enhance the mortality benefits of PSA screening, while greatly minimizing its harms and costs.

NARRATIVE Currently, the best way in which to screen men for prostate cancer (PCa) is unknown, resulting in a large burden of invasive, expensive, and unnecessary PCa diagnostic investigations and therapies. Our proposed R01 will address this problem by optimizing screening and identifying “who”, “when”, and “how often” men should be screened for PCa to prevent the high morbidity and mortality of this cancer, while also reducing the physical, mental, and economic harms of screening.