Prostate cancer is the most common non-skin cancer among Veterans and the second leading cause of male cancer death. Current methods of screening men for prostate cancer are inaccurate and cannot identify which men do not have prostate cancer or have low-grade cases that will not cause harm and which men have significant prostate cancer needing treatment. False-positive screening tests can result in unnecessary prostate biopsies for men who do not need them. However, new genetic testing might help identify which men are at highest risk for prostate cancer. This study will examine whether a genetic test helps identify men at risk for significant prostate cancer while helping men who are at low risk for prostate cancer avoid unnecessary biopsies. If this genetic test proves beneficial, it will improve the way that healthcare providers screen male Veterans for prostate cancer.

Prostate cancer is the most common non-cutaneous cancer in US men and in the Veterans Health Administration (VHA): 1 in 8 will be diagnosed with the disease in their lifetime. Many cases are non-lethal, but prostate cancer remains the 2nd leading cause of cancer death among US men, representing 2.5% of all deaths. VHA diagnoses >16,000 new cases annually and cares for >400,000 men living with prostate cancer. As a result, prostate cancer diagnosis and treatment is a national priority for VHA.

A major impediment to reducing the incidence of metastatic prostate cancer and prostate cancer death is the lack of an optimal screening strategy to identify men at high risk. Screening with prostate-specific antigen (PSA) testing modestly reduces prostate cancer deaths but at the cost of overdiagnoses and overtreatment. Current screening approaches do not adequately distinguish men without prostate cancer or with low-grade prostate cancer amenable to active surveillance from men with clinically significant prostate cancer, who need treatment. As a result, clinical guidelines do not recommend universal prostate cancer screening, including those from the United States Preventive Services Task Force (USPSTF) and the VHA National Center for Health Promotion and Disease Prevention. Still, many men undergo screening based on variable and subjective assessments of their race/ethnicity, family history, and other risk factors.

A new paradigm of precision screening could improve the benefit-to-harm ratio of screening by implementing screening strategies tailored to an individual's specific genetic profile. Due to advances in high-throughput genotyping and sequencing, increasingly large and diverse cohort studies, and standardization of genetic variant classification, germline genetic testing is emerging as a powerful predictor for prostate cancer, including metastatic and lethal disease. This includes both rare highly penetrant variants and polygenic risk scores (PRS), which characterize an individual's predisposition to prostate cancer due to common genetic variation. Rare and common genetic variation is now an equally powerful predictor of clinically significant disease as self-reported race or family history, including in the Million Veteran Program.

This clinical trial will evaluate the promise of precision risk stratification to identify men most likely to benefit from prostate cancer screening. During the proof-of-concept phase, the investigators will achieve the following aims:

1. Develop a precision prostate cancer screening intervention consisting of genetic testing for rare variants and a transancestry PRS, delivered to participants and their primary care providers along with individualized, genetic risk-informed screening recommendations.
2. Determine the feasibility of enrolling men aged 55-70 ( 35% of whom are of racial/ethnic minority groups) to a pragmatic randomized clinical trial (RCT) comparing the precision screening intervention to usual care.
3. Perform an interim assessment to determine whether the observed trajectory of negative prostate biopsy event rates is consistent with rates needed to detect a meaningful between-group difference at the end of the 7-year project period.

If the investigators demonstrate feasibility of enrollment and adequate event rates during the proof-of-concept phase, the RCT will continue to the clinical trial phase to test the following co-primary hypotheses:

1. Compared with men in the usual care arm, men in the precision screening arm will have a time-to-diagnosis of clinically significant prostate cancer (csPCa, defined as NCCN classification intermediate risk or higher) that is not inferior by a margin of >30 days over a median 4 years of follow-up.

   a. If non-inferiority is demonstrated, the investigators will sequentially test the hypothesis that time-to-diagnosis of csPCa is shorter in the precision screening arm than in the usual care arm (superiority).

2. Compared with usual care, men in the precision screening arm overall will undergo fewer negative prostate biopsies over a median 4 years of follow-up.

Pre-specified subgroup analyses will test these hypotheses in Black men specifically, to evaluate whether this population benefits equally or more from the intervention. Enrollees will be followed for additional outcomes including all prostate cancer diagnoses, PSA testing, prostate MRI, rare variants identified, preferences for or against prostate cancer screening, and health-related quality of life.

The investigators expect that precision screening will increase screening among high-risk patients but decrease screening among low- and average-risk patients, thereby maintaining or improving overall csPCa detection while improving the population-level benefit-to-harm ratio. Rigorous RCT evidence that genetic risk-informed screening maintains the benefits of screening while minimizing the harms of unnecessary procedures and treatments among low-risk men will change clinical practice and policy around prostate cancer screening.

Inclusion Criteria:

• baseline age 55-69 years
• receipt of regular VA care
• Veteran status

Exclusion Criteria:

• personal history of prostate cancer
• prior prostate biopsy, prostatectomy, or prostate MRI
• known carrier status of rare variant associated with cancer syndrome

Individual participant data will be stored in a data repository available for request by approved individuals.

Requestors may be required to have IRB approval, data use agreements, and other regulatory and administrative credentials and authorizations prior to receiving data.