The Prostate Cancer, Genetic Risk, and Equitable Screening Study (ProGRESS): A Pragmatic Trial of Precision Prostate Cancer Screening

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.