Prostate cancer is not only the most common male malignancy and a leading cause of male cancer deaths, it is also one of the most heritable conditions.¹ Individuals with strong family history² or Black/African ancestry³ carry nearly double the risk of developing prostate cancer (and lethal disease in particular). Recent work has demonstrated that germline rare pathogenic variants in high-risk genes (eg, BRCA2)⁴ as well as polygenic risk scores derived from hundreds of common single nucleotide polymorphisms can further distinguish high-risk populations that might benefit from targeted screening efforts.^5,6

Universal screening with serum PSA has been fraught with controversy over low specificity and concerns regarding overdiagnosis and overtreatment of indolent tumors that are unlikely to cause harm.⁷ Using prostate multiparametric MRI (mpMRI) to triage patients with an elevated PSA has improved specificity for detecting clinically significant prostate cancer (ie, grade group ≥2),⁸ but the utility of MRI as a primary screening tool is unknown. Still, many individuals at high risk of dying of prostate cancer do not undergo any or adequate prostate cancer screening. Thus, there is a critical need to address the gap in prostate cancer screening to improve outcomes for individuals at high risk of developing clinically significant prostate cancer, particularly among genetically predisposed populations and individuals of Black/African ancestry.

There is growing evidence and enthusiasm for moving from a one-size-fits-all approach to risk-adapted screening, where testing is intensified for high-risk individuals and de-intensified (or even omitted) for low-risk individuals.⁹ The goal of risk-adapted screening is to facilitate early detection of clinically significant cancers among individuals at greatest risk of dying of prostate cancer, while avoiding overdiagnosis and overtreatment of indolent tumors. Two key components of a risk-adapted screening strategy are (1) identifying individuals at high risk of developing potentially lethal prostate cancer (ie, using the aforementioned risk factors) and (2) utilizing screening tests that can reliably distinguish individuals likely to harbor significant cancers from those with insignificant or no cancer. The clinical utility of modern prostate cancer screening approaches integrating mpMRI among high-risk individuals is now the subject of investigation among several ongoing and recently completed clinical trials.

The Prostate Cancer Genetic Risk Evaluation and Screening Study (PROGRESS) is a prospective prostate cancer early detection study among males from 3 populations considered to be high risk for developing aggressive prostate cancer (Figure 1; NCT05129605): (1) rare germline pathogenic variant carriers, (2) individuals with strong family history of prostate cancer and/or genetically related malignancies, and (3) individuals of self-reported Black American or Black Caribbean background. Participants ages 35 to 74 years are screened with an annual PSA and digital rectal examination (DRE) as well as an mpMRI of the prostate every 3 years. PSA is considered elevated based on age-adjusted cutoffs corresponding to approximately the 90th percentile for each age bracket: > 1.5 ng/mL (35-49 years), > 2.0 ng/mL (50-54 years), and > 3.0 ng/mL (55-74 years). If an abnormality is detected by DRE, PSA (above age-adjusted cutoffs), or mpMRI (Prostate Imaging Reporting and Data System [PI-RADS] ≥3 lesion), a prostate biopsy is recommended in accordance with clinical decision-making of the treating clinician. The primary end point of the study is detection rate of clinically significant prostate cancer, defined as grade group ≥ 2 prostate adenocarcinoma on prostate biopsy or radical prostatectomy pathology. The secondary end point is detection rate of any prostate cancer.

We recently reported interim results from 101 germline rare pathogenic variant carriers in PROGRESS Cohort A who completed the first round of screening, where we observed a 9% overall cancer detection rate and 7% clinically significant cancer detection rate.¹⁰ In our updated analysis presented at the 2025 AUA Annual Meeting, the cancer detection rate has remained steady among 170 Cohort A participants who have completed at least 1 round of screening: 17/170 (10%) for overall prostate cancer and 12/170 (7.1%) for clinically significant prostate cancer. Thirty-three participants had an abnormal screening MRI, and 41 participants underwent a prostate biopsy, over half of whom (24/41) were indicated for an abnormal MRI in the setting of normal PSA and DRE (Figure 2, A). For detection of clinically significant prostate cancer, abnormal MRI (PI-RADS ≥4) demonstrated 83% sensitivity with a positive predictive value of 56%, whereas elevated age-adjusted PSA had 58% sensitivity with a positive predictive value of 41%. Of 6 screening strategies evaluated in decision curve analysis, MRI-based screening achieved superior net benefit at all threshold probabilities compared with PSA screening (Figure 2, B). Compared with age-adjusted PSA, the MRI PI-RADS ≥ 4 strategy detected ∼1 additional significant cancer per 12 patients, without an increase in unnecessary biopsies. Conventional PSA screening (cutoff >4.0 ng/mL) would have missed more than 75% of these cases.

In addition to PROGRESS, other ongoing clinical trials are investigating targeted screening strategies for high-risk germline pathogenic variant carriers using mpMRI and/or age-adjusted PSA (eg, NCT03805919, PATROL [NCT04472338]), as well as evaluating how polygenic risk scores can be used to identify high-risk individuals for mpMRI- and PSA-based detection of clinically significant prostate cancer (eg, BARCODE1,⁶ NCT06398639). Together, these approaches, if successful, have the potential to shift our screening paradigm from a one-size-fits-all approach to a risk-adapted approach with the goal of improving early detection of prostate cancers most likely to cause harm while avoiding the harms of overdiagnosis and overtreatment.