Background: Early detection of prostate cancer to reduce mortality remains controversial because there is often also overdiagnosis of low-risk disease and unnecessary treatment. Genetic scores may provide an objective measure of a man’s risk of dying from prostate cancer and thus inform screening decisions. This might be especially useful in men of African ancestry, who have a higher average risk of prostate cancer death but are often treated as a homogeneous group. Our object was to determine whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with risk of metastatic or fatal prostate cancer in a racially and ethnically diverse population. Methods: We analyzed the Million Veteran Program (MVP), a multi-ancestry population of over 500,000 individuals participating in the VA healthcare system. Genotype data were used to calculate the genetic score, PHS290. Family history of prostate cancer (first-degree relative) and ancestry group (harmonized genetic ancestry and self-reported race/ethnicity: European, African, Hispanic, or Asian) were also studied. The primary outcome studied was age at death from prostate cancer. The key secondary outcome was age at diagnosis of prostate cancer metastases. Cox regression was used to test associations. Results: 513,997 MVP participants were included. Median age at last follow-up: 69 years. PHS290 was associated with age at death from prostate cancer in the full cohort and for each ancestry group (p<10^-16). Comparing men in the highest 20% of PHS290 to those in the lowest 20%, the hazard ratio (HR_80/20) for death from prostate cancer was 4.41 [95% CI: 3.9-5.02]. Corresponding hazard ratios for European, African, Hispanic, and Asian subsets were 4.26 [3.66-4.9], 2.4 [1.77-3.23], 4.72 [2.68-8.87], and 10.46 [2.01-101.0]. When accounting for family history and ancestry group, PHS290 remained a strong independent predictor of fatal prostate cancer (Table). PHS290 was also associated with metastasis. PHS290 was higher, on average, among men with African ancestry. Conclusions: PHS290 stratified US veterans of diverse ancestry for lifetime risk of metastatic or fatal prostate cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.

* (p<0.01). *** (p<10-16).