Abstract
Polygenic risk scores (PRSs) have generated considerable interest as a means of personalizing prostate cancer (PC) screening by stratifying individuals according to their genetic risk. The single-arm BARCODE1 study recently showed that PRS-based screening detected more PCs than prostate-specific antigen (PSA) testing or magnetic resonance imaging (MRI). The absence of a comparator arm limits the interpretability of this finding. We compared outcomes from BARCODE1 with those from two contemporaneous, large-scale screening trials-Göteborg-2 and ProScreen-that used MRI with or without a PC blood marker to risk-stratify men for biopsy. When standardized to 10 000 men tested, BARCODE1 biopsied more men (704 vs 386 and 338), diagnosed more low-grade PCs (126 vs 103 and 41), and detected fewer high-grade PCs (155 vs 178 and 165) versus Göteborg-2 and ProScreen. Combining PRS with PSA or MRI in BARCODE1 reduced the detection of high-grade PCs by 50-75% in comparison to Göteborg-2 and ProScreen. These findings reflect the limited risk discrimination of PRSs and their inability, unlike MRI and blood-based markers, to preferentially detect aggressive disease. PRS-based PC screening underperforms relative to current best practice and, on the basis of BARCODE1 data, should not be adopted in clinical practice.