The role of PSA density in the follow up of men with a negative MRI in the Göteborg‐2 trial

Objectives To assess whether prostate‐specific antigen density (PSAD) stratifies long‐term risk of clinically significant prostate cancer (csPCa) after a negative magnetic resonance imaging (MRI; Prostate Imaging‐Reporting and Data System score ≤2) and to evaluate the potential of PSAD to guide follow‐up in a screening setting. Patients and Methods This pre‐specified sub‐analysis of the population‐based, randomised Göteborg‐2 screening trial included 1685 men who underwent PSA testing between October 2015 and June 2021 and had a subsequent negative initial MRI. Follow‐up continued until 30 September 2024. The primary endpoint was cumulative incidence of csPCa (Gleason score ≥3 + 4). Men were categorised by baseline PSAD (<0.10, 0.10 to <0.15, and ≥0.15 ng/mL 2 ). Cumulative incidence was estimated using Kaplan–Meier methods and compared using the log‐rank test. The clinical implications of PSAD‐based follow‐up strategies were explored. Results Over a median follow‐up of 5.5 years, 160 PCas were diagnosed, of which 80 were csPCa, including 22 cases of Gleason score ≥4 + 3. At 7 years, cumulative csPCa incidence was 7.1% overall and 5.5%, 13.8%, and 11.9% in the PSAD <0.10, 0.10 to <0.15, and ≥0.15 ng/mL 2 groups, respectively ( P < 0.001 for PSAD <0.10 ng/mL 2 vs both higher groups). Overall, 87% of repeat MRIs remained negative. Although men with baseline PSAD <0.10 ng/mL 2 had the lowest overall risk, 42 csPCas occurred in this group, including 12 Gleason score ≥4 + 3, emphasising the importance of continued regular PSA‐based follow‐up. A PSAD‐guided strategy with biennial PSA testing and repeat MRI triggered by PSAD ≥0.10 ng/mL 2 could reduce MRI use by 60% and biopsies by 46%, halve detection of clinically insignificant PCa, and delay csPCa diagnosis in 17% of cases including 10 men with Gleason score 3 + 4 and one with Gleason score ≥4 + 3. Conclusions The PSAD stratifies long‐term risk of csPCa after a negative MRI and supports risk‐adapted follow‐up in PCa screening.