Prostate cancer screening using a combination of risk-prediction, MRI, and targeted prostate biopsies (STHLM3-MRI): a prospective, population-based, randomised, open-label, non-inferiority trial

Background Screening for prostate cancer using prostate-specific antigen (PSA) reduces prostate cancer mortality but can lead to adverse outcomes. We aimed to compare a traditional screening approach with a diagnostic strategy of blood-based risk prediction combined with MRI-targeted biopsies. Methods We did a prospective, population-based, randomised, open-label, non-inferiority trial (STHLM3-MRI) in Stockholm county, Sweden. Men aged 50-74 years were randomly selected by Statistics Sweden and invited by mail to participate in screening; those with an elevated risk of prostate cancer, defined as either a PSA of 3 ng/mL or higher or a Stockholm3 score of 0.11 or higher were eligible for randomisation. Men with a previous prostate cancer diagnosis, who had undergone a prostate biopsy within 60 days before the invitation to participate, with a contraindication for MRI, or with severe illness were excluded. Eligible participants were randomly assigned (2:3) using computer-generated blocks of five, stratified by clinically significant prostate cancer risk, to receive either systematic prostate biopsies (standard group) or biparametric MRI followed by MRI-targeted and systematic biopsy in MRI-positive participants (experimental group). The primary outcome was the detection of clinically significant prostate cancer at prostate biopsy, defined as a Gleason score of 3+4 or higher. We used a margin of 0.78 to assess non-inferiority for the primary outcome. Key secondary outcome measures included the proportion of men with clinically insignificant prostate cancer (defined as a Gleason score of 3+3), and the number of any prostate MRI and biopsy procedures done. We did two comparisons: Stockholm3 (using scores of 0.11 and 0.15 as cutoffs) versus PSA in the experimental group (paired analyses) and PSA plus standard biopsy versus Stockholm3 plus MRI-targeted and systematic biopsy (unpaired, randomised analyses). All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT03377881. Findings Between Feb 5, 2018, and March 4, 2020, 49 118 men were invited to participate, of whom 12 750 were enrolled and provided blood specimens, and 2293 with elevated risk were randomly assigned to the experimental group (n=1372) or the standard group (n=921). The area under the receiver-operating characteristic curve for detection of clinically significant prostate cancer was 0.76 (95% CI 0.72-0.80) for Stockholm3 and 0.60 (0.54-0.65) for PSA. In the experimental group, a Stockholm3 of 0.11 or higher was non-inferior to a PSA of 3 ng/mL or higher for detection of clinically significant prostate cancer (227 vs 192; relative proportion [RP] 1.18 [95% CI 1.09-1.28], p<0.0001 for non-inferiority), and also detected a similar number of low-grade prostate cancers (50 vs 41; 1.22 [0.96-1.55], p=0.053 for superiority) and was associated with more MRIs and biopsies. Compared with PSA of 3 ng/mL or higher, a Stockholm3 of 0.15 or higher provided identical sensitivity to detect clinically significant cancer, and led to fewer MRI procedures (545 vs 846; 0.64 [0.55-0.82]) and fewer biopsy procedures (311 vs 338; 0.92 (0.86-1.03). Compared with screening using PSA and systematic biopsies, a Stockholm3 of 0.11 or higher combined with MRI-targeted and systematic biopsies was associated with higher detection of clinically significant cancers (227 [3.0%] men tested vs 106 [2.1%] men tested; RP 1.44 [95% CI 1.15-1.81]), lower detection of low-grade cancers (50 [0.7%] vs 73 [1.4%]; 0.46 [0.32-0.66]), and led to fewer biopsy procedures. Patients randomly assigned to the experimental group had a lower incidence of prescription of antibiotics for infection (25 [1.8%] of 1372 vs 41 [4.4%] of 921; p=0.0002) and a lower incidence of admission to hospital (16 [1.2%] vs 31 [3.4%]; p=0.0003) than those in the standard group. Interpretation The Stockholm3 test can inform risk stratification before MRI and targeted biopsies in prostate cancer screening. Combining the Stockholm3 test with an MRI-targeted biopsy approach for prostate cancer screening decreases overdetection while maintaining the ability to detect clinically significant cancer. Funding The Swedish Cancer Society, the Swedish Research Council, and Stockholm City Council. Copyright (C) 2021 Elsevier Ltd. All rights reserved.