Anton P. Kravchuk, Ingmar Wolff, Christian Gilfrich, Ralph M. Wirtz, Paula Soares, Kay-Patrick Braun, Sabine D. Brookman-May, Lisa Kollitsch, Katharina Hauner, Martin Burchardt, Johannes Bründl, Maximilian Burger, Matthias May

• Simple Summary Better tests are needed to detect serious bladder cancer (BC), additionally avoiding unnecessary follow-up tests. This study looked at Uromonitor®, a urine-based test, which checks for specific changes in DNA related to BC. Previous tests were good but not perfect, and more information is needed to use this new one in daily routine. We gathered and analyzed data from four studies using Uromonitor®, involving nearly 1200 urine tests. Results showed that Uromonitor® detects existing BC with an accuracy of over 90%. It rarely indicates BC in cases where BC is absent (reaching 97% accuracy). In comparison with urinary cytology, Uromonitor® spotted BC better. If applied in a group of 1000 people including around 15% with active BC, this test could prevent about 825 unnecessary cystoscopies while missing around 30 BC cases. However, more studies are needed to finally confirm the performance of Uromonitor®. Abstract Optimal urine-based diagnostic tests (UBDT) minimize unnecessary follow-up cystoscopies in patients with non-muscle-invasive bladder-cancer (NMIBC), while accurately detecting high-grade bladder-cancer without false-negative results. Such UBDTs have not been comprehensively described upon a broad, validated dataset, resulting in cautious guideline recommendations. Uromonitor®, a urine-based DNA-assay detecting hotspot alterations in TERT, FGFR3, and KRAS, shows promising initial results. However, a systematic review merging all available data is lacking. Studies investigating the diagnostic performance of Uromonitor® in NMIBC until November 2023 were identified in PubMed, Embase, Web-of-Science, Cochrane, Scopus, and medRxiv databases. Within aggregated analyses, test performance and area under the curve/AUC were calculated. This project fully implemented the PRISMA statement. Four qualifying studies comprised a total of 1190 urinary tests (bladder-cancer prevalence: 14.9%). Based on comprehensive analyses, sensitivity, specificity, positive-predictive value/PPV, negative-predictive value/NPV, and test accuracy of Uromonitor® were 80.2%, 96.9%, 82.1%, 96.6%, and 94.5%, respectively, with an AUC of 0.886 (95%-CI: 0.851–0.921). In a meta-analysis of two studies comparing test performance with urinary cytology, Uromonitor® significantly outperformed urinary cytology in sensitivity, PPV, and test accuracy, while no significant differences were observed for specificity and NPV. This systematic review supports the use of Uromonitor® considering its favorable diagnostic performance. In a cohort of 1000 patients with a bladder-cancer prevalence of ~15%, this UBDT would avert 825 unnecessary cystoscopies (true-negatives) while missing 30 bladder-cancer cases (false-negatives). Due to currently limited aggregated data from only four studies with heterogeneous quality, confirmatory studies are needed.