Liquid Biopsy in Genitourinary Cancers: Circulating Tumor DNA as a Predictive Biomarker for Treatment Selection and Resistance Monitoring

Background: Genitourinary (GU) cancers — encompassing prostate, urothelial, and renal cell carcinomas — collectively represent a leading source of oncologic morbidity and mortality worldwide. Tumor heterogeneity and the dynamic evolution of resistance mechanisms limit the clinical utility of static tissue biopsies, creating an urgent need for real-time, non-invasive biomarkers. Circulating tumor DNA (ctDNA), isolated from peripheral blood or urine, captures the somatic mutational landscape of the tumor in a temporally resolved manner and has emerged as a compelling candidate predictive biomarker for treatment selection and resistance monitoring across GU malignancies. Methods: An integrative review was conducted following the Whittemore and Knafl (2005) framework. A systematic literature search was performed across PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Embase, and Web of Science, covering the period January 2020 to April 2026. Search strategies combined MeSH and free-text terms pertaining to ctDNA, liquid biopsy, and the three principal GU cancer types. After duplicate removal and staged screening, 23 studies met inclusion criteria and formed the basis of the qualitative synthesis. Results: The integrated evidence demonstrates that ctDNA functions as a dynamic predictive biomarker across three GU cancer domains. In castration-resistant prostate cancer (CRPC), ctDNA tumor fraction detected at cycle 3, day 1 of enzalutamide therapy independently predicts radiographic progression-free survival and overall survival (mOS 16.0 vs. 22.1 months for ctDNA-positive vs. ctDNA-negative patients). In muscle-invasive bladder cancer (MIBC), post-cystectomy ctDNA identifies metastatic relapse with 94% sensitivity and 98% specificity and stratifies benefit from adjuvant atezolizumab in IMvigor010. In renal cell carcinoma (RCC), emerging data support ctDNA for VHL and PBRM1 mutation tracking and treatment response assessment, though prospective validation remains limited. ctDNA-guided detection of androgen receptor splice variant 7 (AR-V7) and FGFR3 alterations enables biologically informed treatment sequencing in CRPC and urothelial carcinoma, respectively. Conclusion: ctDNA constitutes a molecularly rigorous, clinically actionable biomarker platform with demonstrated predictive and prognostic value across the GU cancer spectrum. Integration into prospective clinical trials and regulatory frameworks represents the critical next step toward embedding ctDNA-guided decision-making into standard oncologic practice.