Immunotherapy in urological cancers: new paradigms and a systematic review of clinical trials and real-world evidence.

Introduction: The therapeutic landscape of urological cancers has undergone a paradigm shift with the advent of immunotherapy. This systematic review synthesizes clinical trials that have established new standards of care, complemented by evidence on immunotherapy-radiotherapy combinations and real-world data. Methods: A comprehensive search of PubMed/MEDLINE and Embase (2010-2026) identified phase II/III trials evaluating ICIs, ADCs, vaccines, or cellular therapies, as well as immunoradiotehrapy, observational studies, and registries reporting real-world outcomes. Results: Fifty-three clinical trials met the inclusion criteria: bladder cancer (n=14), kidney cancer (n=21), and prostate cancer (n=18), complemented by immunoradiotherapy trials (n=20), and real-world evidence (n=19). In bladder cancer, perioperative durvalumab and Enfortumab Vedotin (EV) plus pembrolizumab improved outcomes in MIBC, and the EV+pembrolizumab combination became a frontline standard for metastatic disease. Disitamab vedotin plus toripalimab improved outcomes in HER2-expressing tumours, and ctDNA-guided adjuvant atezolizumab introduces precision therapy for molecular residual disease. Emerging immunoradiotherapy combinations showed promising bladder-sparing potential (CR rates 64-88%). In kidney cancer, dual ICI and ICI+TKI combinations demonstrated long-term survival benefits. The RAMPART trial introduced adjuvant durvalumab ± tremelimumab, while transcriptomic-guided therapy and treatment of rare translocation RCC emerged from 2025-2026 trials. In prostate cancer, sipuleucel-T remains the first approved cancer vaccine, while newer trials explored ICIs (durvalumab+tremelimumab) and personalized peptide vaccines. Biomarker-driven approaches emerged across all tumor types, including ctDNA-guided therapy in bladder cancer, KIM 1 in kidney cancer, and PD-L1/DDR status in prostate cancer. Immunoradiotherapy combinations demonstrated activity in mCRPC (CA184-043, 5-year OS 7.9% vs 2.7%) and oligometastatic RCC (RAPPORT, ORR 63%). Real-world evidence confirmed trial findings while revealing critical gaps in access, the prognostic dominance of performance status, and the potential for radiotherapy-immunotherapy synergy. Conclusion: Immunotherapy has become a cornerstone of urological oncology. Current paradigms include early ICI/ADC intensification in bladder cancer, ICI-based combinations in renal cell carcinoma, and the gradual integration of vaccines and checkpoint inhibitors in prostate cancer. Real-world evidence and immunoradiotherapy represents an emerging frontier, though optimal fractionation and sequencing require further investigation. Despite major advances, challenges remain in overcoming resistance, optimizing sequencing, and ensuring equitable access.