Evaluating early systemic therapies in the neoadjuvant setting for the treatment of urological cancers

INTRODUCTION: Neoadjuvant systemic therapy represents an evolving cornerstone in the multidisciplinary management of urological malignancies. While cisplatin-based neoadjuvant chemotherapy historically represented the sole standard of care for muscle-invasive bladder cancer, novel perioperative regimens - combining preoperative induction with adjuvant maintenance - have established chemotherapy as only a standard of care alongside emerging antibody-drug conjugate and immunotherapy combinations. In renal cell carcinoma and prostate cancer, preoperative approaches remain largely investigational. AREAS COVERED: A structured search of PubMed/MEDLINE, Embase, and ClinicalTrials.gov was conducted up to August 2026. This review critically appraises prospective Phase I and II investigational trials evaluating novel systemic therapies across renal cell carcinoma, upper tract urothelial carcinoma, muscle-invasive bladder cancer, and prostate cancer, contextualizing pivotal Phase III benchmarks. EXPERT OPINION: Neoadjuvant and perioperative paradigms are shifting toward personalized, biomarker-driven strategies. Key challenges include determining the independent necessity of postoperative maintenance in pathological complete responders, establishing validated surrogate endpoints in renal cell carcinoma and prostate cancer, and overcoming significant socioeconomic and geographic access disparities. Incorporating circulating tumor DNA kinetics and predictive biomarkers will be pivotal for optimizing patient selection and guiding response-adaptive therapy.