Abstract
Immune checkpoint inhibitors have transformed the management of several genitourinary malignancies, but they have not solved the problem of patient selection. Across urothelial carcinoma, renal cell carcinoma, and prostate cancer, immunotherapy can produce durable benefit in selected patients; however, many patients do not respond, receive treatment in settings where benefit is modest, or experience clinically meaningful toxicity without sufficient gain. The central challenge is therefore not simply to identify a positive biomarker, but to determine whether that biomarker can improve a specific treatment decision for a specific patient in a specific clinical context.
This narrative review reframes immunotherapy selection in genitourinary cancers as a clinical decision problem. Urothelial carcinoma illustrates a setting-driven paradigm, in which treatment selection is increasingly shaped by disease stage, perioperative strategy, antibody-drug conjugate-immunotherapy combinations, maintenance therapy, circulating tumor DNA or molecular residual disease, and treatment feasibility rather than by programmed death-ligand 1 status alone. Renal cell carcinoma illustrates a phenotype-driven paradigm, in which routine selection remains largely clinical and pathologic, integrating histology, prognostic risk frameworks, sarcomatoid or rhabdoid features, disease tempo, metastatic burden, symptoms, toxicity profile, and treatment goal. Prostate cancer illustrates a biomarker-defined exception paradigm: checkpoint inhibitors have limited activity in unselected metastatic castration-resistant disease, but rare subsets such as microsatellite instability-high or mismatch repair-deficient tumors, and selected tumor mutational burden-high tumors, may derive clinically meaningful benefit.
We propose SELECT-IO as a practical six-step framework for clinical reasoning: set tumor type and disease setting; establish whether validated actionable biomarkers are present; label the decision type; evaluate host and implementation modifiers; compare competing standards; and target the therapeutic goal. The aim is to move beyond biomarker positivity toward contextualized, feasible, and clinically meaningful immunotherapy selection.