Predictors of Benefit from Immune Checkpoint Inhibitors in Urothelial Carcinoma of the Bladder: The Limits of PD-L1 and the Rise of Circulating Tumor DNA-Guided Adjuvant Therapy
7 affiliations
- 1Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
- 2Bastion Policlinic, Mircea cel Batran Street, No. 122C, 300600 Timisoara, Romania
- 3Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
- 4Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
- 5Department XV, Discipline of Radiology and Medical Imaging, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
- 6Department of Oncology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
- 7Department X—Surgery II, Discipline of Anesthesia and Intensive Care, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
Abstract
Immune checkpoint inhibitors (ICIs) are established across the treatment continuum of urothelial carcinoma of the bladder, yet most patients derive no durable benefit. This narrative review appraises candidate predictors of ICI benefit in bladder urothelial carcinoma, distinguishing prognostic from predictive biomarkers, applying the same three evidentiary standards to every biomarker, classifying the supporting studies by design and separating evidence from regulatory status. Programmed death-ligand 1 (PD-L1) immunohistochemistry meets the enrichment standard in three co-primary PD-L1-positive populations, in trials also positive overall, but not the predictive standard: its four registrational assays are not interchangeable; randomized comparisons show inconsistent subgroup effects, failed prespecified tests in IMvigor211 and DANUBE and no significant treatment-by-PD-L1 interaction; and the benefit of first-line enfortumab vedotin plus pembrolizumab is independent of combined positive score. Its remaining role is confined to label restrictions, chiefly European. Tumor mutational burden, molecular subtypes, expression signatures, DNA damage response and FGFR3 alterations remain investigational. Tumor-informed circulating tumor DNA (ctDNA) answers a different question: whether residual disease persists after cystectomy. After an exploratory signal in IMvigor010, the prospective enrichment trial IMvigor011 showed that ctDNA-positive patients derive disease-free and overall survival benefit from adjuvant atezolizumab; persistently ctDNA-negative patients were observed without randomization, so their 88% two-year disease-free survival does not exclude a benefit of treatment. This underpins US companion-diagnostic approval and a Category 1 guideline recommendation, not yet European authorization. Post-cystectomy ctDNA thus meets the same enrichment standard as PD-L1 and, like PD-L1, neither the predictive nor the strategy standard; what sets it apart is that the marker was necessary for the result, adjuvant atezolizumab having failed unselected, and that it directs whether to treat rather than which regimen; its role after perioperative immunotherapy is unresolved.
Related
- The SChISM study: Circulating cell-free DNA size profiles as predictors of progression in advanced carcinoma treated with immune-checkpoint inhibitors
- Multiplexed FRET-FLIM Profiling of Immune Checkpoint Interactions Predicts Response to Atezolizumab in Urothelial Carcinoma
- Circulating and tumor microenvironment immunomarkers associate with immunotherapy efficacy in advanced bladder urothelial carcinoma: an exploratory multicenter study integrating genomic and immunophenotypic profiling
- Baseline circulating immunophenotype as a predictor of immune-related adverse events in NSCLC patients treated with immune checkpoint inhibitors
- Long-term survival with immune checkpoint inhibitors combined with bevacizumab in advanced clear cell renal cell carcinoma : A case report
BibTeX
@article{novacescu2026predictors,
title = {{Predictors of Benefit from Immune Checkpoint Inhibitors in Urothelial Carcinoma of the Bladder: The Limits of PD-L1 and the Rise of Circulating Tumor DNA-Guided Adjuvant Therapy}},
author = {Dorin Novacescu and Mihael Musta and Radu Caprariu and Cristina Stefania Dumitru and Alina Cristina Barb and Antonia Armega-Anghelescu and Radu Dragomir and Adelina Baloi and Silviu Latcu and Flaviu Lucian Petrica and Alin Cumpanas and Flavia Zara},
journal = {Cancers},
year = {2026},
month = nov,
doi = {10.3390/cancers18213581},
url = {https://www.mdpi.com/2072-6694/18/21/3581},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Predictors of Benefit from Immune Checkpoint Inhibitors in Urothelial Carcinoma of the Bladder: The Limits of PD-L1 and the Rise of Circulating Tumor DNA-Guided Adjuvant Therapy
AU - Dorin Novacescu
AU - Mihael Musta
AU - Radu Caprariu
AU - Cristina Stefania Dumitru
AU - Alina Cristina Barb
AU - Antonia Armega-Anghelescu
AU - Radu Dragomir
AU - Adelina Baloi
AU - Silviu Latcu
AU - Flaviu Lucian Petrica
AU - Alin Cumpanas
AU - Flavia Zara
PY - 2026
DA - 2026/11/07
JO - Cancers
DO - 10.3390/cancers18213581
UR - https://www.mdpi.com/2072-6694/18/21/3581
AB - Immune checkpoint inhibitors (ICIs) are established across the treatment continuum of urothelial carcinoma of the bladder, yet most patients derive no durable benefit. This narrative review appraises candidate predictors of ICI benefit in bladder urothelial carcinoma, distinguishing prognostic from predictive biomarkers, applying the same three evidentiary standards to every biomarker, classifying the supporting studies by design and separating evidence from regulatory status. Programmed death-ligand 1 (PD-L1) immunohistochemistry meets the enrichment standard in three co-primary PD-L1-positive populations, in trials also positive overall, but not the predictive standard: its four registrational assays are not interchangeable; randomized comparisons show inconsistent subgroup effects, failed prespecified tests in IMvigor211 and DANUBE and no significant treatment-by-PD-L1 interaction; and the benefit of first-line enfortumab vedotin plus pembrolizumab is independent of combined positive score. Its remaining role is confined to label restrictions, chiefly European. Tumor mutational burden, molecular subtypes, expression signatures, DNA damage response and FGFR3 alterations remain investigational. Tumor-informed circulating tumor DNA (ctDNA) answers a different question: whether residual disease persists after cystectomy. After an exploratory signal in IMvigor010, the prospective enrichment trial IMvigor011 showed that ctDNA-positive patients derive disease-free and overall survival benefit from adjuvant atezolizumab; persistently ctDNA-negative patients were observed without randomization, so their 88% two-year disease-free survival does not exclude a benefit of treatment. This underpins US companion-diagnostic approval and a Category 1 guideline recommendation, not yet European authorization. Post-cystectomy ctDNA thus meets the same enrichment standard as PD-L1 and, like PD-L1, neither the predictive nor the strategy standard; what sets it apart is that the marker was necessary for the result, adjuvant atezolizumab having failed unselected, and that it directs whether to treat rather than which regimen; its role after perioperative immunotherapy is unresolved.
SN - 2072-6694
ER -