{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania",
    "Bastion Policlinic, Mircea cel Batran Street, No. 122C, 300600 Timisoara, Romania",
    "Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania",
    "Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania",
    "Department XV, Discipline of Radiology and Medical Imaging, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania",
    "Department of Oncology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania",
    "Department 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"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Dorin Novacescu",
      "orcid": "0000-0002-2520-7636"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Mihael Musta"
    },
    {
      "affs": [
        4
      ],
      "name": "Radu Caprariu"
    },
    {
      "affs": [
        0
      ],
      "name": "Cristina Stefania Dumitru",
      "orcid": "0000-0001-8933-3060"
    },
    {
      "affs": [
        0
      ],
      "name": "Alina Cristina Barb"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Antonia Armega-Anghelescu"
    },
    {
      "affs": [
        5
      ],
      "name": "Radu Dragomir",
      "orcid": "0000-0002-5994-9160"
    },
    {
      "affs": [
        6
      ],
      "name": "Adelina Baloi",
      "orcid": "0009-0008-5097-2947"
    },
    {
      "affs": [
        1,
        2,
        3
      ],
      "name": "Silviu Latcu"
    },
    {
      "affs": [
        1
      ],
      "name": "Flaviu Lucian Petrica",
      "orcid": "0009-0001-7134-6434"
    },
    {
      "affs": [
        3
      ],
      "name": "Alin Cumpanas"
    },
    {
      "affs": [
        0
      ],
      "name": "Flavia Zara",
      "orcid": "0000-0002-5755-179X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cgjy9h0zg480q.bib",
  "cited_by": 0,
  "doi": "10.3390/cancers18213581",
  "fulltext_url": null,
  "id": "cgjy9h0zg480q",
  "issns": [
    "2072-6694"
  ],
  "landing_url": "https://www.mdpi.com/2072-6694/18/21/3581",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-07",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/cgjy9h0zg480q.ris",
  "sources": [
    {
      "first_seen": "2026-11-10T00:21:40Z",
      "native_id": "10.3390/cancers18213581",
      "source": "crossref",
      "url": "https://www.mdpi.com/2072-6694/18/21/3581"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "issn:2072-6694",
      "subfield": "oncology"
    }
  ],
  "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",
  "title_text": "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",
  "type": "peer-reviewed",
  "updated_at": "2026-11-10T00:21:40Z",
  "url": "https://research.draconitic.com/paper/cgjy9h0zg480q",
  "venue": "Cancers",
  "versions": []
}