PURPOSE OF REVIEW: Bladder cancer incidence is on the rise, and until recently, there has been little to no change in treatment regimens over the last 40 years. Hence, it is imperative to work on strategies and approaches to untangle the complexity of intra- and inter-tumour heterogeneity of bladder cancer with the aim of improving patient-specific care and treatment outcomes. The focus of this review is therefore to highlight novel targets, advances, and therapy approaches for bladder cancer patients. RECENT FINDINGS: The success of combining an antibody-drug conjugate (ADC) with immunotherapy has been recently hailed as a game changer in treating bladder cancer patients. Hence, interest in other ADCs as a treatment option is also rife. Furthermore, strategies to overcome chemoresistance to standard therapy have been described recently. In addition, other studies showed that targeting genomic alterations (e.g. mutations in FGFR3 , DNA damage repair genes and loss of the Y chromosome) could also be helpful as prognostic and treatment stratification biomarkers. The use of single-cell RNA sequencing approaches has allowed better characterisation of the tumour microenvironment and subsequent identification of novel targets. Functional precision medicine could be another avenue to improve and guide personalized treatment options. SUMMARY: Several novel preclinical targets and treatment options have been described recently. The validation of these advances will lead to the development and implementation of robust personalized treatment regimens for bladder cancer patients.

Center for Cancer Research and Comprehensive Cancer Center Medical University of Vienna Austria

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Comprehensive Cancer Center

Department of Urology University of Texas Southwestern Dallas Texas USA

Department of Urology Weill Cornell Medical College New York New York

Institute for Urology University of Jordan Amman Jordan

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Research center for Evidence Medicine Urology Department Tabriz University of Medical Sciences Tabriz Iran

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Alfred Witjes J, Max Bruins H, Carrión A, et al. . European Association of Urology Guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2023 guidelines. Eur Urol 2024; 85:17–31. PubMed

Tran L, Xiao J-F, Agarwal N, et al. . Advances in bladder cancer biology and therapy. Nat Rev Cancer 2021; 21:104–121. PubMed PMC

Dyrskjøt L, Hansel DE, Efstathiou JA, et al. . Bladder cancer. Nat Rev Dis Primers 2023; 9:1–21. PubMed PMC

Powles TB, Valderrama BP, Gupta S, et al. . LBA6 EV-302/KEYNOTE-A39: open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol 2023; 34:S1340.

Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature 2019; 575:299–309. PubMed PMC

Shi ZD, Hao L, Han XX, et al. . Targeting HNRNPU to overcome cisplatin resistance in bladder cancer. Mol Cancer 2022; 21:37. PubMed PMC

Chen L, Liu Z, Tang H, et al. . Knockdown of ZBTB11 impedes R-loop elimination and increases the sensitivity to cisplatin by inhibiting DDX1 transcription in bladder cancer. Cell Prolif 2022; 55:e13325. PubMed PMC

Wang M, Chen X, Tan P, et al. . Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer. Cancer Cell 2022; 40:1044–1059. e8. PubMed

Ertl IE, Lemberger U, Ilijazi D, et al. . Molecular and pharmacological bladder cancer therapy screening: discovery of clofarabine as a highly active compound. Eur Urol 2022; 82:261–270. PubMed

Kamoun A, de Reyniès A, Allory Y, et al. . A consensus molecular classification of muscle-invasive bladder cancer. Eur Urol 2020; 77:420–433. PubMed PMC

Teo MY, Bambury RM, Zabor EC, et al. . DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma. Clin Cancer Res 2017; 23:3610–3618. PubMed PMC

Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 2013; 14:197–210. PubMed

Zhou Y, Börcsök J, Adib E, et al. . ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer. Sci Adv 2023; 9:eadg2263. PubMed PMC

Gil-Jimenez A, van Dorp J, Contreras-Sanz A, et al. . Assessment of predictive genomic biomarkers for response to cisplatin-based neoadjuvant chemotherapy in bladder cancer. Eur Urol 2023; 83:313–317. PubMed

Loriot Y, Matsubara N, Park SH, et al. . Phase 3 THOR study: results of erdafitinib (erda) versus chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select fibroblast growth factor receptor alterations (FGFRalt). JCO 2023; 41:LBA4619.

Research C for DE and: FDA approves erdafitinib for locally advanced or metastatic urothelial carcinoma. FDA 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-erdafitinib-locally-advanced-or-metastatic-urothelial-carcinoma.

Jing W, Wang G, Cui Z, et al. . FGFR3 destabilizes PD-L1 via NEDD4 to control T-cell–mediated bladder cancer immune surveillance. Cancer Res 2022; 82:114–129. PubMed

Okato A, Utsumi T, Ranieri M, et al. . FGFR inhibition augments anti–PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression. J Clin Invest 2024; 134:e169241. PubMed PMC

Sauter G, Moch H, Wagner U, et al. . Y chromosome loss detected by FISH in bladder cancer. Cancer Genet Cytogenet 1995; 82:163–169. PubMed

Cáceres A, Jene A, Esko T, et al. . Extreme downregulation of chromosome Y and cancer risk in men. J Natl Cancer Inst 2020; 112:913–920. PubMed PMC

Abdel-Hafiz HA, Schafer JM, Chen X, et al. . Y chromosome loss in cancer drives growth by evasion of adaptive immunity. Nature 2023; 619:624–631. PubMed PMC

van Dorp J, van der Heijden MS. The bladder cancer immune micro-environment in the context of response to immune checkpoint inhibition. Front Immunol 2023; 14:1235884. PubMed PMC

Lyu T, Lin Y, Wu K, et al. . Single-cell sequencing technologies in bladder cancer research: applications and challenges. Front Genet 2022; 13:1027909. PubMed PMC

Liu L, Hou Y, Deng C, et al. . Single cell sequencing reveals that CD39 inhibition mediates changes to the tumor microenvironment. Nat Commun 2022; 13:6740. PubMed PMC

Borgeaud M, Sandoval J, Obeid M, et al. . Novel targets for immune-checkpoint inhibition in cancer. Cancer Treat Rev 2023; 120:102614. PubMed

Borst L, van der Burg SH, van Hall T. The NKG2A–HLA-E axis as a novel checkpoint in the tumor microenvironment. Clin Cancer Res 2020; 26:5549–5556. PubMed

Salomé B, Sfakianos JP, Ranti D, et al. . NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer. Cancer Cell 2022; 40:1027–1043. e9. PubMed PMC

Chhabra Y, Weeraratna AT. Fibroblasts in cancer: unity in heterogeneity. Cell 2023; 186:1580–1609. PubMed PMC

Ma Z, Li X, Mao Y, et al. . Interferon-dependent SLC14A1+ cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer. Cancer Cell 2022; 40:1550–1565. e7. PubMed

Zheng H, An M, Luo Y, et al. . PDGFRα+ITGA11+ fibroblasts foster early-stage cancer lymphovascular invasion and lymphatic metastasis via ITGA11-SELE interplay. Cancer Cell 2024; 10.1016/j.ccell.2024.02.002 PubMed DOI

Dumontet C, Reichert JM, Senter PD, et al. . Antibody–drug conjugates come of age in oncology. Nat Rev Drug Discov 2023; 22:641–661. PubMed

Reches A, Ophir Y, Stein N, et al. . Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity. J Immunother Cancer 2020; 8:e000266. PubMed PMC

Research C for DE and: FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. FDA 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-advanced-urothelial-cancer.

Thomas J, Sun M, Getz T, et al. . Antibody-drug conjugates for urothelial carcinoma. Urol Oncol 2023; 41:420–428. PubMed

Gilead Sciences. A randomized open-label Phase III study of sacituzumab Govitecan versus treatment of physician's choice in subjects with metastatic or locally advanced unresectable urothelial cancer. clinicaltrials.gov; 2024. https://clinicaltrials.gov/study/NCT04527991?id=NCT04527991&rank=1.

Okajima D, Yasuda S, Maejima T, et al. . Datopotamab deruxtecan, a novel TROP2-directed antibody–drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. Mol Cancer Ther 2021; 20:2329–2340. PubMed PMC

Lisberg A, Drakaki A, Meric-Bernstam F, et al. . Datopotamab deruxtecan in locally advanced/metastatic urothelial cancer: preliminary results from the phase 1 TROPION-PanTumor01 study. JCO 2024; 42:603–1603. PubMed PMC

Krüger S, Weitsch G, Büttner H, et al. . HER2 overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic implications. Int J Cancer 2002; 102:514–518. PubMed

Rosenberg JE, O’Donnell PH, Balar AV, et al. . Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 2019; 37:2592–2600. PubMed PMC

Bahlinger V, Branz A, Strissel PL, et al. . Associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 with molecular subtypes, PD-L1 expression, and FGFR3 mutational status in two advanced urothelial bladder cancer cohorts. Histopathology 2024; 84:863–876. PubMed

Klümper N, Ralser DJ, Ellinger J, et al. . Membranous NECTIN-4 expression frequently decreases during metastatic spread of urothelial carcinoma and is associated with enfortumab vedotin resistance. Clin Cancer Res 2023; 29:1496–1505. PubMed PMC

Dolgin E. The future of precision cancer therapy might be to try everything. Nature 2024; 626:470–473. PubMed

Kornauth C, Pemovska T, Vladimer GI, et al. . Functional precision medicine provides clinical benefit in advanced aggressive hematologic cancers and identifies exceptional responders. Cancer Discov 2022; 12:372–387. PubMed PMC

Minoli M, Cantore T, Hanhart D, et al. . Bladder cancer organoids as a functional system to model different disease stages and therapy response. Nat Commun 2023; 14:2214. PubMed PMC

Garioni M, Tschan VJ, Blukacz L, et al. . Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer. NPJ Precis Oncol 2023; 7:112. PubMed PMC

Tian L, Chen F, Macosko EZ. The expanding vistas of spatial transcriptomics. Nat Biotechnol 2023; 41:773–782. PubMed PMC

Rose KM, Huelster HL, Meeks JJ, et al. . Circulating and urinary tumour DNA in urothelial carcinoma — upper tract, lower tract and metastatic disease. Nat Rev Urol 2023; 20:406–419. PubMed