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Focuses on updated results from the EV-302/KEYNOTE-A39 trial, building on earlier phase III findings and comparing efficacy and safety against platinum-based chemotherapy. Discusses clinical context, prior pivotal trials, guideline alignment, and key outcomes including overall survival, progression-free survival, response rates, and consistency across biomarker and cisplatin eligibility subgroups.",{"@graph":14,"@context":72},[15,34,55],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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clinical problem does the commentary address in locally advanced or metastatic urothelial carcinoma?","Question",{"text":62,"@type":63},"It addresses the poor prognosis of la/mUC and the limited durability of response for many patients treated with first-line platinum chemotherapy and immune checkpoint inhibitors.","Answer",{"name":65,"@type":60,"acceptedAnswer":66},"Which trial update is emphasized, and what is its focus?",{"text":67,"@type":63},"The commentary emphasizes the extended follow-up data update from the EV-302/KEYNOTE-A39 trial, focusing on durable response outcomes for the EV-302 regimen.",{"name":69,"@type":60,"acceptedAnswer":70},"How do the updated results relate to earlier EV-302 findings?",{"text":71,"@type":63},"They extend the follow-up beyond the primary analysis, maintaining superior efficacy and safety for the EV-302 regimen compared with conventional platinum-based 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systemic treatment for patients with locally advanced or metastatic urothelial carcinoma:  \ndata update of EV-302/KEYNOTE-A39 trial  \nMakito Miyake^  \nDepartment of Urology, Nara Medical University, Kashihara, Japan  \nCorrespondence to: Makito Miyake, MD, PhD. Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Japan.  \n[Email: makitomiyake@yahoo.co.jp](Email: makitomiyake@yahoo.co.jp).  \nComment on: Powles TB, Van der Heijden MS, Loriot Y, et al. Enfortumab vedotin plus pembrolizumab in untreated locally advanced or metastatic  \nurothelial carcinoma: 2.5-year median follow-up of the phase III EV-302/KEYNOTE-A39 trial. Ann Oncol 2025;36:1212-9 .  \nKeywords: Combination; durable response; enfortumab vedotin (EV); pembrolizumab; urothelial carcinoma (UC)  \nSubmitted Aug 16, 2025. Accepted for publication Nov 20, 2025. Published online Dec 22, 2025.  \ndoi: 10.21037/tau-2025-587  \nView this article at: [https://dx.doi.org/10.21037/tau-2025-587](https://dx.doi.org/10.21037/tau-2025-587)  \nUrothelial carcinoma (UC) originates from the urothelial lining of the renal pelvis, ureter, bladder, and urethra. Upper urinary tract UC is more prevalent in Asian countries and accounts for only approximately 5% of all urinary tract cancers (1). According to the Global Cancer Statistics 2020 report, bladder cancer (BCa) is the 7th and 13th most frequent malignancy among men worldwide, with approximately 573,000 new cases and 213,000 deaths in 2020 (2). By 2040, the annual number of new BCa cases and deaths is projected to rise to 991,000 (a 72.8% increase) and 397,000 (an 86.6% increase), respectively (3) . Therefore, to reduce the global burden, there is an urgent need to accelerate control initiatives for high-risk populations with UC, including those with BCa.  \nLocally advanced or metastatic UC (la/mUC) is a progressive disease with poor prognosis. The median overall survival (OS) is approximately 19–26 months following first-line platinum-based chemotherapy and subsequent administration of immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 (PD-1) and antiprogrammed death-ligand 1 (PD-L1) inhibitors (4-7) . A substantial proportion of the population responds poorly to chemotherapy and ICIs, which results in poor survival rates. Novel drug combinations, including chemotherapy,  \nICIs, antibody-drug conjugates (ADCs), and tyrosine kinase inhibitors (TKIs), have been explored for a longtime to overcome inherent drug resistance and improve antineoplastic activity (8) .  \nThis unmet need was addressed by two pivotal trials, CheckMate-901 and EV-302/KEYNOTE-A39 (hereinafter referred to as EV-302), presented at the European Society for Medical Oncology (ESMO)-2023 plenary session. The approval of nivolumab (anti-PD-1 inhibitor) in combination with gemcitabine and cisplatin (GC) and pembrolizumab (anti-PD-1 inhibitor) with enfortumab vedotin (EV) based on the positive results has revolutionized the firstline treatment of la/mUC in many countries (9,10) . In the CheckMate-901 trial, which compared conventional GC with and without nivolumab in previously untreated, cisplatin-eligible la/mUC, the primary endpoint was met with a median OS benefit favoring the GC plus nivolumab (GCN) arm [21.7 vs. 18.9 months, hazard ratio (HR) 0.75; 95% confidence interval (CI): 0.63–0.96; P=0 .017](9) . The GCN achieved an objective response rate (ORR) of 58%, with a complete response (CR) rate of 22%, compared to 43% ORR and 12% CR of GC alone (9) . The EV- 302 trial compared EV with pembrolizumab (EVP) with platinum-based combination chemotherapy [comparator  \n^ ORCID: 0000-0001-9503-7356.  \n© AME Publishing Company. Transl Androl Urol 2025;14(12):3799-3805 | [https://dx.doi.org/10.21037/tau-2025-587](https://dx.doi.org/10.21037/tau-2025-587)  \n3800 Miyake. Durable response to first-line therapy in advanced UC  \narm: either GC or gemcitabine plus ca","cbCaihyhmS34Rfth","https://ap.wps.com/l/cbCaihyhmS34Rfth","pdf",404710,"English","# Editorial Commentary\n## Background and unmet need in la/mUC\n## Pivotal trials: CheckMate-901 and EV-302/KEYNOTE-A39\n## Guideline recommendations and clinical implications\n## Updated EV-302 follow-up: efficacy endpoints and durability","[{\"question\":\"What clinical problem does the commentary address in locally advanced or metastatic urothelial carcinoma?\",\"answer\":\"It addresses the poor prognosis of la/mUC and the limited durability of response for many patients treated with first-line platinum chemotherapy and immune checkpoint inhibitors.\"},{\"question\":\"Which trial update is emphasized, and what is its focus?\",\"answer\":\"The commentary emphasizes the extended follow-up data update from the EV-302/KEYNOTE-A39 trial, focusing on durable response outcomes for the EV-302 regimen.\"},{\"question\":\"How do the updated results relate to earlier EV-302 findings?\",\"answer\":\"They extend the follow-up beyond the primary analysis, maintaining superior efficacy and safety for the EV-302 regimen compared with conventional platinum-based chemotherapy.\"}]","Impact of durable response of first-line systemic treatment for patients with locally advanced or metastatic urothelial carcinoma - data update of EV-302/KEYNOTE-A39 trial | PDF",1790746714,18]