ESMO 2025: Updates in Bladder Cancer

Vishesh Khanna, MD Knight Cancer Institute, Oregon Health & Science University

The European Society of Medical Oncology (ESMO) Congress 2025 showcased remarkable advancements in the field of bladder cancer, spanning non-muscle invasive disease through the metastatic setting. Among the many novel datasets and findings presented, three practice-changing studies presented in the Presidential Sessions stand out. 

A New Standard of Care for Cisplatin-Ineligible Patients

The combination of the antibody-drug conjugate (ADC) enfortumab vedotin (EV) and the immune checkpoint inhibitor pembrolizumab (P) has become the new standard of care for bladder cancer in the first-line metastatic setting. KEYNOTE-905/EV-303 (LBA2) now extends this combination into the localized, muscle-invasive setting by comparing perioperative EV+P versus cystectomy alone in cisplatin-ineligible patients.¹

Relative to surgery alone, the combination significantly improved event-free survival (median not reached [NR] vs 15.7 months; HR 0.40, 95% CI 0.28-0.57) and overall survival (OS; NR vs 41.7 months; HR 0.50, 95% CI 0.33-0.74). The pathologic complete response rate of 57.1% in the EV+P arm—relative to 8.6% in the control arm—is especially striking and well exceeds the rates achieved by cisplatin-based neoadjuvant chemotherapy. In terms of safety signals, grade 3 or greater adverse events (AEs) were more frequent with EV+P (71% vs 46%), with expected signals of rash, neuropathy, ocular toxicity, hyperglycemia, and immune-related skin and thyroid disorders. 

Overall, these data represent a major advance in the bladder cancer field, changing practice for a patient group that has historically been unable to receive neoadjuvant systemic therapy. Outstanding questions remain, including the relative importance of pre- versus post-operative systemic treatment and how to treat patients who develop relapsed or metastatic disease.

Disitamab Vedotin Plus Toripalimab in HER2-Expressing Metastatic Disease

The phase 3 RC48-C016 (LBA7) study evaluating disitamab vedotin (DV), a HER2-directed ADC, plus toripalimab (T), an anti-PD-1 antibody, in first-line HER2-expressing (IHC 1+, 2+, or 3+) metastatic urothelial carcinoma also showed striking results.² The trial enrolled 484 patients and compared DV+T against standard gemcitabine/platinum chemotherapy. DV+T nearly doubled OS (31.5 vs 16.9 months; HR, 0.54; 95% CI 0.41-0.73) and significantly improved progression-free survival (13.1 vs 6.5 months; HR, 0.36; 95% CI 0.28-0.46). Objective response rates were 76% versus 50%, respectively. Moreover, grade 3 or greater AEs were lower with DV+T compared with chemotherapy (55% vs 87%).

This is the first randomized phase 3 trial in which a HER2-targeted ADC plus immunotherapy (IO) outperformed chemotherapy in bladder cancer, with benefit extending even to HER2-low tumors. While the control arm used chemotherapy rather than the now standard chemo-immunotherapy backbone, a global phase 3 trial (RC48-G001) is underway testing DV+P versus platinum chemotherapy, which should clarify its role in international practice.³

Clinically, the results raise an important new question: should HER2-expressing patients receive EV+P or DV+T/P in the frontline setting? No comparative data exist, and both ADCs share a similar MMAE payload, raising theoretical concerns about cross-resistance, particularly given that HER2 and Nectin-4 are often co-expressed in luminal tumors. Regardless, these results firmly establish HER2 testing as a necessary component of frontline biomarker profiling and highlight the accelerating shift toward biomarker-driven ADC plus IO combinations in bladder cancer.

IMvigor011 and the Emerging Role of MRD-Guided Adjuvant Therapy

IMvigor011 (LBA8), the third pivotal presentation, delivered the first level 1 evidence supporting circulating tumor DNA (ctDNA)-guided adjuvant immunotherapy in muscle-invasive disease.⁴ Following cystectomy, patients underwent serial surveillance using the Signatera tumor-informed ctDNA assay. Those who tested ctDNA-positive (ctDNA+) were randomized to atezolizumab or placebo in the phase 3 study, while ctDNA-negative (ctDNA-) patients were observed without adjuvant treatment.

In the ctDNA+ cohort, atezolizumab significantly improved disease-free survival (DFS; 9.9 vs 4.8 months; HR, 0.64; 95% CI 0.47-0.87) and OS (32.8 vs 21.1 months; HR, 0.59; 95% CI 0.39-0.90). In contrast, patients who remained ctDNA- without adjuvant treatment had excellent outcomes, with a 12-month DFS of approximately 95% and a 2-year DFS of 88%. Building upon prior data from studies such as TOMBOLA and NIAGARA, these findings strongly support minimal residual disease (MRD) as both a prognostic and predictive biomarker in urothelial cancer, identifying patients most likely to benefit from adjuvant therapy.

These exciting data bring with them a host of new questions. The Signatera assay, while validated, tracks a limited number of tumor-specific variants and may have lower sensitivity than broader whole genome sequencing approaches, raising the possibility of false-negative results in patients with low ctDNA shedding. In addition, the trial’s follow-up remains relatively short, and how best to integrate ctDNA monitoring into real-world practice, particularly in patients who have already received neoadjuvant systemic therapy, is yet to be defined.

Ongoing studies such as MODERN (NCT05987241) are expanding this paradigm by prospectively randomizing post-surgical patients based on ctDNA status—ctDNA+ patients receive either nivolumab or nivolumab plus relatlimab, while ctDNA- patients are randomized to nivolumab versus active surveillance.⁵ MODERN will test both escalation and de-escalation strategies in a single platform, helping further define how MRD can individualize adjuvant immunotherapy.

Clinical Implications and Outlook

Altogether, these three landmark presentations from ESMO 2025 mark a clear inflection point in the management of bladder cancer. EV+P redefines perioperative therapy for cisplatin-ineligible disease, DV+T establishes HER2 as a meaningful and actionable biomarker in the first-line metastatic setting, and IMvigor011 ushers in an era of ctDNA-guided adjuvant immunotherapy.

Collectively, they signal a future in which treatment is no longer dictated solely by stage or performance status, but by biologic subtype, biomarker expression, and molecular residual disease, a framework that will undoubtedly continue to evolve in the years ahead.

References

1. Vulsteke C, Kaimakliotis H, Danchaivijitr P, et al. Perioperative (periop) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin-ineligible: The phase III KEYNOTE-905 study. LBA2. Presented at: ESMO Congress 2025, Oct. 17-21, 2025, Berlin, Germany. 
2. Guo J, Sheng X, Zeng G, et al. Disitamab vedotin (DV) plus toripalimab (T) versus chemotherapy (C) in first-line (1L) locally advanced or metastatic urothelial carcinoma (la/mUC) with HER2-expression. LBA7. Presented at: ESMO Congress 2025, Oct. 17-21, 2025, Berlin, Germany. 
3. Powles T, Yu EY, Iyer G, et al. Phase 2 clinical study evaluating the efficacy and safety of disitamab vedotin with or without pembrolizumab in patients with HER2-expressing urothelial carcinoma (RC48G001). J Clin Oncol. 2023;31(6_suppl). 
4. Powles TB, Kann A, Castellano Gauna DE, et al. IMvigor011: a phase III trial of circulating tumour (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer. LBA8. Presented at: ESMO Congress 2025, Oct. 17-21, 2025, Berlin, Germany. 
5. Smith ZL, et al. MODERN: a phase 2/3 randomized trial of ctDNA-guided adjuvant immunotherapy in muscle-invasive bladder cancer. J Clin Oncol. 2025;43(5_suppl).