Top Poster Takeaways for Urothelial Carcinoma From The 2026 ESMO Congress

At the 2026 European Society for Medical Oncology (ESMO) Congress, 3 posters examined outcomes in advanced urothelial carcinoma. Two exploratory analyses from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) showed that the overall survival (OS) benefit of frontline enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) over platinum-based chemotherapy held in patients with clinically challenging features. A third poster showed that early deaths still limit how far treatment advances reach patients with metastatic disease.

• 4761P: after a median follow-up of about 3.5 years, enfortumab vedotin plus pembrolizumab improved OS vs chemotherapy in patients aged 75 years or older, patients with obesity or diabetes, and patients with renal impairment.¹
• 4760P: the OS benefit was consistent regardless of where the primary tumor originated and whether patients had visceral, liver, or lung metastases.²
• 4827eP: in a Surveillance, Epidemiology, and End Results (SEER) analysis, about one-third of patients with metastatic urothelial bladder cancer died within 3 months of diagnosis, and this proportion barely changed between 2004 and 2022.³

Long-Term EV-302 Outcomes in Challenging Subgroups

In EV-302, 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma were randomly assigned to enfortumab vedotin plus pembrolizumab (n = 442) or platinum-based chemotherapy (n = 444). With about 3.5 years of median follow-up, the combination roughly doubled median OS in the intention-to-treat population compared with chemotherapy, at 33.6 vs 15.9 months (HR, 0.53; 95% CI, 0.45-0.63). As of the October 6, 2025, data cutoff, median follow-up was 42.8 months (95% CI, 41.7-43.9). Both analyses below were post hoc.

4761P: Enfortumab Vedotin Plus Pembrolizumab for Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma: Updated Exploratory Analysis of EV-302 in Older Patients and Those With Comorbidities

Enfortumab vedotin plus pembrolizumab kept its OS advantage over chemotherapy in older patients and in those with obesity, diabetes, or renal impairment, with no new safety concerns, according to Srikala S. Sridhar, MD, professor in the Department of Medicine at the University of Toronto and genitourinary oncologist at the Princess Margaret Cancer Centre, in Ontario, Canada, and coauthors.

The investigators looked at 4 subgroups, which were not mutually exclusive:

• patients aged 75 years or older;
• patients with a body mass index (BMI) of 30 kg/m² or higher;
• patients with diabetes, defined as ongoing hyperglycemia or a hemoglobin A1c of 6.5% or higher;
• patients with moderate or severe renal impairment, defined as a glomerular filtration rate (GFR) below 60 mL/min.

In the older subgroup, the median age was 79.0 years (range, 75-87) in the combination arm and 78.0 years (range, 75-91) in the chemotherapy arm. In the other subgroups, the median ages were similar between arms:

• BMI of 30 kg/m² or higher: 68.0 years in both arms (ranges, 53-86 and 35-91).
• Diabetes: 70.0 years in both arms (ranges, 45-86 and 48-91).
• Renal impairment: 72.0 years (range, 40-86) vs 73.0 years (range, 47-91).

Among patients aged 75 years or older, the median OS was 24.4 months (95% CI, 19.8-31.5) with enfortumab vedotin plus pembrolizumab (n = 102) vs 11.6 months (95% CI, 9.5-15.0) with chemotherapy (n = 108; HR, 0.593; 95% CI, 0.422-0.834).

In patients with a BMI of 30 kg/m² or higher, the median OS was 42.6 months (95% CI, 32.9-not estimable [NE]) vs 16.6 months (95% CI, 13.1-21.0; HR, 0.441; 95% CI, 0.295-0.657). Among patients with diabetes, median OS was NE with the combination (95% CI, 27.3-NE) vs 14.5 months (95% CI, 10.3-19.5) with chemotherapy (HR, 0.331; 95% CI, 0.216-0.506). In patients with a GFR below 60 mL/min, the median OS was 25.6 months (95% CI, 20.5-33.6) vs 13.3 months (95% CI, 10.9-15.9; HR, 0.551; 95% CI, 0.429-0.707).

The benefit was also seen in the other BMI and GFR categories. In patients with a BMI below 25 kg/m² (n = 391), median OS was 26.5 months (95% CI, 22.8-36.3) vs 15.3 months (95% CI, 12.1-18.7; HR, 0.61; 95% CI, 0.47-0.79). In those with a BMI of 25 to below 30 kg/m² (n = 299), it was 35.4 months (95% CI, 26.1-NE) vs 16.0 months (95% CI, 13.3-19.1; HR, 0.47; 95% CI, 0.35-0.64).

In patients with a GFR of 90 mL/min or higher (n = 179), median OS was NE with the combination (95% CI, 29.6-NE) vs 18.6 months (95% CI, 14.5-28.6) with chemotherapy (HR, 0.49; 95% CI, 0.33-0.74). In those with a GFR of 60 to below 90 mL/min (n = 327), it was 38.7 months (95% CI, 27.8-NE) vs 18.4 months (95% CI, 13.7-21.1; HR, 0.53; 95% CI, 0.40-0.72).

Grade 3 or higher treatment-related adverse events (TRAEs) were less frequent with enfortumab vedotin plus pembrolizumab than with chemotherapy in every subgroup:

• Age 75 years or older: 58% vs 73%.
• BMI of 30 kg/m² or higher: 60% vs 67%.
• Diabetes: 64% vs 70%.
• GFR below 60 mL/min: 61% vs 78%.

TRAEs of special interest for enfortumab vedotin were mostly low grade. Grade 3 or higher peripheral neuropathy occurred in 13% of patients aged 75 years or older, compared with 7% in the other subgroups. Grade 3 or higher hyperglycemia occurred in 9% of patients with a BMI of 30 kg/m² or higher and 15% of those with diabetes, compared with 4% or less elsewhere. No patients discontinued treatment because of hyperglycemia.

For pembrolizumab, the most common AEs of special interest at any grade were severe skin reactions (18% to 28% across subgroups), hypothyroidism (10% to 17%), and pneumonitis (7% to 14%).

4760P: Enfortumab Vedotin + Pembrolizumab in Previously Untreated Locally Advanced or Metastatic Urothelial Cancer: Exploratory Analyses Based on Disease-Related Characteristics From EV-302

The OS benefit of enfortumab vedotin plus pembrolizumab was consistent across subgroups defined by disease characteristics, including those associated with poor prognosis, according to Jens Bedke, MD, senior consultant in the Department of Urology and Transplantation Surgery at the Eva Mayr-Stihl Cancer Center Stuttgart, Klinikum Stuttgart in Germany, and coauthors.

By primary tumor site, patients with upper tract disease had a median OS of 29.8 months (95% CI, 23.8-39.8) with the combination (n = 135) vs 18.3 months (95% CI, 12.5-23.8) with chemotherapy (n = 104; HR, 0.614; 95% CI, 0.436-0.866). Those with lower tract disease had a median OS of 35.0 months (95% CI, 26.1-43.2; n = 305) vs 15.5 months (95% CI, 13.3-18.0; n = 339; HR, 0.513; 95% CI, 0.421-0.625).

By site of metastasis, the median OS was not reached with the combination in patients with lymph node–only disease (95% CI, 40.7-NE; n = 103), compared with 24.4 months (95% CI, 18.3-40.8; n = 104) with chemotherapy (HR, 0.525; 95% CI, 0.353-0.781). In patients with visceral metastases, the median OS was 26.1 months (95% CI, 23.8-33.6) vs 13.3 months (95% CI, 11.6-15.5), with 318 patients in each arm (HR, 0.519; 95% CI, 0.429-0.628).

The benefit was similar regardless of liver metastases, a feature associated with poor prognosis. With liver metastases, median OS was 19.1 months (95% CI, 14.5-24.3; n = 100) vs 10.1 months (95% CI, 7.9-11.8; n = 99; HR, 0.538; 95% CI, 0.390-0.742). Without them, it was 41.3 months (95% CI, 35.4-NE; n = 342) vs 18.3 months (95% CI, 15.9-20.1; n = 345; HR, 0.530; 95% CI, 0.434-0.646).

Results were similar by lung metastases. With lung metastases, the median OS was 28.0 months (95% CI, 22.6-37.2; n = 170) vs 15.3 months (95% CI, 12.5-18.4; n = 157; HR, 0.600; 95% CI, 0.456-0.789). Without them, it was 36.5 months (95% CI, 27.8-NE; n = 272) vs 16.0 months (95% CI, 13.3-18.8; n = 287; HR, 0.498; 95% CI, 0.401-0.620).

The objective response rates (ORRs) and complete response (CR) rates by blinded independent central review were higher with the combination in every subgroup as of an August 8, 2024, data cutoff.

By primary site, the ORRs were 68% vs 41% in upper tract disease, with CR rates of 29% vs 11%. In lower tract disease, the ORRs were 68% vs 45%, and CR rates were 31% vs 16%.

Among patients with lymph node–only disease, the ORR was 77% vs 53%, and half of patients receiving the combination had a CR compared with 26% of those receiving chemotherapy. In patients with visceral metastases, the ORRs were 64% vs 39%, and CR rates were 23% vs 10%.

With liver metastases, the ORRs were 59% vs 40%, and CR rates were 20% vs 7%; without them, the ORRs were 70% vs 45%, and CR rates were 34% vs 17%. With lung metastases, the ORRs were 60% vs 43%, and CR rates were 22% vs 10%; without them, the ORRs were 70% vs 45%, and CR rates were 34% vs 17%.

Grade 3 or higher TRAEs were less frequent with the combination than with chemotherapy in all subgroups. TRAEs of special interest for enfortumab vedotin were mostly low grade and none were fatal. Skin reactions were the only such event that reached grade 3 or higher in more than 10% of patients in any subgroup.

Real-World Outcomes in Metastatic Disease

4827eP: Persistent Early Mortality and the Real-World Efficacy–Effectiveness Gap in Metastatic Urothelial Bladder Cancer

About 36% of patients with metastatic urothelial bladder cancer died within 3 months of diagnosis, and this rate stayed nearly unchanged from 2004 to 2022. Most survival gains went to patients who lived past 3 months. Faris T. Tamimi, MD, medical oncologist at King Hussein Cancer Center in Amman, Jordan, presented the findings.

The investigators analyzed 11,542 patients in the SEER database with de novo metastatic transitional or papillary transitional cell carcinoma of the bladder. They grouped patients into 3 diagnosis eras: before checkpoint inhibitors (2004 to 2015), after checkpoint inhibitors (2016 to 2019) and after maintenance avelumab (Bavencio; 2020 to 2022). The eras reflect the period of diagnosis, not confirmed drug exposure.

Overall, 72% of patients were aged 65 years or older, and 26% were aged 80 years or older; 72% were male, and 77% were non-Hispanic White.

OS improved only modestly across eras. The median OS was 6, 6, and 7 months across each diagnosis era, and the 2-year OS rates were 12.5%, 17.4%, and 19.2%, respectively. Compared with 2004 to 2015, unadjusted HRs for death were 0.91 (95% CI, 0.86-0.95) for 2016 to 2019 and 0.84 (95% CI, 0.80-0.89) for 2020 to 2022.

Early death, defined as death within 3 months of diagnosis, occurred in 4146 patients (36.0%). The annual rates ranged from 33% to 40% from 2004 to 2021, and era means were 36.8%, 36.3%, and 33.3%.

Only 15.7% (n = 649/4146) of patients who died early had documented chemotherapy, compared with 63.7% (n = 4704/7384) of those who survived beyond 3 months. Non-cancer causes accounted for a similar share of early deaths (12.5%; n = 520/4146) and later deaths (12.3%; n = 750/6092). The investigators concluded that competing causes of death do not explain the early-mortality burden.

Several factors were associated with early death. The strongest was age 80 years or older compared with younger than 65 years (OR, 2.57; 95% CI, 2.31-2.86). Others were:

• transitional cell carcinoma not otherwise specified vs papillary histology (OR, 1.56; 95% CI, 1.42-1.70);
• low vs high income (OR, 1.30; 95% CI, 1.04-1.63);
• non-Hispanic Black vs non-Hispanic White race (OR, 1.21; 95% CI, 1.06-1.40).

Male sex (OR, 0.90; 95% CI, 0.82-0.98) and diagnosis in 2020 to 2022 compared with 2004 to 2015 (OR, 0.85; 95% CI, 0.77-0.95) were associated with lower odds of early death.

Gains across eras were larger among patients who survived at least 3 months. In this group, the median OS rose from 11 to 12 and then to 13 months, and the 2-year OS rate rose from 19.8% to 27.3% and then to 29.3%. The adjusted HRs vs 2004 to 2015 were 0.86 (95% CI, 0.80-0.92) for 2016 to 2019 and 0.77 (95% CI, 0.70-0.86) for 2020 to 2022.

The investigators noted that persistent early mortality dilutes the population-level effect of therapeutic advances, creating a real-world gap between efficacy and effectiveness. They called for faster oncology referral, earlier treatment access, and strategies to prevent early attrition so that advances seen in trials reach patients.

They noted several limitations. SEER lacks data on immunotherapy, line of therapy, performance status, and platinum eligibility. Chemotherapy coded as “no/unknown” may undercount treatment. Era comparisons also cannot attribute survival changes to specific drugs.

Disclosures

4761P: Sridhar reported consulting or advisory roles with AstraZeneca, Bayer, Bicycle Therapeutics, Bristol Myers Squibb, Daiichi Sankyo, EMD Serono, Gilead, Janssen, Merck & Company, Merck Sharp & Dohme, and Pfizer, and institutional research funding from Bayer, EMD Serono, and Pfizer. EV-302 was funded by Astellas Pharma; MSD, a subsidiary of Merck & Co.; and Seagen, which was acquired by Pfizer in December 2023. Medical writing support was provided by Samantha O’Dwyer, PhD, of Nucleus Global, an Inizio Company, and funded by Pfizer and Astellas Pharma.

4760P: Bedke reported research funding from AstraZeneca, Bayer, Daiichi Sankyo, Johnson & Johnson, MSD, Pfizer, Roche, and Seagen. He reported consulting fees, honoraria, and travel support from Apogepha, Arcus Biosciences, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Ipsen, Janssen, Johnson & Johnson, MSD, Pfizer, and Roche. He is vice chair of the European Association of Urology Renal Cell Carcinoma Guidelines Panel. EV-302 was funded by Astellas Pharma, Merck Sharp & Dohme, and Seagen (acquired by Pfizer). Medical writing support was provided by Tina Wasmeier, PhD, of Nucleus Global, an Inizio Company, and funded by Pfizer and Astellas Pharma.

4827eP: Tamimi reported no conflicts of interest.

References

1. Sridhar SS, van der Heijden MS, Powles T, et al. Enfortumab vedotin plus pembrolizumab for previously untreated locally advanced or metastatic urothelial carcinoma: updated exploratory analysis of EV-302 in older patients and those with comorbidities. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract 4761P.
2. Bedke J, Powles T, Perez Valderrama B, et al. Enfortumab vedotin + pembrolizumab in previously untreated locally advanced or metastatic urothelial cancer: exploratory analyses based on disease-related characteristics from EV-302. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract 4760P.
3. Tamimi FT, Sharf BS, Al-batsh T, et al. Persistent early mortality and the real-world efficacy–effectiveness gap in metastatic urothelial bladder cancer. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract 4827eP.