Enfortumab Vedotin Combo Shows Real-World Benefit in Urothelial Carcinoma

Enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda; EVP) demonstrated clinically meaningful efficacy and a manageable safety profile across a large, heterogeneous real-world population with metastatic/locally advanced urothelial carcinoma (UC), according to results from the GUARDIANS retrospective study published in Cancer Immunology, Immunotherapy. The study included patients with clinical characteristics that would have excluded them from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856).

What outcomes did EVP treatment confer in the real-world?

Among 468 evaluable patients, the objective response rate (ORR) was 50.2% (95% CI, 45.6%–54.8%), comprising a complete response (CR) rate of 12.8% (95% CI, 9.9%–16.2%) and a partial response rate of 37.4% (95% CI, 33.0%–42.0%). The disease control rate (DCR) was 65.0% (95% CI, 60.4%–69.3%).

The median progression-free survival (PFS) was 10.2 months (95% CI, 8.0–12.7), with 6- and 12-month PFS rates of 64.6% (95% CI, 59.8%–69.8%) and 45.5% (95% CI, 39.6%–52.2%), respectively. The median overall survival (OS) was 33.7 months (95% CI, 33.7–not reached [NR]), with 12- and 24-month OS rates of 71.9% (95% CI, 66.6%–77.6%) and 60.6% (95% CI, 50.5%–72.8%), respectively.

A consistent and independent association between skin toxicity, defined as any documented bullous or non-bullous exanthema occurring during EVP treatment, and superior outcomes across all efficacy end points was observed. Patients who experienced skin-related adverse effects (AEs; n = 171) had a median PFS of 13.8 months (95% CI, 12.5–NR) compared with 7.4 months (95% CI, 6.0–10.5) in those without skin toxicity (n = 297; P <.001). The median OS was NR vs 18.4 months (95% CI, 14.0–NR; P <.001), respectively.

In multivariable analyses, skin toxicity was independently associated with improved PFS (HR, 0.56; 95% CI, 0.41–0.78; P < .001), OS (HR, 0.45; 95% CI, 0.27–0.74; P = .002), and ORR (OR, 2.31; 95% CI, 1.53–3.43; P <.001). An ECOG performance status greater than 1 (HR, 1.68; 95% CI, 1.12–2.53; P = .001) and Bellmunt risk score greater than or equal to 2 (HR, 1.60; 95% CI, 1.11–2.31; P = .01) were independently associated with worse PFS in the same models, with consistent signals for OS.

Any-grade AEs were observed in 81.8% of patients and grade 3 or higher AEs occurred in 35.8%. The most common any-grade AEs were sensory polyneuropathy (41.0%), exanthematous skin reactions without bullae (29.7%), pruritus (29.7%), fatigue (22.9%), and anemia (20.3%). The most common grade 3 or higher AEs included infections (6.6%), sensory polyneuropathy (5.6%), and hepatitis or elevated transaminases (5.1%).

Ten patients experienced treatment-associated grade 5 toxicities, including infection (n = 3), gastrointestinal bleed (n = 2), and cardiac toxicity (n = 2). Dose reductions of enfortumab vedotin occurred in 40.4% of patients, and pembrolizumab interruptions occurred in 31.5%. Disease progression remained the primary reason for treatment discontinuation.

“Our analysis presents the largest real-world evaluation of EVP to date and demonstrates high response rates, durable survival, and a manageable safety profile across a broad patient population,” Stefanie Zschäbitz, MD, head of Translational Uro-Oncology and urologic oncologist in the Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, wrote with study coinvestigators in the publication. “These findings complement and extend results from the [KEYNOTE-A39] trial, supporting EVP as the preferred first-line therapy for [metastatic urothelial carcinoma] and offering insights into tolerability, treatment modification patterns, and subsequent therapy utilization in clinical practice.”

How was GUARDIANS designed?

GUARDIANS was a retrospective observational cohort study conducted across 25 community and university hospitals in Germany. Investigators enrolled patients with metastatic/locally advanced urothelial carcinoma, including those with divergent differentiation or subtype histology, who received at least 1 dose of EVP between March 2022 and August 2025.

The standard regimen was enfortumab vedotin 1.25 mg/kg on days 1 and 8 combined with pembrolizumab 200 mg every 21 days. AEs were graded per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, and responses were assessed locally per RECIST v1.1 guidelines.

Among 468 patients enrolled, the median age at start of EVP was 69 years (range, 25–90), and 32.1% were aged 75 years or older. A total of 16.4% had an ECOG PS of 2, and 53.3% had more than 1 metastatic site at treatment initiation. Bladder was the predominant primary tumor site (68.6%), followed by upper urinary tract (25.2%). The primary histology was urothelial carcinoma in 91.9%, with divergent differentiation or subtype histology noted in 31 patients.

The primary efficacy end points of GUARDIANS were PFS and OS, both analyzed using Kaplan–Meier methodology. Secondary outcomes included ORR, DCR, drug exposure characterization, AE profiling, and subsequent systemic therapy patterns.

The investigators acknowledged limitations inherent to retrospective observational data, including OS immaturity resulting from short median follow-up, heterogeneous imaging intervals across centers, locally performed response assessments without central quality control, and potential underreporting of AEs.

How do the GUARDIANS data compare with clinical trial data?

These real-world outcomes in GUARDIANS expand on prior data from the pivotal EV-302/KEYNOTE-A39 trial, in which EVP yielded a median PFS of 12.5 (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy, respectively (HR, 0.48; 95% CI, 0.41-0.57; P <.00001); the median OS was 33.6 months (95% CI, 26.6-39.8) vs 15.9 months (95% CI, 13.6-18.3; HR, 0.53; 95% CI, 0.45-0.63), respectively, in a more selected trial population.^2,3

References

1. Zschäbitz S, Bhatti I, Casuscelli J, et al. Effectiveness and safety of enfortumab vedotin and pembrolizumab in a real-world patient population with urothelial carcinoma: results from a multi-institutional cohort (GUARDIANS). Cancer Immunol Immunother. 2026;75(7):184. doi:10.1007/s00262-026-04448-2
2. Salous T, Hassoun R, Althouse S, et al. Neuropathy, skin rash, and hyperglycemia as predictors of response to enfortumab vedotin in locally advanced and metastatic bladder and upper tract urothelial carcinoma. J Clin Oncol. 2025;43(suppl 5):771. doi:10.1200/JCO.2025.43.5_suppl.771
3. Powles TB, van der Heijden MS, Bedke J, et al. Enfortumab vedotin plus pembrolizumab vs chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma: 3.5-year follow-up and response analyses from the phase 3 EV-302 study. J Clin Oncol. 2026;44(suppl 16):4503. doi:10.1200/JCO.2026.44.16_suppl.4503