Introduction
Locally advanced or metastatic urothelial carcinoma (la/mUC) carries a historically dismal prognosis, with a 5-year survival rate of approximately 5%. For decades, platinum-based chemotherapy—gemcitabine plus cisplatin (GC) for eligible patients and gemcitabine plus carboplatin (GCb) for cisplatin-ineligible patients—represented the only viable first-line standard of care. The emergence of enfortumab vedotin (EV), a Nectin-4–directed antibody–drug conjugate (ADC) delivering monomethyl auristatin E, combined with pembrolizumab (an anti–programmed death receptor-1 [PD-1] immune checkpoint inhibitor), has fundamentally transformed this paradigm. The phase 3 EV-302/KEYNOTE-A39 trial demonstrated superiority of EV plus pembrolizumab (EV+P) over platinum-based chemotherapy across primary endpoints, leading to its inclusion as a preferred first-line regimen in major guidelines, including NCCN, ESMO, and EAU, for patients with or without cisplatin eligibility. 121314
Pivotal Efficacy Evidence: EV-302/KEYNOTE-A39
The EV-302 trial enrolled 886 previously untreated patients with la/mUC, randomizing them 1:1 to EV+P or gemcitabine plus cisplatin or carboplatin. At the primary analysis (median follow-up 17.2 months), EV+P achieved a median overall survival (OS) of 31.5 months compared with 16.1 months for chemotherapy (hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.38–0.58; P<0.001), representing a 53% reduction in the hazard of death. 1 With extended follow-up to approximately 2.5 years, the updated median OS was 33.8 months (95% CI: 26.1–39.3) versus 15.9 months (95% CI: 13.6–18.3) for chemotherapy (HR 0.51), cementing a near-doubling of survival benefit. 17
Progression-free survival (PFS) was 12.5 months with EV+P versus 6.3 months with chemotherapy (HR 0.45; 95% CI 0.38–0.54; P<0.001). The objective response rate (ORR) was 67% with EV+P—including a complete response (CR) rate of 29%—compared with 49% ORR and approximately 21% CR with chemotherapy. Critically, the median duration of response (DoR) was not reached for EV+P versus 7.0 months for chemotherapy, underscoring sustained disease control with the combination. 1
Subgroup Analyses
Subgroup analyses reinforce the broad applicability of EV+P. Among 478 cisplatin-eligible patients, median OS was 31.5 months (EV+P) versus 18.4 months (chemotherapy; HR 0.53), and ORR reached 70.8% (32.5% CR) versus 53.0% (15.5% CR). 2 PD-L1 status did not predict differential benefit—OS hazard ratios were 0.49 for combined positive score (CPS)-high and 0.44 for CPS-low tumors—overcoming a key limitation of checkpoint inhibitor monotherapy approaches. 3 Patients with visceral metastases and liver involvement also derived substantial OS benefit with hazard ratios comparable to the overall population, though absolute OS was lower in those with liver metastases. 3
An exploratory analysis presented at ESMO 2025 confirmed consistent efficacy in clinically challenging subgroups: ORR was 66% (EV+P) versus 38% (chemotherapy) in patients aged 75 years or older, 70% versus 35% in those with diabetes, and 66% versus 38% in those with renal impairment (GFR <60 mL/min). The frequency of grade 3 or higher treatment-related adverse events (TRAEs) was lower in the EV+P arm than in the chemotherapy arm across all these subgroups. 19
Historical Context: Platinum Chemotherapy and Maintenance Immunotherapy
Prior to EV-302, GC achieved a median OS of approximately 14–15 months in cisplatin-eligible patients, while GCb yielded 9–12 months in cisplatin-ineligible cohorts. The JAVELIN Bladder 100 trial demonstrated that maintenance avelumab (anti–PD-L1) after non-progressive platinum chemotherapy extended median OS to 21.4 months (versus 14.3 months with best supportive care alone; HR 0.69), with enhanced benefit in PD-L1–positive patients (HR 0.56). 18 While this sequential approach improved outcomes compared with chemotherapy alone, the 21.4-month median OS observed with platinum induction followed by avelumab maintenance remains substantially shorter than the 33.8-month OS achieved with upfront EV+P, suggesting that the sequential paradigm does not fully substitute for combination chemoimmunotherapy.
Real-World Evidence
Real-world data corroborate pivotal trial findings. A US community oncology analysis (2026 ASCO GU Symposium) of 535 patients—76% receiving EV+P—demonstrated a median time to discontinuation (TTD) of 5.9 months with EV+P versus 2.3 months with chemotherapy (adjusted HR 0.41; P<0.001), and a median time to next treatment (TTNT) of 9.7 months versus 6.6 months. 16 A Japanese database analysis of 1,006 patients treated with EV or taxane chemotherapy after platinum and pembrolizumab showed significantly longer OS with EV (HR 0.71; P=0.013), with EV as an independent prognostic factor on multivariate analysis. 8 Importantly, a single-center analysis found that dose modifications of EV (reduced dose intensity [RDI] 60–80% or <60%) did not compromise OS compared with RDI >80%, supporting proactive toxicity management without compromising survival outcomes. 9
Comparative Safety Profiles
EV+P carries a distinct toxicity profile from platinum chemotherapy. Grade 3 or higher TRAEs occurred in 55.9% of EV+P recipients versus 69.5% in the chemotherapy arm in EV-302. 1 Key EV+P-associated adverse events include peripheral neuropathy (PN; any grade 50–56%, predominantly grade 1–2; median onset approximately 6 months; 87% of affected patients had residual neuropathy at last evaluation), skin reactions (any grade 61–67%; severe cutaneous reactions including Stevens–Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN] requiring boxed warning; median onset 1.7 months; led to discontinuation in 6% of patients), and hyperglycemia (grade 3–4, 7%; fatal diabetic ketoacidosis reported). Ocular toxicity affects approximately 28–40% of patients (dry eye, keratitis, blurred vision, increased lacrimation), and immune-related adverse events (irAEs) such as pneumonitis (grade 3–4, approximately 4%; fatal in 0.4% of cases) require pembrolizumab-specific vigilance. 1012
Platinum chemotherapy carries nephrotoxicity and ototoxicity (cisplatin-specific), clinically significant cytopenias, nausea and vomiting requiring aggressive antiemetic prophylaxis, and cumulative dose-dependent neuropathy. These toxicities typically limit cisplatin use in patients with GFR <60 mL/min, hearing impairment, or cardiac dysfunction.
Comparative Summary Table
| Domain | EV + Pembrolizumab | Gemcitabine + Cisplatin | Gemcitabine + Carboplatin |
|---|---|---|---|
| Median OS | 33.8 months | ~14–15 months | ~9–12 months |
| Median PFS | 12.5 months | ~6 months | ~5–6 months |
| ORR / CR Rate | 67% / 29% | ~40% / ~15% | ~30–35% / lower |
| Median DoR | Not reached | ~7–8 months | ~4–6 months |
| Cisplatin Eligibility | Not required; all patients eligible | GFR ≥60, no major comorbidity | GFR 30–60; alternative for ineligible |
| Grade ≥3 TRAE | 55.9% | ~60–70% | ~40–50% |
| Peripheral Neuropathy | 50–56% any grade; grade 3+: ~6% | Rare (<5%) | Rare (<5%) |
| Skin Reactions | 61–67% any grade; SJS/TEN (rare, fatal) | <5% | <5% |
| Hyperglycemia | 20–30% any grade; grade 3–4: 7% | <5% | <5% |
| Ocular Toxicity | 28–40% any grade (mild) | Absent | Absent |
| Nephrotoxicity | Minimal; no renal dose adjustment | Significant; hydration required | Moderate (Calvert dosing) |
| Ototoxicity | Absent | Significant (audiometry required) | Absent |
| Cytopenias | Uncommon (<10% grade 3–4) | Common (30–50%) | Moderate (10–20%) |
| irAEs (pneumonitis, colitis) | Pembrolizumab-related; 4% grade ≥3 pneumonitis | Absent | Absent |
| Nausea/Vomiting | Mild to moderate | Moderate to severe | Mild to moderate |
| Preferred Monitoring | PN exam, glucose/HbA1c, ophthalmology, skin, pulmonary | Renal function, audiometry, CBC, electrolytes | Renal function, CBC |
| Guideline Status (2025–2026) | NCCN Category 1 Preferred; ESMO/EAU preferred | NCCN Alternative; retained for contraindications | NCCN Alternative; retained for cisplatin-ineligible |
Treatment Selection by Clinical Scenario
Cisplatin-eligible, fit patient (ECOG PS 0–1, GFR ≥60 mL/min, no contraindications): EV+P is the preferred first-line standard of care. EV-302 demonstrated superior OS (33.8 vs. 15.9 months), PFS, ORR, and DoR versus platinum chemotherapy, with consistent benefit in the cisplatin-eligible subgroup (median OS 31.5 vs. 18.4 months; HR 0.53). GC with avelumab maintenance remains an appropriate alternative only when EV+P is contraindicated or declined. 1212
Cisplatin-ineligible, carboplatin-eligible patient (GFR 30–60 mL/min, ECOG PS 0–1): EV+P is strongly preferred. GCb historically yields inferior OS and ORR compared with cisplatin-based therapy, and EV-302 demonstrated maintained benefit in cisplatin-ineligible patients. EV does not require renal dose adjustment, offering practical advantages in this population. 19
Patient with renal impairment (GFR <60 mL/min): EV+P is preferred. Cisplatin is contraindicated; EV+P demonstrated 66% ORR (vs. 38% with chemotherapy) in the GFR <60 subgroup at ESMO 2025. 19
Patient with high visceral disease burden requiring rapid response: EV+P remains the preferred option given its 67–73% ORR and durable response. While platinum chemotherapy can offer initial cytoreduction, EV+P provides superior absolute OS and response durability. 13
Patient with older age (≥75 years) or ECOG PS 2: EV+P is appropriate and effective; ESMO 2025 subgroup data showed 66% ORR with EV+P versus 38% with chemotherapy in patients ≥75 years, with manageable toxicity. Real-world dose reduction data confirm that RDI <80% does not compromise OS. Individualized risk-benefit assessment and proactive monitoring are essential. 919
Patient with pre-existing grade ≥2 peripheral neuropathy: GCb (or GC if cisplatin-eligible) is preferred, as EV carries a >50% neuropathy risk and can substantially worsen baseline neuropathy. If EV+P is required, careful grading, close monitoring, and low threshold for EV dose modification are mandatory. 10
Patient with uncontrolled diabetes (HbA1c ≥8%) or active autoimmune disease / requirement for immunosuppression: Platinum-based chemotherapy is preferred. EV carries hyperglycemia and diabetic ketoacidosis risk; pembrolizumab is contraindicated with active autoimmune disease or immunosuppression. 1012
Patient with active interstitial lung disease (ILD) or history of SJS/TEN: Platinum-based chemotherapy is preferred. EV+P carries fatal pneumonitis and severe cutaneous toxicity risks. Baseline pulmonary function testing and skin assessment are required if EV+P is considered in borderline cases. 1014
Adverse Event Monitoring and Management
All patients initiating EV+P require baseline assessment of neurological function, fasting glucose and HbA1c (particularly in diabetic patients), ophthalmologic status, skin examination, and pulmonary evaluation. Weekly or biweekly monitoring during the first two to three cycles is recommended, transitioning to every-three-week monitoring thereafter. Early dermatology consultation for grade ≥2 rash, liberal topical corticosteroid use, and prompt withholding for suspected SJS/TEN with immediate specialist referral are essential. EV should be permanently discontinued for confirmed SJS/TEN or grade 4 skin reactions. 10 Peripheral neuropathy of grade ≥2 requires EV dose reduction or interruption; grade ≥3 mandates permanent discontinuation. Blood glucose exceeding 250 mg/dL necessitates EV withholding until normalization. Prophylactic artificial tears and ophthalmologic evaluation for ocular symptoms are recommended. irAEs (pneumonitis, colitis, hepatitis) require prompt recognition, corticosteroid management, and pembrolizumab hold or permanent discontinuation per grade. 1012
For platinum chemotherapy, aggressive intravenous hydration, antiemetic prophylaxis, baseline and serial audiometry (cisplatin), and regular complete blood count and electrolyte monitoring are required. Dose adjustments for myelosuppression and renal function deterioration should follow established protocols.
Conclusion
The EV-302/KEYNOTE-A39 trial, supported by updated follow-up data (median OS 33.8 months vs. 15.9 months for chemotherapy) and consistent subgroup findings across cisplatin eligibility, age, renal function, and disease burden, establishes EV+P as the new standard of care for first-line treatment of previously untreated la/mUC. 117 This recommendation is now codified as Category 1 preferred by NCCN, ESMO, and EAU. 121314 Real-world evidence confirms durable disease control and manageable toxicity with proactive dose modification, without compromising survival outcomes. 916 Platinum-based chemotherapy retains an important role for patients with pre-existing grade ≥2 peripheral neuropathy, uncontrolled diabetes, active autoimmune disease, severe ILD, or history of severe cutaneous reactions. For the majority of patients with la/mUC, EV+P represents a transformative therapeutic advance, and oncologists should prioritize individualized baseline risk stratification and robust adverse event monitoring to optimize both efficacy and tolerability outcomes.