Editor’s Note: Urothelial carcinoma (UC) is the second most common malignancy of the urinary system, characterized by poor prognosis and low five-year survival rates. For decades, platinum-based chemotherapy has remained the standard first-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC). However, limited clinical benefit and poor tolerability have left many unmet treatment needs.The EV-302 trial has brought new hope to the field. Presented at both the 2023 and 2024 ESMO Congresses, the study demonstrated the efficacy and safety of enfortumab vedotin (EV) plus pembrolizumab (P) (EV+P) in la/mUC patients, marking the beginning of a new era in urothelial cancer treatment. At ASCO GU 2025, new follow-up data from the EV-302 trial (Abstract #664) reinforced the role of EV+P as a first-line treatment for la/mUC, solidifying its position in clinical practice.
To discuss the latest findings and their impact on clinical practice, Urology Frontier invited Dr. Thomas Powles, Professor of Genitourinary Oncology at the University of London and Director of Barts Cancer Centre, to share his insights on the EV-302 study and the future of urothelial cancer treatment.
Urology Frontier: For la/mUC patients, platinum-based chemotherapy has been the standard first-line treatment for decades. Based on your clinical experience, how effective has this regimen been, and what unmet needs remain?
Dr. Thomas Powles: Radical cystectomy (RC) has historically been the primary surgical approach for muscle-invasive bladder urothelial carcinoma (UCB), involving the removal of the entire bladder, surrounding lymph nodes, and sometimes other affected organs. This surgical approach has been widely used since the 1940s through the 1960s.
The 1980s saw the rise of platinum-based chemotherapy, particularly gemcitabine plus cisplatin (Gem-Cis), which demonstrated a survival advantage in urothelial carcinoma. Studies confirmed that neoadjuvant chemotherapy (before surgery) provided greater survival benefits than adjuvant chemotherapy (after surgery), improving overall survival by approximately 5%. However, despite these advances, about 50% of patients still experience disease relapse. The risk of recurrence depends on tumor staging and aggressiveness.
Platinum-based chemotherapy has been shown to reduce recurrence risk and improve five-year survival rates from 60% to 65%. However, its significant toxicity and potential to delay surgery have led some countries and clinicians to hesitate in adopting chemotherapy widely. Despite the progress of other treatment options, platinum-based chemotherapy remains the standard of care in la/mUC.
Urology Frontier: With the development of novel combination therapies, enfortumab vedotin plus pembrolizumab (EV+P) has significantly improved survival outcomes in advanced UC. You presented data on this at ASCO GU 2025—could you elaborate on the efficacy and safety of this regimen?
Dr. Thomas Powles: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting Nectin-4, linked to a microtubule inhibitor, while pembrolizumab (P) is a PD-1 inhibitor. The combination has demonstrated a strong synergistic effect, improving response rates and prolonging disease control in la/mUC patients.
At ESMO 2023, the EV-302/KEYNOTE-A39 (NCT04223856) study demonstrated that EV+P significantly outperformed chemotherapy. Compared to standard chemotherapy, EV+P improved median progression-free survival (PFS) to 12.5 months, reducing the risk of disease progression or death by 55%. The median overall survival (OS) was extended to 31.5 months, reducing the risk of death by 53%. These results strongly support EV+P as the new first-line standard of care for la/mUC patients.
The study results were published in The New England Journal of Medicine (NEJM) on March 7, 2024. Based on these findings, EV+P has been included as the preferred first-line treatment recommendation in the NCCN and ESMO guidelines.
To further refine treatment strategies, our team presented EV-302 subgroup analyses at ESMO 2024, investigating whether Nectin-4 expression influences treatment outcomes. The results confirmed that EV+P provides consistent survival benefits across all subgroups, regardless of Nectin-4 expression levels, reinforcing its superiority over chemotherapy. This resolved previous controversies regarding Nectin-4 as a predictive biomarker for EV+P efficacy. Immunohistochemistry (IHC) analysis showed that most la/mUC patients exhibit high levels of Nectin-4 expression, but Nectin-4 alone is not an optimal predictor of response. Further research is needed to identify more precise biomarkers to predict which patients will derive the greatest benefit from EV+P therapy.
At ASCO GU 2025, we updated the EV-302 study with 29.1 months of median follow-up data and examined outcomes in patients who achieved complete response (CR). Compared to chemotherapy, EV+P nearly doubled median PFS (12.5 months vs. 6.3 months) and reduced the risk of disease progression or death by 52% (HR = 0.48; 95% CI: 0.41–0.57; P < 0.00001). The median OS was extended to 33.8 months, compared to 15.9 months in the chemotherapy group, marking an increase of 17.9 months—nearly doubling survival outcomes while reducing the risk of death by 49% (HR = 0.51; 95% CI: 0.43–0.61; P < 0.00001).
Notably, nearly half of patients remained in response beyond two years, with a median duration of response (DOR) of two years. These survival benefits were observed regardless of cisplatin eligibility, PD-L1 expression levels, or liver metastases, demonstrating broad applicability of EV+P across patient subgroups.
Historically, the median survival for la/mUC patients was only one year, as chemotherapy provided only temporary benefits before resistance and disease progression occurred. Now, EV+P has nearly doubled median OS and PFS, marking one of the most transformative breakthroughs I have witnessed in bladder, kidney, and other cancer treatments.
Urology Frontier: What future research directions will you and your team pursue to further improve outcomes for advanced and early-stage UC patients?
Dr. Thomas Powles: The EV-302 study has provided compelling evidence that EV+P offers significant survival advantages over chemotherapy. This breakthrough not only redefines survival expectations for la/mUC patients but also paves the way for a new era in urothelial cancer treatment. As a result, there is a global push to integrate EV+P earlier in the treatment landscape.
At the same time, as treatment strategies continue to evolve, the combination of targeted therapy and immunotherapy is offering unprecedented hope for patients. Ongoing trials are comparing chemotherapy versus EV+P in different settings, including neoadjuvant use. Although results are pending, given the consistent benefit of EV+P across multiple subgroups, we anticipate these studies will yield positive results.
About Dr. Thomas Powles
Dr. Thomas Powles is a Professor of Genitourinary Oncology at the University of London and Director of Barts Cancer Centre.
The EV-302 study represents a transformative milestone in the treatment of urothelial cancer, firmly establishing EV+P as the new first-line standard of care. As global research efforts continue to explore the full potential of this regimen, the field is entering a new era of treatment innovation for bladder cancer patients.
