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Patients who cannot or choose not to have cisplatin-based chemotherapy alongside surgery to remove the bladder when diagnosed with muscle-invasive bladder cancer (MIBC) cut their risk of disease progression or death by 60% by having enfortumab vedotin (EV) and pembrolizumab alongside surgery, according to data presented Saturday.¹

Results from the phase 3 EV-303/KEYNOTE-905 trial (NCT03924895) were presented during the first Presidential Session at the 50th European Society for Medical Oncology Congress (ESMO) in Berlin, Germany.¹ They show patients receiving the antibody drug conjugate (ADC) and pembrolizumab (P) combination with surgery had superior outcomes across a range of measures than those treated with surgery alone.

Bladder cancer is the ninth most common cancer worldwide, diagnosed in more than 614,000 patients each year, with MIBC accounting for 30% of all cases of bladder cancer.

The combination of EV (Padcev; Astellas/Pfizer) and the PD-1 pembrolizumab (Keytruda; Merck) previously received full FDA approval in December 2023² for first-line treatment of patients with locally advanced or metastatic urothelial cancer based on EV-302 (NCT04223856), which will have new data on older adults presented at the congress.³

As EV-303 principal investigator Christof Vulsteke, MD, PhD, said in a press briefing ahead of the session, the results in first-line care are as transformative as those in the metastatic setting presented 2 years ago at ESMO. He predicted this regimen might become the standard of care for patients who have had grim prospects.

“What is the standard of care in this population with muscle-invasive bladder cancer?” asked Vulsteke, who is head of the Integrated Cancer Center Ghent (IKG, Belgium) and Clinical Trial Unit Oncology Ghent. “We took the patients who are not fit for chemotherapy, and this is half of all the patients with [MIBC]. In half of these patients, you cannot give upfront chemotherapy—you go straight to surgery, and you know that more than half of these patients will relapse. It will be up to 70% of patients who will relapse, and after 5 years, you will lose most of these patients.”

Pointing to widely separated curves between patients receiving the EV + P regimen with surgery and those having surgery alone, Vulsteke noted the HR of 0.40 but said, “It’s also important that… you live longer,” and that overall survival (OS) is just as impressive.

Those results showed that after 25 months, OS was 50% higher for the EV + P group compared with the surgery-only group, and that median event-free survival (EFS) was not reached for patients in EV + P group compared with 15.7 months for those in the surgery-only group.¹

Study authors said that radical surgery, called cystectomy, completed with pelvic lymph node dissection, has been the standard treatment for patients with MIBC who cannot have cisplatin. Up to half of patients with MIBC may have comorbidities that make them ineligible or have developed resistance to this backbone chemotherapy. In other cases, patients may decide the benefits are not worth the toxicity.

Cisplatin shortages in recent years have also forced physicians to treat bladder cancer patients with EV off guidelines in lieu of cisplatin—which caused some controversy. (Shortages are now considered resolved.⁴) Asked if these results combined with the prior trial have implications in light of past use for patients who were eligible for cisplatin, Vulsteke noted that precise question is being studied in an ongoing trial.

“This [trial] is in the cisplatin-ineligible population, but the same trial is running also in the eligible population, and if it wins there also, this will also replace, in my opinion, the platinum-based [chemotherapy].”

Study Methods and Results

Patients were randomized 1:1 to the EV + P combination, which called for 3 cycles of EV 1.25 mg/kg on day 1 and day 8, plus P at 200 mg on day 1 at 3-week cycles, followed by the surgery, then 6 cycles of EV plus 14 cycles of P. The control group received the surgery only. Study therapy continued until progression, unacceptable toxicity, withdrawal of consent, or completion of planned treatment.¹

The primary end point was EFS as determined by blinded independent central review. Secondary end points were OS, pathological complete response (pCR) rate, and safety.

Results were as follows¹:

• 170 patients received the EV + P regimen and 174 were in the control group; more than 80% of patients were cisplatin ineligible per the Galsky criteria
• As of June 6, 2025, median follow-up time was 25.6 months (range, 11.8-53.7), with 149 patients (87.6%) in the EV + P arm and 156 (89.7%) in the control undergoing surgery
• EV + P significantly improved EFS, with the median not reached (NR) vs 15.7 months (HR, 0.40; 95% CI, 0.28-0.57; P < .001)
• OS was NR vs 41.7 months (HR 0.50; 95% CI, 0.33-0.74; P < .001)
• pCR rate was 57.1% vs 8.6%, for an estimated difference of 48.3 percentage points (95% CI, 39.5-56.5; P < .001) vs control.
• Treatment-emergent adverse events (AEs) occurred in 100% (grade ≥ 3, 71.3%) of patients in the EV + P arm and 64.8% (grade ≥ 3, 45.9%) in the control group; the most frequent grade ≥ 3 AE of special interest was severe skin reactions, for 11.4% from P and 10.8% from EV
• The study remains ongoing to assess EFS, OS, and pCR data as they mature

“The compelling EV-303 results may establish a new efficacy benchmark in muscle-invasive bladder cancer,” said Moitreyee Chatterjee-Kishore, PhD, MBA, head of oncology development, Astellas. “For the first time, a systemic treatment approach used before and after surgery has improved survival over standard surgery in cisplatin-ineligible patients. These data underscore the transformative potential of [enfortumab vedotin] plus [pembrolizumab] as we continue to explore this combination in a broad population of patients with muscle-invasive bladder cancer.”⁵

“The ability of [enfortumab vedotin] plus [pembrolizumab] to reduce the risk of death by half in this setting is a remarkable advancement for patients who have seen limited treatment options and often face poor prognosis,” said Jeff Legos, PhD, MBA, chief oncology officer, Pfizer. “These unprecedented results suggest that the transformational efficacy of this combination in advanced bladder cancer may extend into an earlier disease setting, potentially providing a life-changing impact for patients.”⁵

Strength of ADCs in First-Line Treatment

EV is a Nectin-4 directed ADC, and the EV-303 trial is among the studies involving ADCs in first-line treatment being featured at ESMO this week. At the opening press conference on Friday, ESMO 2025 President Fabrice André, MD, PhD, and scientific co-chairs Toni Choueiri, MD, and Myriam Chalabi, MD, PhD, highlighted EV-303 as well as a pair of breast cancer trials also presented during Saturday’s Presidential Session involving trastuzumab deruxtecan, the groundbreaking treatment sold as Enhertu (AstraZeneca).

During Friday’s press conference, André explained the mechanism of ADCs and how they deliver a payload of high-dose cytotoxic agents inside the cancer cell. “What we knew before is that there is this new class of agents that has some impact on patients with metastatic cancer,” he said. “What we didn’t know so far is whether this new class of drug is having an impact on patients with early-stage cancer—that is usually at the stage where patients can relapse and ultimately die.”

That question, André said, would be answered at the ESMO 2025 Congress.

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 in eligible : the phase III KEYNOTE-905 study. Presented at: 50th European Society for Medical Oncology Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA2.
2. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. News release. FDA. December 15, 2023. Accessed October 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
3. Powles T, Valderama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi: 10.1056/NEJMoa2312117.
4. Reed T. Critical chemo drug no longer in shortage. Axios. July 1, 2024. Accessed October 18, 2025. https://www.axios.com/2024/07/01/critical-chemo-drug-no-longer-in-shortage-vitals
5. Padcev plus Keytruda, given before and after surgery, cuts the risk of recurrence, progression or death by 60% and the risk of death by 50% for certain patients with bladder cancer. News release. PR Newswire. Astellas and Pfizer. October 18, 2025. Accessed October 18, 2025. https://www.prnewswire.com/news-releases/padcev-plus-keytruda-given-before-and-after-surgery-cuts-the-risk-of-recurrence-progression-or-death-by-60-and-the-risk-of-death-by-50-for-certain-patients-with-bladder-cancer-302587853

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