Enfortumab Vedotin Plus Pembrolizumab Shows Promise as a Platinum-Free Option in Earlier Bladder Cancer

In the interim analysis of the phase 3 EV-304 clinical trial, enfortumab vedotin (Padcev; Astellas Pharma Inc), a Nectin-4 directed antibody-drug conjugate, in combination with pembrolizumab (Keytruda; Merck & Co), a PD-1 inhibitor, demonstrated positive results among patients with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin-based chemotherapy. This ongoing, open-label, randomized, controlled clinical trial is evaluating the combination's use as a neoadjuvant and adjuvant treatment compared to standard-of-care neoadjuvant chemotherapy among this patient population.¹

"Building on the recent US approval for cisplatin-ineligible patients living with MIBC, these positive EV-304 findings reinforce the potential of [enfortumab vedotin] plus pembrolizumab to improve survival outcomes for a broad population of patients living with muscle-invasive bladder cancer,” Moitreyee Chatterjee-Kishore, PhD, MBA, Head of Oncology Development, Astellas, said in a news release. “Together with the EV-303 data, these results strengthen the evidence supporting this combination regimen as a treatment option for patients regardless of cisplatin eligibility. We are committed to bringing forth much-needed advancements and hope to more patients.”¹

What is Muscle-Invasive Bladder Cancer?

MIBC is found in the detrusor muscle of the bladder, which is the thick muscle deep in the bladder wall, and is more likely to spread to other parts of the body. The cancer accounts for nearly 30% of all bladder cancer cases and is classified as the third most common cancer in men residing in the US, frequently affecting individuals aged 75 to 84 years.²

Treatments for MIBC include bladder removal, or a cystotomy with chemotherapy or without chemotherapy, along with chemotherapy with radiation, in addition to transurethral resection of bladder tumor.²

"Despite available treatment options, nearly half of patients with muscle-invasive bladder cancer progress to metastatic disease within 3 years of diagnosis," Christopher Hoimes, DO, director of the bladder cancer program and center for cancer immunotherapy at Duke Cancer Institute and an EV-304 principal investigator, said in the news release.¹

How Does Enfortumab Vedotin Treat MIBC?

As a first-in-class antibody drug conjugate (ADC), enfortumab vedotin is directed against Nectin-4, which is a protein located on the surface of cells and is highly expressed in bladder cancer. The study authors noted that data suggest enfortumab vedotin targets Nectin-4-expressing cells, delivering monomethyl auristatin E (MMAE) intracellularly to induce cell cycle arrest and apoptosis.¹

"For the first time, patients with MIBC are seeing significant survival benefits from combination therapy in a perioperative setting without the need for platinum-based chemotherapy, signaling the potential for a new standard of care for this community,” Jeff Legos, PhD, MBA, chief oncology officer, Pfizer, said in the news release.¹

What did the EV-304 and EV-303 studies find?

In the EV-304 trial, researchers compared neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab with neoadjuvant gemcitabine and cisplatin in cisplatin-eligible patients with MIBC. The trial met its primary end points, demonstrating clinically meaningful and statistically significant improvements in event-free survival and overall survival, which is a key secondary end point.¹

The positive EV-304 data, together with results from the EV-303 trial, support the potential of this combination in earlier-stage bladder cancer. In EV-303, enfortumab vedotin plus pembrolizumab significantly improved event-free survival and overall survival compared to surgery alone. The findings suggest that the combination could become a new platinum-free standard of care for earlier bladder cancer.¹

“The EV-304 results represent a key milestone in the new era of urothelial cancer treatment. Together, the EV-303 and EV-304 results show that perioperative enfortumab vedotin plus pembrolizumab can positively impact the treatment journey for patients with MIBC, offering significant survival gains across cisplatin-ineligible and cisplatin-eligible patients, signaling a shift from conventional platinum-based chemotherapy and the potential to transform the standard of care,” Chatterjee-Kishore said in the news release.¹

REFERENCES

1.PADCEV™ Plus Keytruda® Significantly Improves Survival for Patients with Muscle-Invasive Bladder Cancer Regardless of Cisplatin Eligibility. News release. Astellas. December 17, 2025. Accessed December 18, 2025. https://www.prnewswire.com/news-releases/padcev-plus-keytruda-significantly-improves-survival-for-patients-with-muscle-invasive-bladder-cancer-regardless-of-cisplatin-eligibility-302644184.html?tc=eml_cleartime

2. Muscle-Invasive Bladder Cancer. Urology Care Foundation. Updated August 2024. Published December 18, 2025. https://www.urologyhealth.org/urology-a-z/m/muscle-invasive-bladder-cancer