Summary
The Phase III EV-303/KEYNOTE-905 trial showed that Padcev (enfortumab vedotin) plus Keytruda (pembrolizumab), given before and after surgery, significantly improved event-free survival, overall survival, and pathologic complete response compared with surgery alone in cisplatin-ineligible patients with muscle-invasive bladder cancer. This marks the first systemic treatment to extend survival in this population beyond surgery. The findings build on earlier EV-302 results in advanced urothelial cancer and are being reviewed for potential regulatory filings.
Pfizer and Astellas have shared new, positive data from the Phase III EV-303/KEYNOTE-905 clinical trial (NCT03924895) of Padcev (enfortumab vedotin) in combination with Keytruda (pembrolizumab) as neoadjuvant and adjuvant treat in patients with muscle-invasive bladder cancer (MIBC) who are not eligible for or declined cisplatin-based chemotherapy.1
Interim analysis meets primary and secondary endpoints
Results from this most recent interim efficacy analysis show the trial demonstrated a clinically meaningful and statistically significant improvement in its primary endpoint of event-free survival (EFS). The key secondary endpoint of overall survival (OS) was also met with neoadjuvant and adjuvant Padcev alongside Keytruda versus surgery alone. Additionally, another secondary endpoint of pathologic complete response (pCR) was met.
In a press release, Christof Vulsteke, MD, PhD, head of Integrated Cancer Center Ghent (IKG, Belgium) and Clinical Trial Unit Oncology Ghent and EV-303 principal investigator, said: “Patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy have not seen any treatment advance beyond surgery and face high rates of disease recurrence and a poor prognosis, even after having their bladder removed. These EV-303 study results mark the first time a systemic treatment approach, used before and after surgery, significantly extended survival over standard-of-care surgery in this population, demonstrating the potential of this combination to address a critical unmet need.”
Study design and ongoing evaluation
The EV-303/KEYNOTE-905 study is ongoing to evaluate the secondary endpoints of EFS, OS, and pCR rate for neoadjuvant and adjuvant Keytruda compared to surgery alone. Pfizer and Astellas plan to submit results from this interim readout for presentation at an upcoming medical congress and discuss them with regulatory agencies for potential filings.
EV-303/KEYNOTE-905 is an open-label, randomized, three-arm trial.
- Patients are randomized to one of three groups: Keytruda alone (arm A), surgery alone (arm B), or Padcev plus Keytruda (arm C).
- The primary endpoint compares EFS between arm C and arm B, defined as time from randomization to disease progression preventing radical cystectomy, failure to undergo surgery with residual disease, gross residual disease after surgery, local or distant recurrence, or death from any cause.
- Key secondary endpoints include OS and pCR rate between arm C and arm B, as well as EFS, OS, and pCR rate between arm A and arm B.
Related ongoing research
Neoadjuvant and adjuvant Padcev in combination with Keytruda is also being evaluated in the Phase III EV-304/KEYNOTE-B15 trial (NCT04700124) in cisplatin-eligible patients with MIBC. This trial is an open-label, randomized, two-arm study, with a primary outcome measure of EFS.2
Previous data in advanced disease
Earlier in February, Pfizer and Astellas shared results from the Phase III EV-302/KEYNOTE-A39 trial (NCT04223856), which showed that the Padcev-Keytruda combination produced sustained benefits in OS and progression-free survival (PFS) compared to chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). The combination had previously received FDA approval for la/mUC in December 2023 based on earlier findings from EV-302/KEYNOTE-A39.
Key efficacy results from EV-302/KEYNOTE-A39
Data from the February readout of EV-302/KEYNOTE-A39 showed:
- Padcev plus Keytruda reduced the risk of death by 49% compared to chemotherapy alone (HR 0.51; 95% CI, 0.43–0.61).
- Median OS was 33.8 months with the combination treatment versus 15.9 months with chemotherapy.
- Survival benefits were seen across all prespecified subgroups, including patients eligible and ineligible for cisplatin.
- The risk of disease progression or death was reduced by 52% compared to chemotherapy (HR 0.48; 95% CI, 0.41–0.57).
- Median PFS was 12.5 months with the combination compared to 6.3 months with chemotherapy.
References
1. PADCEV™ Plus KEYTRUDA™ Significantly Improves Survival for Certain Patients with Bladder Cancer When Given Before and After Surgery. News release. Pfizer. August 12, 2025. Accessed August 12, 2025. https://www.pfizer.com/news/press-release/press-release-detail/padcevtm-plus-keytrudatm-significantly-improves-survival
2. Perioperative Enfortumab Vedotin (EV) Plus Pembrolizumab (MK-3475) Versus Neoadjuvant Chemotherapy for Cisplatin-Eligible Muscle Invasive Bladder Cancer (MIBC) (MK-3475-B15/ KEYNOTE-B15 / EV-304) (KEYNOTE-B15). ClinicalTrials.gov. Updated December 24, 2024. Accessed August 12, 2025. https://clinicaltrials.gov/study/NCT04700124
