PADCEV plus Keytruda shows survival benefit in muscle-invasive bladder cancer regardless of cisplatin eligibility

Astellas Pharma Inc. (TSE: 4503) and Pfizer Inc. (NYSE: PFE) have announced topline results from the Phase 3 EV-304 trial showing that PADCEV (enfortumab vedotin) in combination with Keytruda (pembrolizumab) significantly improved survival outcomes in muscle-invasive bladder cancer (MIBC), including in patients eligible for cisplatin-based chemotherapy. The findings position this platinum-free combination as a potential new standard of care in perioperative treatment.

The EV-304 results not only reinforce PADCEV plus pembrolizumab’s emerging role in the cisplatin-ineligible population, already supported by EV-303 data and U.S. FDA approval, but also extend its relevance to the broader MIBC population. The companies intend to present the data at an upcoming medical congress and initiate regulatory discussions globally.

Why is the PADCEV plus Keytruda combination significant for bladder cancer treatment in cisplatin-eligible patients?

The core clinical significance of EV-304 lies in its demonstration of both event-free survival (EFS) and overall survival (OS) benefit in patients who would typically receive cisplatin-based neoadjuvant chemotherapy. This marks the first time a platinum-free regimen has outperformed the cisplatin-gemcitabine standard in this setting. The trial also achieved a key secondary endpoint, with higher rates of pathologic complete response (pCR), reinforcing the mechanistic synergy between antibody-drug conjugates and immune checkpoint inhibitors.

According to Duke Cancer Institute’s Dr. Christopher Hoimes, these results point to a shift in standard perioperative therapy by offering a non-platinum-based approach with survival benefit, particularly critical in an era of increasing scrutiny on chemotherapy toxicity. Astellas executive Moitreyee Chatterjee-Kishore emphasized that the data expands the survival benefit to a wider MIBC population, further validated by the prior EV-303 trial in cisplatin-ineligible patients.

Pfizer’s oncology leadership added that the combination may now represent a platform approach for MIBC treatment, potentially reshaping the treatment journey for both cisplatin-ineligible and cisplatin-eligible patients. If approved, this regimen could erode the longstanding dominance of platinum chemotherapy in early-stage urothelial carcinoma.

How do the EV-304 results position PADCEV for regulatory expansion beyond the current FDA label?

As of December 2025, PADCEV plus pembrolizumab is approved by the U.S. Food and Drug Administration for cisplatin-ineligible MIBC patients in both neoadjuvant and adjuvant settings, based on EV-303 (KEYNOTE-905). The EV-304 trial extends this use case into cisplatin-eligible patients, potentially doubling the market footprint for this platinum-free combination.

The regulatory path now involves formal submissions supported by the statistically significant EFS and OS data. PADCEV is also approved as a monotherapy in patients with locally advanced or metastatic urothelial cancer (la/mUC) who have progressed after PD-1/L1 inhibitors and chemotherapy. Adding the MIBC perioperative indication would position the drug as a continuity agent across early and advanced bladder cancer stages.

With the trial meeting both its primary and key secondary endpoints, and with safety data aligning with prior studies, the regulatory risk appears moderate. However, health authorities may scrutinize long-term tolerability, especially given the relatively high incidence of adverse events and discontinuations seen in the neoadjuvant and adjuvant phases.

What safety risks and tolerability challenges may affect adoption of PADCEV plus pembrolizumab in the perioperative setting?

While the combination demonstrates clear clinical benefit, its tolerability profile presents potential headwinds. In the EV-303 and EV-304 trials, skin reactions occurred in over 60% of patients, with Grade 3 or higher severity in up to 17%. Peripheral neuropathy was another major concern, affecting more than half of patients in several cohorts, with many showing residual symptoms even at final assessment.

In the neoadjuvant phase of the EV-303 trial, serious adverse events occurred in 27% of patients, including fatal cases of toxic epidermal necrolysis and myasthenia gravis. A small subset of patients were unable to proceed to surgery due to treatment-related toxicity, which could influence real-world adoption.

In the adjuvant setting, 43% of patients experienced serious adverse events, and 7% experienced fatal events. These include urosepsis and intracranial hemorrhage. Peripheral neuropathy and rash were the leading causes for discontinuation.

Such safety signals raise questions about how oncologists will balance survival gains with quality-of-life impacts, particularly for patients already burdened by comorbidities or frailty. This becomes more pressing in community settings where monitoring capabilities may be limited.

How large is the potential commercial market for PADCEV in muscle-invasive bladder cancer?

Globally, more than 614,000 new cases of bladder cancer are diagnosed annually, with muscle-invasive subtypes representing roughly 30% of cases. In the United States, around 85,000 patients are diagnosed each year. MIBC accounts for a significant clinical burden due to its aggressive nature and high recurrence risk even after surgery.

Traditionally, treatment involves neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. However, nearly 50% of patients relapse within three years, creating a high unmet need for more effective perioperative therapies.

The expansion of PADCEV plus Keytruda to cisplatin-eligible patients would significantly increase the addressable market. Pfizer and Astellas are also expected to benefit from earlier-line use, longer treatment duration across neoadjuvant and adjuvant settings, and a broader eligible population. If commercialized successfully, the regimen could become a backbone of therapy across the MIBC continuum.

How does this impact Merck, the collaboration dynamics, and competitive PD-1 landscapes?

Merck & Co. remains a key stakeholder through its co-development of Keytruda. The combination’s success further cements pembrolizumab’s position as the PD-1 inhibitor of choice in urothelial carcinoma, maintaining its edge over competitors like nivolumab (Bristol Myers Squibb) and avelumab (Pfizer–EMD Serono).

The alliance, which was originally between Seagen, Astellas, and Merck, has evolved following Pfizer’s acquisition of Seagen. This reshuffling raises execution questions but also consolidates rights under a pharma giant with global commercialization infrastructure. Keytruda’s ability to sustain broad combination strategies across tumor types continues to provide a durable competitive moat for Merck in immuno-oncology.

The result also puts pressure on other platinum-sparing regimens in development and may crowd out second-tier immunotherapy or ADC contenders lacking survival data or perioperative validation.

What are the investor signals and broader oncology takeaways from this trial milestone?

For Pfizer, the EV-304 data supports its oncology thesis post-Seagen acquisition. The data serves as validation of its antibody-drug conjugate strategy and its belief that ADCs can deliver therapeutic power beyond late-line settings. Astellas also solidifies its foothold in the U.S. bladder cancer market, where it previously faced limitations outside its core territories.

Institutional sentiment may be cautiously optimistic. The survival win is significant, but investor focus is likely to shift to FDA filing timelines, commercial execution, payer uptake, and margin implications from safety-related drug discontinuation. Analysts may also seek real-world utilization data to assess whether PADCEV plus Keytruda can maintain adherence outside controlled clinical settings.

More broadly, the result reaffirms that perioperative combination strategies are no longer limited to chemotherapy backbones. The shift towards ADC + IO regimens could reshape neoadjuvant pipelines across multiple cancers, from breast to lung.

What are the key takeaways for investors, clinicians, and industry strategists from the EV-304 update?

• PADCEV plus pembrolizumab significantly improved event-free and overall survival in cisplatin-eligible muscle-invasive bladder cancer patients, a first for a platinum-free combination.

• The combination has already been approved in cisplatin-ineligible MIBC patients; EV-304 extends potential use to a broader perioperative population.

• Regulatory filings are expected following the full data presentation, with the potential to double the commercial opportunity for Astellas and Pfizer.

• Safety concerns remain a barrier, particularly due to high incidence of skin reactions, peripheral neuropathy, and serious adverse events that delayed or cancelled surgery in some patients.

• Investor sentiment will hinge on the timing of approval, reimbursement dynamics, and real-world tolerability data as the regimen scales beyond clinical trials.

• The data reinforces Merck’s leadership in PD-1 checkpoint inhibitors and supports the growing role of ADC + IO combinations in reshaping early-stage cancer treatment.

• Pfizer’s oncology pipeline gains strategic validation post-Seagen acquisition, with PADCEV emerging as a central franchise in urothelial carcinoma.

• The EV-304 milestone sets a precedent for replacing cisplatin backbones in other solid tumors, expanding the paradigm for neoadjuvant and adjuvant immunotherapy-ADC approaches.