Bladder cancer breakthrough: Why Keytruda plus Padcev could replace chemo in cisplatin-ineligible patients

The United States Food and Drug Administration has granted approval to Merck’s checkpoint inhibitor Keytruda (pembrolizumab) and its subcutaneous formulation Keytruda QLEX (pembrolizumab and berahyaluronidase alfa-pmph), each in combination with Padcev (enfortumab vedotin-ejfv), for use as perioperative treatment in adult patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy. This regulatory clearance marks the first time a PD-1 checkpoint inhibitor and an antibody-drug conjugate regimen has been approved for this specific patient population in the perioperative setting, providing a new option for those traditionally limited to surgery alone.

The approvals are based on results from the Phase 3 KEYNOTE-905 trial, also referred to as EV-303, which was conducted through a collaborative effort involving Merck, Pfizer, and Astellas Pharma. The clinical data revealed that the combination of pembrolizumab and enfortumab vedotin achieved a 60 percent reduction in the risk of event-free survival events compared to surgery alone. The event-free survival hazard ratio was 0.40 with a confidence interval of 0.28 to 0.57 and a p-value of less than 0.0001. Median event-free survival was not reached in the combination arm versus 15.7 months in the control arm. Overall survival also improved significantly, with a hazard ratio of 0.50 and a p-value of 0.0002, translating to a 50 percent reduction in the risk of death.

How strong were the clinical outcomes from KEYNOTE-905 in perioperative bladder cancer patients?

The trial enrolled 344 patients who were either ineligible for cisplatin or declined to receive it. They were randomized to receive either surgery alone or a combination of pembrolizumab and Padcev as neoadjuvant therapy followed by surgery, and then as adjuvant therapy post-surgery. Patients in the treatment arm received pembrolizumab intravenously every 21 days for three cycles prior to surgery, combined with Padcev given on Days 1 and 8 of each cycle. Postoperatively, pembrolizumab was continued every three weeks for up to 14 cycles, while Padcev was administered for an additional six cycles.

At a median follow-up of over two years, the combination regimen demonstrated significant improvements across all primary endpoints. The pathologic complete response rate, which is a measure of tumor eradication at the time of surgery, was 57.1 percent compared to just 8.6 percent in the surgery-alone arm. These results support a fundamental shift in the standard of care for cisplatin-ineligible MIBC patients, who previously had few therapeutic options beyond radical cystectomy.

What makes this approval clinically and commercially significant for Merck and its partners?

The FDA’s decision opens up a new chapter for immunotherapy and ADC combinations, particularly in earlier disease stages. Previously, most approvals for checkpoint inhibitors and antibody-drug conjugates in urothelial cancer were restricted to metastatic settings. With this perioperative approval, Merck, Pfizer, and Astellas Pharma now have a foot in the door for pre- and post-surgical treatment, expanding the commercial runway for both Keytruda and Padcev.

Analysts tracking the oncology pipeline believe this move will create ripple effects throughout the immuno-oncology field. Merck already dominates the PD-1 space with Keytruda across multiple tumor types, but by moving into the perioperative bladder cancer segment, it strengthens its position against competitors like Bristol-Myers Squibb, which has pursued similar strategies with nivolumab.

The co-approval of Keytruda QLEX, a subcutaneous formulation enabled by berahyaluronidase alfa, also introduces new administration flexibility. Merck emphasized that patients now have the choice between intravenous and subcutaneous administration routes, a point that could improve adherence and accessibility in real-world practice.

What safety concerns emerged in the neoadjuvant and adjuvant phases of the trial?

While efficacy results were compelling, the safety profile remains a key consideration. In the neoadjuvant phase, 27 percent of patients experienced serious adverse events. The most common included urinary tract infections and hematuria. There were also two fatal immune-mediated events, which are myasthenia gravis and toxic epidermal necrolysis.

Adverse events led to surgery cancellations in 4.2 percent of patients, including two deaths. Meanwhile, in the adjuvant phase, 43 percent of patients experienced serious adverse reactions, with seven percent resulting in death. These included complications such as urosepsis, myocardial infarction, and multiple organ dysfunction syndrome. Approximately 28 percent of patients permanently discontinued pembrolizumab in the adjuvant phase due to adverse effects.

Despite these risks, the benefit-to-risk ratio appeared favorable, especially considering the historically poor prognosis of patients ineligible for cisplatin-based regimens. The FDA label includes detailed guidance on immune-mediated side effects, infusion reactions, and fetal risk during pregnancy.

How does this reshape the treatment algorithm for muscle-invasive bladder cancer?

Bladder cancer accounts for over 614,000 new cases worldwide each year, with muscle-invasive disease representing a large share of cases. Until now, cisplatin-based chemotherapy remained the primary systemic option for patients eligible for such therapy. Those unable to tolerate cisplatin due to renal function, hearing loss, or other comorbidities had little recourse beyond surgery.

This new approval provides those patients a dual-agent systemic approach that delivers survival benefits even in the absence of platinum therapy. Physicians now have a rationale to administer immunotherapy and ADCs both before and after surgery, rather than relying solely on curative resection.

Experts believe that the FDA’s support for this regimen reflects a growing acceptance of aggressive perioperative strategies in earlier-stage cancers. Similar trends are visible in lung and breast cancer, where neoadjuvant immunotherapy has gained traction.

What’s next for Merck, Pfizer, and Astellas in the bladder cancer space?

Regulatory filings in other major markets, including the European Union and Japan, are likely to follow. If global approvals align with the FDA’s decision, the combination of Keytruda and Padcev could become the new global standard for treating cisplatin-ineligible MIBC.

Commercially, the expanded indication could boost revenue for both Keytruda and Padcev. For Merck, Keytruda already generated over $25 billion globally in 2024, and continued label expansions are essential to maintaining momentum as biosimilar threats inch closer in the 2030s. For Pfizer and Astellas Pharma, the approval could revitalize Padcev’s positioning beyond metastatic urothelial carcinoma, where competition has begun to increase.

On the clinical side, further studies may dissect the individual contributions of the neoadjuvant versus adjuvant components of the combination. As the KEYNOTE-905 trial was not designed to isolate those effects, new trials may be required to optimize sequencing and duration.

Key takeaways from the FDA approval of Keytruda and Padcev in MIBC:

• The FDA has approved Keytruda and Keytruda QLEX, each in combination with Padcev, for perioperative use in muscle-invasive bladder cancer patients who are not eligible for cisplatin.

• The approval is based on the Phase 3 KEYNOTE-905 trial, which showed statistically significant improvements in event-free survival, overall survival, and complete pathological response rates.

• Merck now offers both intravenous and subcutaneous versions of pembrolizumab, adding flexibility for clinical administration.

• Despite promising efficacy, safety remains a consideration, with serious and fatal adverse events observed in both treatment phases.

• This regulatory win expands the role of antibody-drug conjugates in earlier-stage oncology settings and cements Merck’s leadership in immuno-oncology.

• Global filings and market uptake will be the next factors to watch as the approval sets a new benchmark in perioperative bladder cancer treatment.