Can immunotherapy finally replace chemo in bladder cancer? Keytruda–Padcev combo shows the way

The recent regulatory approval of Merck’s immunotherapy Keytruda (pembrolizumab) and its subcutaneous formulation Keytruda QLEX, in combination with Padcev (enfortumab vedotin-ejfv), marks a significant inflection point in the treatment of muscle-invasive bladder cancer. Announced by the United States Food and Drug Administration on November 21, 2025, the decision allows these agents to be used together before and after surgery in adult patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy.

This is the first time a perioperative PD-1 inhibitor and antibody-drug conjugate combination has been approved for any muscle-invasive bladder cancer patient population. The decision establishes a new treatment paradigm and expands systemic options for patients who previously had surgery as their only realistic path to disease control. The implications extend beyond urology and into the future structure of oncology treatment timelines.

How did the KEYNOTE-905 trial support the FDA approval of Keytruda and Padcev in bladder cancer?

The regulatory decision is grounded in the Phase 3 KEYNOTE-905 clinical trial, also known as EV-303. The trial was conducted in partnership with Astellas Pharma and Pfizer, and enrolled 344 adult patients with muscle-invasive bladder cancer who either declined or were medically ineligible for cisplatin therapy. These patients were randomized to receive either immediate radical cystectomy and pelvic lymph node dissection or a systemic perioperative regimen that included three cycles of pembrolizumab and Padcev prior to surgery, followed by adjuvant continuation of pembrolizumab for up to 14 cycles and Padcev for an additional six cycles.

At a median follow-up of 25.6 months, the data showed that the combination of pembrolizumab and Padcev led to a 60 percent reduction in the risk of event-free survival events compared to surgery alone. The hazard ratio for event-free survival was 0.40, while the hazard ratio for overall survival was 0.50, translating to a 50 percent reduction in the risk of death. Median survival had not been reached in the combination arm, while the control group showed a median event-free survival of 15.7 months and a median overall survival of 41.7 months. Importantly, the pathologic complete response rate rose to 57.1 percent in the combination arm, compared to only 8.6 percent among patients who received surgery without systemic therapy.

These statistically and clinically significant results helped secure a breakthrough for a patient population that has historically seen few innovations in systemic treatment.

Why this perioperative approval redefines systemic options for cisplatin-ineligible patients

For decades, radical cystectomy has been the cornerstone of treatment for patients with muscle-invasive bladder cancer who could not tolerate platinum-based chemotherapy. However, outcomes for these patients have been suboptimal, with high recurrence rates and limited long-term survival. The new FDA approval directly addresses this unmet need by offering a systemic therapeutic option that begins before and extends after surgery, targeting micrometastatic disease and reducing the risk of early recurrence.

This development is particularly meaningful because it moves immune-based and targeted therapies into the perioperative setting, a space traditionally dominated by chemotherapy. Although the current indication is limited to patients ineligible for cisplatin, industry analysts believe the regulatory milestone will influence future study designs and guideline updates for broader patient segments.

The approval reflects a shift in how oncologists are managing early-stage cancers. By introducing immunotherapy and targeted cytotoxics earlier in the disease course, developers aim to increase curative outcomes while minimizing the toxicities associated with traditional chemotherapeutics.

What the FDA approval of Keytruda and Padcev means for Merck, Pfizer, and Astellas Pharma

For Merck, the approval strengthens Keytruda’s position as one of the most dominant oncology brands globally. The addition of Keytruda QLEX, a subcutaneous fixed-dose version co-formulated with berahyaluronidase alfa, also opens doors for improved administration logistics. Subcutaneous delivery could reduce patient chair time, increase outpatient flexibility, and potentially ease resource burdens on infusion centers, especially in high-volume community practices.

Astellas Pharma and Pfizer also benefit from the expanded use of Padcev. Previously approved in metastatic urothelial carcinoma, Padcev’s move into the perioperative setting broadens its commercial relevance and reinforces the broader trend of using antibody-drug conjugates earlier in the treatment timeline. It also positions both companies to explore combination strategies beyond bladder cancer, including solid tumors such as breast and lung cancer.

More broadly, the FDA’s decision validates the strategy of combining checkpoint inhibitors and ADCs for maximal effect, an approach that is already being evaluated in other tumor types and clinical settings. The approval also demonstrates regulatory willingness to embrace combination therapies earlier in the disease journey, which may accelerate pipeline momentum across the immuno-oncology landscape.

How serious are the safety risks associated with perioperative immunotherapy–ADC regimens?

While efficacy results were promising, the safety profile for the pembrolizumab–Padcev regimen demands attention. In the neoadjuvant phase of KEYNOTE-905, 27 percent of patients experienced serious adverse reactions, including urinary tract infections and hematuria. Two deaths occurred due to myasthenia gravis and toxic epidermal necrolysis. In the adjuvant phase, 43 percent of patients reported serious adverse reactions, with fatal outcomes in 7 percent of patients. These included urosepsis, myocardial infarction, multiple organ dysfunction, and pseudomonal pneumonia.

Across both treatment phases, 15 to 28 percent of patients discontinued treatment due to adverse events. The most frequently observed side effects included rash, pruritus, fatigue, peripheral neuropathy, diarrhea, and urinary tract infections.

These safety signals underscore the importance of patient selection, monitoring, and proactive management in real-world settings. Oncologists will need to weigh the potential for meaningful survival benefit against the risks of immune- and ADC-related toxicities, particularly in older and comorbid patients.

Could this be the beginning of chemotherapy-free pathways in solid tumors beyond bladder cancer?

The implications of the KEYNOTE-905 approval extend beyond bladder cancer. It could act as a template for other solid tumors where chemotherapy remains the primary systemic intervention in earlier-stage disease. For instance, similar perioperative checkpoint–ADC strategies are being investigated in non-small cell lung cancer, triple-negative breast cancer, and head and neck squamous cell carcinoma.

If comparable combinations can replicate the efficacy shown in KEYNOTE-905 while maintaining manageable toxicity profiles, systemic chemotherapy may face increasing displacement from its long-held position as the backbone of early-stage cancer care. Moreover, these developments align with broader oncology trends favoring biomarker-driven, immune-enhanced, and patient-personalized approaches over cytotoxic generalizations.

Additionally, the inclusion of Keytruda QLEX as a subcutaneous option highlights how innovations in delivery mechanisms can further improve accessibility and patient experience, potentially accelerating adoption in outpatient and community oncology settings.

What do oncologists, payers, and investors need to monitor after this FDA approval?

From a market dynamics standpoint, reimbursement decisions will be crucial. The combined regimen’s cost, especially in systems already under pressure from high drug expenditures, will likely prompt value assessments from payers and health technology assessment bodies. Global regulatory filings are anticipated, and uptake outside the United States will depend heavily on regional cost-effectiveness evaluations.

Oncologists will watch for guideline inclusion, particularly in updates from the National Comprehensive Cancer Network and the European Society for Medical Oncology. Real-world data from academic and community settings will help validate efficacy and safety outside clinical trials, and could influence practice patterns in broader patient segments.

Pipeline developers are also likely to respond competitively, accelerating efforts to bring similar regimens to market across adjacent indications. Investors will track how Merck, Pfizer, and Astellas Pharma scale commercial deployment, manage manufacturing and distribution of subcutaneous Keytruda, and engage with payers on pricing and access models.

Final thoughts on the long-term potential of checkpoint–ADC combinations in early-stage oncology

The approval of Keytruda and Padcev as perioperative therapy in muscle-invasive bladder cancer marks a significant milestone in the evolution of systemic oncology. For a patient population long underserved due to cisplatin ineligibility, this decision introduces a new standard that offers real survival benefit.

While chemotherapy is not yet obsolete, its role is clearly being challenged by the growing convergence of immunotherapy and ADCs. The Keytruda–Padcev combination signals not just a clinical advance, but a broader strategic shift in how cancer is treated in the perioperative window. If the adoption curve continues, and if future trials confirm benefits in wider populations, this approval may be remembered as one of the key turning points in the long decline of chemotherapy’s reign in curative-intent oncology.