Bladder Cancer Study Receives a Standing Ovation at ESMO 2025
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ESMO 2025 (Berlin) | Presidential Symposium —At one of oncology's most prestigious sessions, results from KEYNOTE-905 / EV-303 were announced. In muscle-invasive bladder cancer , this long-awaited development showed that, in cisplatin-ineligible patients, the perioperative (before and after surgery) enfortumab vedotin + pembrolizumab combination provided a clear survival advantage over surgery. The entire auditorium's standing ovation at the end symbolized more than a phase 3 success: it marked a new era in bladder cancer treatment.
Why Is This So Important?
Muscle-invasive bladder cancer (MIBC, muscle-invasive bladder cancer) is one of uro-oncology's most challenging areas. For years, the standard approach was radical cystectomy , surgery to remove the bladder, preceded bycisplatin-based neoadjuvant chemotherapy . But the harsh clinical reality was that approximately 40% of patients could not receive cisplatin. Because of kidney dysfunction, heart failure, or advanced age, these patients were deprived of the most effective treatment option and had to rely on surgery alone.
For years, bladder cancer literature therefore repeated a familiar statement: "There is no truly effective option for patients who cannot receive cisplatin." Although adjuvant immunotherapy in the early 2020s (such as CheckMate-274with nivolumab) raised hopes, its effect was limited to PD-L1-positive, high-risk subgroups.
Against this background, when KEYNOTE-905 / EV-303 results were announced at ESMO 2025, the hall at Berlin's congress center briefly fell silent. The data that followed— risk reductions of up to 60% for event-free survival and 50% for overall survival —were interpreted as more than statistical significance: they marked the start of a new era in medical oncology. When the speaker, Dr. Christof Vulsteke, displayed a slide reading "A new standard for cisplatin-ineligible MIBC" appeared, approximately 5000 audience members gave a standing ovation. For the first time in this long-considered "untreatable" population, combined systemic treatment both before and after surgery had extended survival.
Historical Milestones: 20 Years of Evolution in Bladder Cancer Treatment
Treatment of muscle-invasive bladder cancer (MIBC) has undergone a quiet but profound transformation over the past 20 years. The timeline below summarizes its evolution from chemotherapy to immunotherapy and then to a new era combining antibody–drug conjugates with immunotherapy.
| Year | Development | Clinical Impact |
|---|---|---|
| 2003 | Neoadjuvant chemotherapy with MVAC (methotrexate–vinblastine–adriamycin–cisplatin) was established as standard. | The first survival benefit from preoperative cisplatin-based treatment was demonstrated. |
| 2010 | Gemcitabine–cisplatin (GC) became a better-tolerated new standard. | Toxicity decreased, but cisplatin-ineligible patients still lacked treatment. |
| 2016 | PD-1/PD-L1 inhibitors (pembrolizumab, atezolizumab) opened the immunotherapy era in metastatic disease. | Immune checkpoint inhibitors introduced a platinum-free treatment alternative. |
| 2021 | Following CheckMate-274, adjuvant nivolumab was approved for PD-L1-positive, high-risk patients. | Immunotherapy entered the curative setting for the first time. |
| 2025 | KEYNOTE-905 / EV-303 results showed that perioperative enfortumab vedotin + pembrolizumab prolonged survival. | The standing ovation at the presidential symposium marked this result as the beginning of a new era in MIBC treatment. |
A disease setting limited to cisplatin 20 years ago is now, through the powerful combination of immunotherapies and antibody–drug conjugates, entering a new biological era .
Study Design
In the phase 3 randomized KEYNOTE-905 / EV-303 study, 344 cisplatin-ineligible MIBC patients were allocated to two arms:
- Experimental arm: Neoadjuvant and adjuvant enfortumab vedotin (EV) + pembrolizumab + standard surgery (radical cystectomy + pelvic lymph node dissection)
- Control arm: Surgery alone
The primary endpoints were event-free survival (EFS) and overall survival (OS) .
Main Findings
| Parameter | EV + Pembrolizumab | Surgery | Statistics |
|---|---|---|---|
| EFS (Median) | Not reached (NR) | 15.7 months | HR 0.40 (95% CI 0.28–0.57, p<0.0001) |
| OS (Median) | Not reached (NR) | 41.7 months | HR 0.50 (95% CI 0.33–0.74, p=0.0002) |
| Pathological complete response (pCR) | 57.1% | 8.6% | Difference: 48.3% (p<0.000001) |
This response rate is substantially higher than with conventional cisplatin-based neoadjuvant chemotherapy (Discov Oncol 2025;16:1197).
Safety and Patient Selection
Grade ≥3 adverse events occurred in 71.3% of the EV + pembrolizumab arm and 45.9% of controls. The most common specific adverse effects were:
- EV-related: Skin rash, peripheral neuropathy, hyperglycemia
- Pembrolizumab-related: Hypothyroidism, severe skin reactions
Therefore, patients with severe neuropathy or uncontrolled diabetes may not be suitable for EV, while patients with active autoimmune disease may not be suitable for pembrolizumab.
Clinical Impact and Future Outlook
Only 67% of patients could start adjuvant treatment after cystectomy. This makes understanding the relative contributions of preoperative and postoperative treatment important. ctDNA monitoring may guide the need for adjuvant treatment in the future.
Moreover, the potential emergence of EV + pembrolizumab as a new standard in cisplatin-ineligible patients will also affect future first-line strategies in metastatic disease.
Points to Consider
- Perioperative treatment did not prevent surgery, but side effects require careful management.
- For the first time, cisplatin-ineligible patients are offered a significant OS benefit.
- The role of the new combination will be clarified further by the ongoing VOLGA (NCT04960709) and KEYNOTE-B15/EV-304 (NCT04700124) studies.
💬 DROZDOGAN Academy Commentary
Enfortumab vedotin + pembrolizumab marks another important step toward cure. This combination could transform treatment not only in metastatic disease but also in locally advanced muscle-invasive bladder cancer. The dramatic increase in pathological complete responses (57%) shows how powerful the synergy can be when immunotherapy is combined with ADCs .
The next few years will determine whether this approach has similar effects in cisplatin-eligible patients. If so, we may be approaching the end of the "pre-chemotherapy" era in bladder cancer treatment.
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