ESMO 2026 On Location - Why pCR is not the whole story in cisplatin-ineligible MIBC

Perioperative durvalumab (Imfinzi) plus neoadjuvant enfortumab vedotin-ejfv (EV, Padcev) offered patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or decline cisplatin an adjuvant phase without EV, according to Alexandra Drakaki, MD, PhD, a senior investigator of the phase 3 VOLGA trial (NCT04960709) presented at the 2026 European Society for Medical Oncology Congress.¹^,2

Drakaki, an associate professor of hematology/oncology at the University of California, Los Angeles, discussed the study during a recent conversation with Joshua J. Meeks, MD, PhD, is the Edward M. Schaeffer, MD, PhD Professor of Urology and an associate professor of urology, biochemistry, and molecular genetics at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

VOLGA was designed before the COVID-19 pandemic for patients who historically went directly to cystectomy, despite worse outcomes than patients who received neoadjuvant therapy. Patients were assigned to 1 of 3 arms:

• 3 cycles of neoadjuvant durvalumab plus EV, then cystectomy and adjuvant durvalumab alone to complete 1 year

• the same regimen with tremelimumab (Imjudo), given as 3 total doses including 1 adjuvant dose

• cystectomy followed by observation, later amended to allow adjuvant nivolumab (Opdivo) where available

Approximately 75% of patients were cisplatin ineligible and 25% declined cisplatin.¹

Investigators were not concerned about omitting adjuvant EV.

“EV is a very effective drug, it is really life-changing and life-saving. But the more you give, the more toxicity you get,” Drakaki said. The KEYNOTE-905/EV-303 (NCT03924895) regimen continued EV plus pembrolizumab (Keytruda) after cystectomy.³ However, according to Drakaki, most patients in EV-303 and EV-304 did not receive the full adjuvant course, and clinicians routinely reduce adjuvant EV to what patients can tolerate.

Durvalumab plus EV improved event-free survival (EFS) and overall survival (OS) vs control. The triplet improved EFS, but OS was not yet significant at the first interim analysis, although Drakaki noted wide curve separation at approximately 45 months. In her experience, toxicity with the triplet did not appear meaningfully different. Some patients with strong responses to the triplet did not want to undergo cystectomy.

Pathologic complete response (pCR) should be interpreted cautiously.

“Pathological complete response is not the whole story. A cancer in a patient is the bladder and the systemic disease burden,” Drakaki said. Circulating tumor DNA (ctDNA) captures micrometastatic disease, but cost limits access in many countries. VOLGA used local pCR review, and its sites and surgeons were largely different from those in EV-303, which limits cross-trial comparisons.

Cisplatin eligibility remains relevant for decisions in later-line metastatic disease. Nearly all patients who receive enough EV cycles develop neuropathy. For that reason, patients with significant preexisting neuropathy, prior stroke, or neuromuscular disease and a low disease burden may be better served by a NIAGARA (NCT03732677)-based approach. Some patients have high baseline ctDNA and substantial disease burden but respond well without toxicity. For them, continued durvalumab with additional EV cycles would not be unreasonable, although that decision would be personalized and is not supported by trial data. Irreversible immune-mediated toxicities, such as adrenal insufficiency and thyroiditis requiring lifelong replacement, remain a key consideration.

KEYNOTE-866 (NCT03924856) and ENERGIZE (NCT03661320) were both negative. The field is now moving toward identifying patients who could forgo cystectomy in favor of bladder preservation with radiation. Drakaki remained a proponent of surgery, citing concern about radiation toxicity 5 to 10 years later.

References

1. Powles T, Grande E, Simone G, et al. Perioperative durvalumab with or without tremelimumab plus neoadjuvant enfortumab vedotin in muscle-invasive bladder cancer: results from the phase 3 VOLGA trial. Presented at: European Society for Medical Oncology Congress 2026; October 23-27, 2026, Madrid, Spain. Abstract LBA2. https://cslide.ctimeetingtech.com/esmo2026/attendee/confcal/show/session/346

2. Powles T, Grande E, Simone G, et al. Durvalumab, tremelimumab, and enfortumab vedotin in muscle-invasive bladder cancer. N Engl J Med. Published online October 24, 2026. Accessed October 24, 2026. https://www.nejm.org/doi/full/10.1056/NEJMoa2608323?query=featured_home

3. Vulsteke C, Adra N, Danchaivijitr P, et al. Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. N Engl J Med. 2026;394(13):1257-1269. https://doi.org/10.1056/NEJMoa2511674