Perioperative immunotherapy is redefining muscle-invasive bladder cancer care

The management of muscle-invasive bladder cancer (MIBC) has rapidly evolved from a traditional “surgery-first” approach to an era defined by precision medicine and perioperative immunotherapy, according to Joshua J. Meeks, MD, PhD. In a presentation at the 2025 LUGPA Annual Meeting, Meeks outlined how modern MIBC care now revolves around 3 key perioperative phases: neoadjuvant, local, and adjuvant therapy.¹

A major driver of this shift is the emergence of novel immunotherapy combinations. Meeks began by spotlighting data from the phase 3 NIAGARA trial (NCT03732677), first presented at ESMO 2024. The study demonstrated that perioperative durvalumab added to neoadjuvant chemotherapy significantly extended event-free survival (EFS) and overall survival (OS) compared with chemotherapy alone.² At 24 months, the estimated EFS was 67.8% (95% CI, 63.6-71.7) with durvalumab vs 59.8% (95% CI, 55.4-64.0) with chemotherapy alone (HR, 0.68; 95% CI, 0.56-0.82; P < .001). The estimated 24-month OS was 82.2% (95% CI, 78.7-85.2) in the durvalumab group vs 75.2% (95% CI, 71.3-78.8) in the control arm (HR, 0.75; 95% CI, 0.59-0.93; P = .011).

He then turned to new perioperative data presented at ESMO 2025. Christof Vulsteke, MD, reported the first results from the KEYNOTE-905/EV-303 trial (NCT03924895), which showed that perioperative pembrolizumab plus enfortumab vedotin (EV) significantly improved EFS, OS, and pathological complete response (pCR) rates compared with surgery alone.³ Based on these findings, the regimen received FDA approval in November 2025.⁴

Overall, the study met its primary end point, showing that perioperative EV plus pembrolizumab reduced the risk of recurrence, progression, or death by 60% compared with surgery alone. The median EFS was not reached (95% CI, 37.3 to NR) in the EV plus pembrolizumab arm vs 15.7 months (95% CI, 10.3 to 20.5) in the control arm (HR, 0.40; 95% CI, 0.28 to 0.57, one-sided P < .0001). The regimen also reduced the risk of death by 50% compared with surgery alone. The median OS was not reached (95% CI, NR to NR) in the EV plus pembrolizumab group vs 41.7 months (95% CI, 31.9 to NR) in the control group (HR, 0.50; 95% CI, 0.33 to 0.74, one-sided P = .0002). The investigators also reported that 97 patients in the EV plus pembrolizumab group achieved a pCR vs 15 patients in the control group. The pCR rate was 57.1% (95% CI, 49.3 to 64.6) in the EV plus pembrolizumab group vs 8.6% (95% CI, 4.9 to 13.8) in the control group.

Meeks also addressed the evolving role of local therapy, which still centers on radical cystectomy or trimodal therapy. He highlighted results from the HCRN GU16-257 trial (NCT03558087), which evaluated outcomes in patients who achieved a clinical complete response (cCR) after 4 cycles of gemcitabine, cisplatin, and nivolumab. Among 33 patients who achieved a cCR, 32 opted to defer immediate cystectomy. These patients experienced improved metastasis-free survival (P = .007) and overall survival (P = .003). cCR predicted treatment benefit with a positive predictive value of 0.97 (95% CI, 0.91 to 1), although Meeks cautioned against this approach outside of a trial setting at this point in time.

Finally, Meeks discussed the expanding role of circulating tumor DNA (ctDNA) in risk stratification and treatment selection. Trials such as IMvigor011 have shown that ctDNA status can identify which patients are more likely to benefit from adjuvant immunotherapy with atezolizumab.⁵

Overall, Meeks emphasized that MIBC care is entering a new era—one defined by perioperative immunotherapy combinations, bladder-preserving strategies, and biomarker-driven decision-making.

REFERENCES

1. Meeks J. MIBC – What You Should Be Doing Today and What We Will Be Doing Tomorrow. Presented at: 2025 LUGPA Annual Meeting. November 6-8, 2025. Chicago, Illinois

2. Powles T, Catto JWF, Galsky MD. Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med. 2024;391:1773-1786. doi:10.1056/NEJMoa2408154

3. Perioperative (periop) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin-ineligible: The phase III KEYNOTE-905 study. Presented at: 2025 European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA2. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA2.html.pdf

4. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. US Food & Drug Adminstration. November 21, 2025. Accessed November 30, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer?utm_medium=email&utm_source=govdelivery

5. Powles T, Kann AG, Castellano D, et al. IMvigor011: A phase III trial of circulating tumour (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. LBA8