Treating MIBC as a systemic disease reshapes bladder preservation

Bladder preservation is now a realistic option for many patients with muscle-invasive bladder cancer (MIBC) as systemic therapy improves, according to Joshua J. Meeks, MD, PhD.¹ Meeks, the Edward M. Schaeffer, MD, PhD Professor of Urology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois, presented “Redefining Organ Preservation in MIBC: Modern Bladder Preservation Strategies” at the 2026 LUGPA Annual Meeting.¹ As a surgeon, he argued radical cystectomy has a role in MIBC but represents one option, not the standard of care, for most patients.¹

“The big change…in 2026 is really thinking about muscle-invasive bladder cancer as a systemic problem,” Meeks said.¹ He suggested urology is following a path breast oncology took decades earlier, when the field moved from maximal surgery toward systemic treatment.¹

Lessons from breast cancer and the cystectomy-alone era in MIBC

Meeks described radical cystectomy as Halstedian, after William Halsted, who viewed locally advanced breast cancer as a regional disease and developed radical mastectomy on the premise more extensive surgery offered a greater chance of cure.¹ Fisher and colleagues challenged this view, finding all breast cancer at risk for progression, with 40% of clinically node-negative patients found to be pathologically node positive.² Among women with negative nodes, surgical approach affected local or regional recurrence (P = .002) but not distant recurrence (P = .61).²

Among women with positive nodes, neither distant recurrence (P = .44) nor local or regional recurrence (P = .67) differed by surgical approach.² Once metastatic recurrence occurred, local treatment made little difference, and Meeks argued MIBC follows the same pattern.¹

He cited a landmark University of Southern California series of 1054 patients treated with radical cystectomy between 1971 and 1997, in which only 49 patients (5%) received perioperative chemotherapy.³ Overall survival was 66% at 5 years and 43% at 10 years, and 30% of patients developed recurrence, 75% of them distant.³ Recurrence-free survival at 5 and 10 years was 85% and 82% for organ-confined disease, 58% and 47% for extravesical disease, and 35% and 31% for lymph node–positive disease (P < .001).³

ctDNA reveals MIBC as a systemic problem

Meeks described circulating tumor DNA (ctDNA) as a better staging tool, calling it a major improvement over prior approaches.¹ In data presented by Ghatalia et al at the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, baseline ctDNA positivity was associated with significantly worse metastasis-free survival (HR, 12.62; 95% CI, 3.74-42.57; P < .0001).⁴ Where patients started mattered most, despite intensive treatment, Meeks said.¹

In data presented by Powles et al at the 2025 ASCO Annual Meeting from NIAGARA (NCT03732677), a trial of perioperative chemoimmunotherapy, 89 patients (22%) were ctDNA positive before radical cystectomy.⁵ Only 3% of these ctDNA-positive patients achieved a pathologic complete response (pCR), and ctDNA positivity was highly correlated with residual disease.⁵

Meeks also revisited a historic phase 3 trial by Grossman et al of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) before cystectomy.⁶ Patients reaching pT0 after M-VAC and cystectomy had a median survival not reached, compared with 2.4 years for patients with residual disease after cystectomy alone.⁶ Patients reaching pT0 did well regardless of treatment arm, highlighting the value of achieving a complete response, he said.⁶

Enfortumab vedotin plus pembrolizumab doubles pathologic complete response in MIBC

Even before modern regimens, some patients with a clinical complete response to neoadjuvant chemotherapy who declined cystectomy did well, Meeks noted.¹ In a series from Columbia University published by Robins et al in 2018, these patients had a 5-year disease-free survival of 60% and a 5-year cancer-specific survival of 90%.⁷

Enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) has since changed the MIBC landscape, according to Meeks.¹ In the KEYNOTE-905/EV-303 trial (NCT03924895) of 344 cisplatin-ineligible patients, perioperative enfortumab vedotin plus pembrolizumab achieved a pCR rate of 57.1% vs 8.6% with no systemic therapy (event-free survival [EFS] HR, 0.40; overall survival [OS] HR, 0.50).⁸ EFS was 77.8% vs 55.1% at 12 months and 74.7% vs 39.4% at 24 months.⁸

In KEYNOTE-B15/EV-304 (NCT04700124), enrolling 808 cisplatin-eligible patients, enfortumab vedotin plus pembrolizumab achieved a pCR in 226 of 405 patients (55.8%; 95% CI, 50.8-60.7) vs 131 of 403 (32.5%; 95% CI, 28.0-37.3) with cisplatin plus gemcitabine.⁹ The estimated difference was 23.4% (95% CI, 16.7-29.8; 1-sided P < .0001), with an EFS HR of 0.53 and an OS HR of 0.65.⁴ EFS was 86.0% vs 75.4% at 12 months and 79.4% vs 66.2% at 24 months.⁹

With chemotherapy alone, about 1 in 3 patients achieved a complete response, whereas urologists can now tell patients roughly 3 in 5 will, Meeks said.⁹

“The drugs are better, our chances of getting rid of the cancer are better, so our approach can change,” he said.¹

Trimodal therapy and the SWOG/NRG S1806 trial in MIBC

Meeks described a patient, a chef, who told him a stoma would prevent him from working around food, prompting a bladder preservation discussion.¹ Before S1806, bladder-sparing approaches were largely reserved for patients with poor functional status, those refusing cystectomy, those unable to tolerate neoadjuvant chemotherapy, and those with advanced cancer.¹

INTACT (SWOG/NRG S1806) is a phase 3 trial randomly assigning 475 patients with cT2-T4N0M0 MIBC 1:1 to concurrent chemoradiation with or without 9 doses of atezolizumab (Tecentriq).¹ The primary end point is bladder-intact event-free survival, defined as muscle-invasive recurrence in the bladder, regional pelvic soft tissue or nodal recurrence, distant metastases, radical cystectomy, or death from any cause.¹ Secondary end points include 5-year OS, clinical response at 5 months, disease-specific and metastasis-free survival, non-muscle-invasive recurrence rate, cystectomy rate, and global quality of life.¹

According to Meeks, the trial helped standardize delivery of bladder preservation and built confidence among community urologists in trimodal therapy as a viable option.¹ He said he looks forward to the final results.¹

A ctDNA- and response-guided algorithm for bladder preservation in MIBC

Meeks outlined his current approach for patients with cT2-cT4b MIBC, node negative or positive.¹ He tells patients the bladder is not the first priority and refers them to medical oncology for 3 or 4 cycles of enfortumab vedotin plus pembrolizumab, with biomarker assessment using PET-CT and ctDNA.¹ Response is then assessed with blue light cystoscopy, transurethral resection of bladder tumor, and mapping biopsies.¹

For patients with a cT0, ctDNA-negative response, observation is reasonable, with continued enfortumab vedotin plus pembrolizumab as tolerated.¹ Patients with cT1, ctDNA-negative disease can be considered for trimodal therapy followed by pembrolizumab.¹ For patients with persistent cT2 or greater disease or ctDNA positivity, Meeks recommends radical cystectomy followed by ctDNA monitoring and observation, describing surgery in this setting as maximal therapy for a tumor resistant to the best available treatment.¹

Meeks identified the best candidates for radical cystectomy in 2026 as patients who want a definitive pathologic response, wish to avoid repeat resection and cystoscopy, or want to stop systemic therapy.¹ Other candidates include patients unable to receive radiation or further systemic therapy, those with sarcomatoid variant histology or prostatic urethral involvement, and those with node-positive disease downstaged to node-negative, bladder-only cancer.¹ A nonfunctional bladder also favors cystectomy, he said.¹

For practicing urologists, Meeks emphasized systemic therapy as critical for all patients with MIBC, noting enfortumab vedotin plus pembrolizumab benefits patients regardless of cisplatin eligibility.¹ Biomarkers can reduce the risk of inaccurate staging, and patient choice should drive selection among multiple bladder preservation options.¹ Ongoing trials will further refine patient selection, he said.¹

REFERENCES

1. Meeks JJ. Redefining organ preservation in MIBC: modern bladder preservation strategies. Presented at: 2026 LUGPA Annual Meeting; November 5-7, 2026, Chicago, Illinois.

2. Fisher B, Jeong J-H, Anderson S, Bryant J, Fisher ER, Wolmark N. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med. 2002;347(8):567-575. doi:10.1056/NEJMoa020128

3. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol. 2001;19(3):666-675. doi:10.1200/JCO.2001.19.3.666

4. Ghatalia P, Ross, EA, Zibelman MR, et al. Circulating tumor DNA (ctDNA) to guide response-adapted bladder preservation in muscle invasive bladder cancer (MIBC): integrated analysis of the RETAIN trials. J Clin Oncol. 2026;44(suppl 7):LBA632. doi:10.1200/JCO.2026.44.7_suppl.LBA632

5. Powles T, Van der Heijden M, Wang Y, et al. Circulating tumor DNA (ctDNA) in patients with muscle-invasive bladder cancer (MIBC) who received perioperative durvalumab (D) in NIAGARA. J Clin Oncol. 2025;43(suppl 17):4503. doi:10.1200/JCO.2025.43.16_suppl.4503

6. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859-866. doi:10.1056/NEJMoa022148

7. Robins D, Matulay J, Lipsky M, et al. Outcomes following clinical complete response to neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma of the bladder in patients refusing radical cystectomy. Urology. 2018;111:116-121. doi:10.1016/j.urology.2017.09.003

8. 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. doi:10.1056/NEJMoa2511674

9. Galsky MD, Valderrama BP, Maruzzo M, et al. Enfortumab vedotin and pembrolizumab in cisplatin-eligible bladder cancer. N Engl J Med. 2026;395(4):338-348. doi:10.1056/NEJMoa2601486