Treating MIBC as a systemic disease reshapes bladder preservation

Systemic therapy now anchors MIBC care and expands bladder preservation options, according to Joshua J. Meeks, MD, PhD. 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.

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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