Introduction: Bladder Cancer Across the Continuum

Bladder cancer management in 2026 has been transformed at multiple stages of disease: in non-muscle invasive disease by the arrival of immune checkpoint inhibitors added to BCG; in muscle-invasive disease by the success of perioperative immunotherapy and novel approaches to bladder preservation; and in advanced disease by the remarkable long-term survival data emerging from enfortumab vedotin combinations. ASCO 2026 brought meaningful updates across all three areas, plus early signals for next-generation ADC approaches beyond the current standard.***

Non-Muscle Invasive Bladder Cancer: Durvalumab Plus BCG Approved

Non-muscle invasive bladder cancer (NMIBC) represents approximately seventy-five percent of newly diagnosed urothelial carcinoma cases. Despite responding well to intravesical BCG therapy, twenty to forty percent of high-risk NMIBC patients do not respond to BCG and ultimately require radical cystectomy, a major surgical procedure with significant quality-of-life implications. The goal of preserving the bladder while preventing progression has driven the investigation of immune checkpoint inhibitors added to BCG.

Three large phase 3 trials have now been reported. CREST (sasanlimab plus BCG induction and maintenance versus sasanlimab plus BCG induction versus BCG alone) and POTOMAC (durvalumab plus BCG induction and maintenance versus durvalumab plus BCG induction versus BCG alone) both showed event-free or disease-free survival improvements with hazard ratios of 0.68. Both trials showed that, immunecheckpoint inhibition  without maintenance BCG did not improve outcomes.  The FDA recently approved durvalumab in combination with BCG induction and maintenance therapy for this setting based on the positive results of the POTOMAC trial. The third trial, ALBAN (atezolizumab plus BCG induction and maintenance versus BCG induction and maintenance) did not meet its primary endpoint.

At ASCO 2026, the POTOMAC trial presented its five-year overall survival analysis. No detriment to OS was observed with the addition of durvalumab to BCG; median OS was not reached in either arm, with the durvalumab arm showing a numerical trend toward benefit (HR 0.81, 95% CI 0.54-1.19). Patient-reported outcomes showed no difference between the arms on most measures; urinary frequency was numerically higher with durvalumab plus intravesical BCG, which was expected and manageable.

Clinical bottom line: Durvalumab plus BCG induction and maintenance is the new standard of care for BCG-naive high-risk NMIBC. The five-year OS data are reassuring, and the safety profile adds no new concerns.***

Muscle-Invasive Disease: Novel Perioperative Approaches

Intravesical BCG Plus Perioperative Chemoimmunotherapy

The current perioperative landscape for muscle-invasive bladder cancer (MIBC) has been reshaped by multiple trials. The NIAGARA trial established cisplatin-based chemotherapy plus durvalumab as a perioperative regimen; Keynote-905 brought perioperative enfortumab vedotin plus pembrolizumab for cisplatin-ineligible patients, now FDA-approved with a significant improvement in event-free and overall survival.

A conceptually novel prospective single-arm study presented at ASCO examined whether adding intravesical recombinant BCG (rBCG) to the perioperative chemoimmunotherapy regimen could further enhance the pathological complete response rate. The approach was designed around the rationale that intravesical therapy directly enhances local immune activation in the bladder, potentially synergizing with the systemic checkpoint inhibitor and chemotherapy.

The treatment plan: induction with one dose of atezolizumab and three weekly doses of recombinant BCG; followed by three doses of neoadjuvant triple therapy (atezolizumab plus chemotherapy plus rBCG for the first three doses, then chemotherapy alone for the fourth); radical cystectomy; and a risk-adapted adjuvant algorithm in which only patients with pT2 or higher disease at cystectomy received adjuvant atezolizumab. The primary endpoint was pathological complete response (pT0 or pN0) at cystectomy by central review.

Results: Sixty-eight percent pathological complete response rate. For context, the NIAGARA trial (which did not include intravesical therapy) achieved approximately forty percent pCR. This is a substantial numerical difference, though the comparison is cross-trial and the populations may differ.

Safety was manageable, with no unexpected systemic toxicity and mostly low-grade local adverse events from intravesical administration. This approach of combining intravesical immune stimulation with systemic neoadjuvant chemoimmunotherapy represents a new and potentially important direction. Building on the growing interest in multimodal immunotherapy approaches, a similar strategy is being investigated at FHCC in the investigator-initiated TRIFECTA trial, evaluating intravesical nadofaragene firadenovec in combination with enfortumab vedotin and pembrolizumab for patients with muscle-invasive bladder cancer.

Chemoradiation Plus Durvalumab (RAD-IO Trial)

The RAD-IO trial evaluated adding durvalumab to chemoradiation for bladder-sparing in patients with clinical T2 to T4 MIBC. The study was conducted at UK centers using a 5-FU plus mitomycin chemoradiation backbone, with induction durvalumab before radiation, a dose of durvalumab on week four of radiation, and eleven cycles of adjuvant durvalumab.

Due to COVID and operational considerations, what began as a randomized study ended up as a single-arm experience in fifty-five patients. Using a historical benchmark of sixty percent twelve-month disease-free survival from the BC2001 study (which established the 5-FU plus mitomycin regimen), the RAD-IO team set a target of greater than seventy-five percent twelve-month DFS. The observed twelve-month DFS was eighty percent, with the bladder in place in all patients, meeting the pre-specified threshold.

This is early, single-arm data, and the lack of a concurrent control arm limits interpretation. The UK standard of care does not include complete transurethralresection of the bladder tumor prior to radiation, which differs from US practice and may affect the comparability of results. Two phase 3 randomized trials [ S1806 & Keynote 992  trials] examining similar concepts of adding checkpoint inhibition to chemoradiation in MIBC are ongoing and will provide more definitive answers.***

Quality of Life in Perioperative Enfortumab Vedotin

Health-related quality of life data from the neoadjuvant KEYNOTE-905 trial (enfortumab vedotin plus pembrolizumab for cisplatin-ineligible MIBC) were presented at ASCO. Multiple validated instruments were assessed at several time points before, during, and after surgery.

The key finding: there were no clinically significant differences between the enfortumab vedotin plus pembrolizumab arm and the surgery-alone arm in functional parameters, role function, or symptomatic indices. Both arms showed substantial changes from baseline in sexual, bowel, and urinary symptoms around the time of surgery, and these were comparable between arms. The quality-of-life impact was primarily attributable to radical cystectomy itself, not to the perioperative drug regimen.

This is a meaningful finding for clinical conversations. It reinforces that perioperative enfortumab vedotin plus pembrolizumab does not impose an additional quality-of-life burden on patients above and beyond the surgical procedure.***

Advanced Urothelial Carcinoma: Complete Responders at Three and a Half Years

Enfortumab vedotin plus pembrolizumab is the established preferred standard of care for eligible patients with locally advanced or metastatic urothelial carcinoma. The three-and-a-half-year follow-up from EV-302, presented at ASCO, provides the most mature survival data yet from this regimen.

Overall survival update: Forty-four percent of patients in the enfortumab vedotin plus pembrolizumab arm are alive at three and a half years, compared to twenty-four percent with chemotherapy, a remarkable long-term survival advantage.

Complete response characterization: Thirty percent of patients achieved a complete response with enfortumab vedotin plus pembrolizumab, versus fourteen percent with chemotherapy. Not all complete responses occur at the first assessment; sixty-six percent of patients at first assessment are in partial response, and many of these deepen to complete response on subsequent imaging. Median time to complete response for all patients is 4.3 months; for those who converted from partial to complete response, 6.6 months. Patients with visceral disease and bone metastases take longer to achieve CR than those with lymph node-only disease.

Among patients with a complete response who were alive at three and a half years, the overall survival rate was approximately eighty-three percent, demonstrating that deep responses translate to very durable long-term outcomes.

Toxicity at extended follow-up: Long-term therapy with enfortumab vedotin plus pembrolizumab carries a meaningful toxicity management burden. At one year of treatment, forty percent of patients remain on therapy; at two years, twenty-three percent. Dose interruptions due to treatment-related adverse events affect up to seventy-five percent of patients at one year, and dose reductions approximately seventy percent. Tight clinical management and patient monitoring are essential for maintaining patients on effective therapy.***

Next-Generation ADCs: Beyond Enfortumab Vedotin

For patients who do not respond to enfortumab vedotin, or who develop resistance, the Nectin-4 target is still expressed on the tumor cell surface even after enfortumab vedotin failure; the primary resistance mechanism is payload (MMAE) efflux rather than target loss. This rationale supports the investigation of alternative ADC payloads targeting the same Nectin-4 antigen.

A phase 1 dose-escalation and randomized dose-optimization study evaluated an anti-Nectin-4 ADC with a topoisomerase I inhibitor payload (camptothecin-98, or Cam-98) instead of MMAE, in patients with advanced urothelial carcinoma including a significant proportion pretreated with enfortumab vedotin.

A critical pharmacogenomic discovery during the trial: CYP2D6 activity predicted severe toxicity. Patients with low CYP2D6 metabolizer status could not adequately clear the drug, causing febrile neutropenia and other severe toxicities. The protocol was amended to enroll only patients with high CYP2D6 metabolizer activity in the urothelial carcinoma cohort; in this selected population, the toxicity profile became manageable (alopecia, nausea, fatigue; low-grade neutropenia at seven percent; no febrile neutropenia).

Efficacy in the CYP2D6-selected population: forty-two percent ORR overall; thirty-three percent in the post-enfortumab vedotin population; sixty-seven percent in the enfortumab vedotin-naive population. Patients who had received prior topoisomerase-based therapy did not respond, as expected given payload cross-resistance.

This is early-phase data but it establishes proof of concept for a key principle: Nectin-4 ADCs with alternative payloads can retain activity in patients who have failed enfortumab vedotin, and pharmacogenomic pre-selection by CYP2D6 status can make these agents safe and effective.***

For Patients

If you have high-risk non-muscle invasive bladder cancer that has not yet been treated with BCG, a new approach combining durvalumab with BCG therapy was recently FDA-approved and has shown improved outcomes with no additional harm at five years of follow-up. If you have muscle-invasive bladder cancer, ask your oncologist about perioperative regimens, including options for patients who cannot receive cisplatin-based chemotherapy, and about bladder-sparing approaches that combine chemotherapy, radiation, and immunotherapy. For patients with advanced or metastatic bladder cancer, the combination of enfortumab vedotin plus pembrolizumab continues to show remarkable long-term outcomes, with nearly half of patients alive at three and a half years. If your disease has progressed after this combination, clinical trials exploring new antibody-drug conjugates with different drug payloads are actively enrolling and represent an important next frontier.***

Key Takeaways

  • POTOMAC five-year OS: No detriment to OS with durvalumab plus BCG induction and maintenance in BCG-naive high-risk NMIBC (HR 0.81, both arms median OS not reached); durvalumab plus BCG now FDA-approved.

  • Intravesical rBCG plus perioperative chemoimmunotherapy (single-arm): 68% pCR rate vs ~40% with chemoimmunotherapy without intravesical therapy; phase 3 confirmation needed.

  • RAD-IO (single-arm, UK): Chemoradiation plus durvalumab achieved 80% twelve-month DFS with bladder preservation in all patients; phase 3 trials ongoing.

  • KEYNOTE-905 QoL: No clinically significant QoL differences between EV plus pembro and surgery alone; surgical procedure drives QoL changes, not the perioperative drug regimen.

  • EV-302 three-and-a-half-year update: 44% OS rate with EV plus pembro vs 24% with chemotherapy; 30% CR rate vs 14%; 83% of CR patients alive at 3.5 years; most CRs convert from partial response; median time to CR 4.3 months.

  • Nectin-4 ADC with topoisomerase I payload: 42% ORR overall, 33% post-EV, 67% EV-naive; CYP2D6 pre-selection essential for safety; patients with prior topoisomerase therapy do not respond.***

About the Author

Rosa M. Nadal Rios, MD, PhD, is an Associate Professor at the University of Washington School of Medicine and Fred Hutchinson Cancer Center in Seattle. Her clinical practice encompasses the full spectrum of bladder cancer, and her research includes perioperative management of muscle-invasive disease, bladder preservation strategies, and novel therapeutic approaches in advanced urothelial carcinoma.***

References

  1. Loriot Y, et al. POTOMAC five-year OS analysis: durvalumab plus BCG in BCG-naive high-risk NMIBC. ASCO 2026.

  2. Powles T, et al. KEYNOTE-905: enfortumab vedotin plus pembrolizumab in cisplatin-ineligible MIBC. ASCO 2025; QoL update ASCO 2026.

  3. Galsky M, et al. Intravesical rBCG plus perioperative chemoimmunotherapy in MIBC. ASCO 2026.

  4. RADIO trial update: durvalumab plus chemoradiation in MIBC. ASCO 2026.

  5. Powles T, et al. EV-302: enfortumab vedotin plus pembrolizumab in advanced urothelial carcinoma, three-and-a-half-year update. ASCO 2026.

  6. Rosenberg JE, et al. Nectin-4 ADC with alternative payload in post-EV urothelial carcinoma. ASCO 2026.

  7. Nadal Rios RM. "Best of Oncology 2026, Seattle: Bladder Cancer." Presented at the 2026 Best of Oncology, Seattle, WA, June 2026.