Interpreting Bladder Cancer Abstracts at GU ASCO 2026 for Real-World Practice

The ASCO Genitourinary Cancers Symposium took place from February 26-28, 2026, with breakthroughs in prostate, kidney, and bladder cancer presented. As a genitourinary oncologist specializing in bladder cancer research, here is my opinion on the most important developments in urothelial cancer presented at the meeting:

A New Standard of Care for Muscle-Invasive Bladder Cancer

The combination of enfortumab vedotin and pembrolizumab (EVP) has previously shown efficacy in the locally advanced/metastatic setting and as perioperative therapy for patients with cisplatin-ineligible muscle-invasive bladder cancer who undergo cystectomy. Results from the phase III KEYNOTE-B15/EV-304 study were presented by Dr. Matt Galsky at this meeting. In this trial patients were randomized to either perioperative EVP with 4 cycles prior to cystectomy and 5 cycles following cystectomy or 4 cycles of neoadjuvant cisplatin and gemcitabine followed by cystectomy. The trial met its primary endpoint of improved median event-free survival (EFS), with hazard ratio of 0.53 (95% confidence interval (CI) 0.41-0.70; p < 0.001). On the EVP arm 1-year EFS was 86.0% and 2-year EFS was 79.4%. At the time of analysis, overall survival benefit was also seen with EVP, with hazard ratio 0.65 (95% CI 0.48-0.89); p = 0.0029). Pathologic complete response rate with EVP was 55.8%, compared to 32.5% in the control group.

Based on these results, there was clear superiority of EVP over cisplatin-based therapy, which had been the standard of care for decades. EVP will be the mainstay of perioperative systemic therapy for all patients with muscle-invasive bladder cancer.

With this shift in management of muscle-invasive bladder cancer, many questions remain. The EVP arms on the EV-303 and EV-304 clinical trials had slightly different treatment schedules, with 9 cycles total in both studies but 3 preoperative cycles in EV-303 and 4 preoperative cycles in EV-304. Given similar pathologic complete response rates with EVP in both studies, I suspect that many providers will give 3 preoperative cycles, thereby reaching cystectomy sooner. Furthermore, the contribution of the postoperative cycles is unclear, and further studies will be necessary to determine which patients could omit these cycles to potentially reduce toxicity. Finally, the efficacy of perioperative EVP in patients with upper tract urothelial carcinoma and in patients with majority subtype histology remains to be determined.

The Future of Bladder Preservation in Muscle-Invasive Bladder Cancer and Biomarkers

With pathologic complete response rates greater than 50 percent in the EV-303 and EV-304 studies, interest in bladder preservation strategies has been increasing. The RETAIN-2 phase II clinical trial was presented by Dr. Pooja Ghatalia at the meeting. In this trial, patients with were treated with 3 cycles of dose dense MVAC plus nivolumab followed by repeat TURBT, cross-sectional imaging, and urine cytology. Patients with clinical complete response and alterations in ATM, RB1, or ERCC2 went on active surveillance, whereas the remainder of patients received further treatment. Among 71 patients in intention-to-treat analysis, 22 underwent active surveillance and 48 received an intervention, which was cystectomy in most cases. The trial met its primary endpoint with 70% 2-year metastasis-free survival. Among patients on the active surveillance arm, 64% remained recurrence-free and 82% were metastasis-free.

In this study, circulating tumor DNA (ctDNA) was collected at baseline and following neoadjuvant therapy. CtDNA at both timepoints was strongly prognostic, with patients who exhibited positive ctDNA had inferior metastasis-free survival. CtDNA collected post-neoadjuvant chemotherapy had strong positive predictive value (90%) but weak negative predictive value (32.4%) for predicting pathologic complete response (ypT0 staging) following systemic therapy in patients who ultimately received cystectomy. This finding highlights caveats of using negative ctDNA to define absence of disease.

Urinary tumor DNA may further enhance ctDNA. An exploratory analysis of the phase 3 NIAGARA study of perioperative gemcitabine, cisplatin, and durvalumab was presented by Dr. Michiel van der Heijden. This analysis evaluated plasma ctDNA and urinary tumor DNA (utDNA) collected at baseline and prior to radical cystectomy. Patients who cleared urinary tumor DNA were more likely to have improved event-free survival, and pre-cystectomy utDNA status was strongly associated with pathologic complete response. Moreover, patients with both negative ctDNA and negative utDNA had statistically superior event-free survival compared to patients who were either ctDNA negative and utDNA positive (HR 0.46, 95% CI 0.23-0.89) or ctDNA positive and utDNA negative. Prospective studies will be necessary to validate the utility of utDNA and ctDNA for predicting the presence of minimal residual disease, but these tests will likely be included in future studies and may have a role in determining patients suitable for bladder preservation.

Novel Therapeutic Approaches in Metastatic Disease

While EVP is the preferred frontline systemic therapy for metastatic urothelial cancer, the KEYMAKER-U04 Substudy 04B presented by Dr. Avivit Peer evaluated novel combinations to potentially improve outcomes in this setting. This phase I/II study consisted of 3 arms – EVP, enfortumab vedotin with coformulated favezelimab (anti-LAG3) and pembrolizumab (EV + fave/pembro), and enfortumab vedotin with coforumulated vibostolimab (anti-TIGIT) and pembrolizumab (EV + vibo/pemro). When compared with EVP, objective response rate was similar between the three arms, with the highest being 68% in EV+fave/pembro, although not statistically superior to 64% with EVP. Median duration of response was similar between the three arms as well. Therefore, addition of anti-LAG-3 or anti-TIGIT did not improve efficacy of EVP.

Another novel antibody drug conjugate, disitimab vedotin, targets HER2 with the same payload as EVP. Results from the RC48G001 phase II clinical trial were presented by Dr. Thomas Powles. All patients enrolled had advanced disease refractory to platinum-based therapy either HER2-positive tissue, defined as 3+ by immunohistochemistry (IHC) or IHC2+ with positive in-situ hybridization (ISH), or HER2-low tissue, defined as IHC 1+ or IHC 2+ with negative ISH. Both patients with HER2-positive and HER2-low disease demonstrated efficacy, with objective response rates of 54.9% and 52.6% and complete response rates of 16.9 % and 18.4%, respectively. 1-year overall survival was 65.8% and 57.7%, respectively, indicating promise of this drug in advanced disease. Common treatment related adverse events included fatigue and peripheral sensory neuropathy. Disitimab vedotin is currently being evaluated as frontline treatment for advanced urothelial cancer and appears to be a potentially attractive therapy due to biomarker selection of patients. Given the pervasiveness of enfortumab vedotin in management of metastatic disease and now muscle invasive bladder cancer, the ability to rechallenge with an antibody drug conjugate with the same payload but different target remains an open question and could affect the adoption of disitimab vedotin.

Conclusions

The 2026 ASCO GU symposium was highlighted by a shift in treatment for muscle-invasive bladder cancer, with EVP demonstrating superiority to neoadjuvant cisplatin-based therapy. With far improved pathologic response rates, bladder preservation will be attractive. Nonetheless, questions remain, especially in how to determine the patients who can undergo surveillance and the utility of ctDNA and utDNA for those decisions. With EVP moving into earlier disease settings, there is a need for novel therapies, whether immunotherapy, antibody-drug conjugates, or other modalities to manage advanced disease.

About the Author

Jason Brown, MD, Phd

Jason Brown is a genitourinary oncologist practicing at the Seidman Cancer Center at University Hospitals Cleveland with appointment as an assistant professor at Case Western Reserve University. He completed an MD and PhD at Yale University, where he studied tumor-infiltrating lymphocytes as predictive biomarkers in breast cancer. He then completed his internal medicine residency and hematology/oncology fellowship at the University of Michigan. His research interests include early-stage clinical trials and application of novel biomarkers in urothelial cancer.