Evaluating Bladder-Sparing Strategies and Key GU Data From ASCO 2026

Genitourinary (GU) cancer research continues to evolve quickly, with new data on antibody-drug conjugates (ADCs), immunotherapy combinations, and bladder-sparing strategies presented across the treatment continuum at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.

CancerNetwork® spoke with Eric Miller, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai and a genitourinary medical oncologist, about the GU cancer abstracts that stood out to him at the meeting, the evolving role of bladder-sparing strategies in muscle-invasive bladder cancer (MIBC), and where the field may be headed next.

Miller began by walking through several abstracts that stood out to him across the stages of urothelial cancer treatment, from localized disease to the later-line metastatic setting. He then discussed how selective bladder-sparing strategies, including those built around enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda), may shift the surgical standard of care for MIBC, and outlined the communication touchpoints between medical oncology, urology, and radiation oncology that he sees as most critical when a patient is being considered for cystectomy omission. Miller also discussed the threshold he currently uses to confidently pivot a patient from neoadjuvant systemic therapy to a bladder-sparing approach, addressed where he sees the next major milestone in GU oncology beyond current checkpoint inhibitor and ADC combinations, and closed by reflecting on the pace of progress in the field.

CancerNetwork: What were some of the key abstracts in genitourinary cancer at the 2026 ASCO Annual Meeting, and were there any that stood out or surprised you?

Miller: I thought this was a big year for genitourinary cancers, and for bladder cancer in particular, with significant presentations across nearly every stage of treatment.

I would start with a presentation by Nicholas D. James, PhD, FRCP, MBBS and colleagues on the combination of chemotherapy with immunotherapy in localized disease [the RAD-IO trial of durvalumab (Imfinzi) plus chemoradiotherapy (NCT43698103)], which showed a 79% one-year disease-free survival [DFS] rate.¹ That is significant because it incorporates immunotherapy into our chemoradiation protocols, which is itself a bladder-sparing strategy.

Dingwei Ye, MD, PhD, also had a [presented a good phase 2] study [NCT06879145] using a Nectin-4–directed antibody-drug conjugate with a topoisomerase I payload [SHR-A2102] plus immunotherapy [adebrelimab] in localized disease, which showed an objective response rate [ORR] of 71% and a pathologic complete response [pCR] rate of 48%.² Those are excellent numbers. They are not directly comparable, of course, but they are on par with currently available agents, and using a topoisomerase payload instead of the microtubule inhibitor payload used in the currently approved enfortumab vedotin is important for patients who might have pre-existing neuropathy and who might benefit from a different mechanism of action.

Moving further into the metastatic setting, Thomas Powles, MBBS, MRCP, MD, presented the 43-month follow-up from the pivotal phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) which showed an improvement in the [CR] rate to 45% compared with the 29% originally presented.³ That is a very impressive finding for a trial that had already changed everything in urothelial cancer. Among patients who achieved a [CR], the 42-month overall survival [OS] rate was between 82% and 84%, which is also very impressive. The follow-up also provided an important data point: for patients who received subsequent platinum chemotherapy after enfortumab vedotin and pembrolizumab, the [ORR] was 21%. That has become the standard second-line therapy, but this prospectively gives us data on what outcomes we might expect further into the metastatic setting.

I thought Gopa Iyer, MD, also presented an important study, the [phase 1] NEXUS-01 trial [NCT06465069] of another Nectin-4–directed ADC with a topoisomerase payload [LY4052031].⁴ It showed that even in patients who had already received enfortumab vedotin, which also targets Nectin-4, there was still a 40% ORR and an 80% disease control rate. You cannot directly compare these, but those numbers numerically exceed the response rates seen with platinum chemotherapy after enfortumab vedotin and pembrolizumab in the EV-302 study, in a way that is not statistically comparable. It is an important signal that it may be possible to target Nectin-4 in multiple different ways, which is something we are still learning.

Finally, in terms of trials in progress, Matthew D. Galsky, MD, presented [data from] TROPION-Urothelial03 [NCT07129993], a trial in progress of datopotamab deruxtecan-dlnk [Datroway; dato-DXd], the next-generation Trop-2–directed antibody-drug conjugate that builds on prior data from sacituzumab govitecan-hziy [Trodelvy].⁵ Datopotamab deruxtecan is given in combination with platinum-based chemotherapy in the trial's experimental arm, and the study looks to improve upon the current standard second-line treatment of gemcitabine plus platinum-based chemotherapy, the comparator arm, by incorporating this highly active Trop-2–targeting agent.

Across the disease states for urothelial cancer, we saw a lot of good data on further treatment modalities.

How do you view the evolution of selective bladder-sparing strategies, particularly those utilizing enfortumab vedotin or pembrolizumab, in terms of their potential to shift the surgical standard of care for muscle-invasive bladder cancer beyond the clinical trial setting?

This is definitely a huge area of research right now. There are 2 ways to define bladder sparing: systemic therapy combined with radiation therapy, such as the [RAD-IO trial] I discussed, which improves upon outcomes from chemoradiotherapy alone and is certainly an important bladder-sparing strategy; and systemic therapy alone, which is being talked about more as a bladder-sparing strategy in its own right.

Our institution has conducted 2 prior trials, plus 1 in progress, that have all been presented: gemcitabine, cisplatin, and nivolumab [Opdivo] in a bladder-sparing protocol; pembrolizumab in a bladder-sparing protocol; and now enfortumab vedotin and pembrolizumab in a bladder-sparing protocol. If we can prove in a prospective fashion that these approaches lead to good outcomes, they could lead to a world where bladder-sparing strategies become much more common, and it does not have to be one approach or the other.

They could be used in sequence: for patients who have persistent or recurrent disease after a systemic-therapy-alone bladder-sparing approach, a chemoradiotherapy-based strategy could potentially be incorporated afterward. That is still being studied, but based on the data we already have from the chemoradiotherapy-plus-immunotherapy trial and the prior bladder-sparing trials done at Mount Sinai with gemcitabine/cisplatin/nivolumab or pembrolizumab, I am optimistic that we will keep seeing more promising data on this.

What are the most critical communication touchpoints between the medical oncologist, the urologic surgeon, and the radiation oncologist to ensure patient safety when the decision is made to omit cystectomy in response-guided bladder-sparing protocols?

Perhaps the no. 1 point I would make is that the decision to omit cystectomy in a bladder-sparing protocol, at least in the trials we have done, is based on a stringently defined clinical [CR]. That is not just 1 good image suggesting things look well; it means a variety of assessments, including MRI imaging, cystoscopy, urine cytology, and transurethral resection of bladder tumor [TURBT] with biopsies of either viable tumor or other areas of the bladder. By definition, that requires close collaboration with urologists, which is a major reason this coordination is so important: defining a [CR] requires working with urology.

Beyond that, sometimes there is not a clinical [CR], and there is persistent or recurrent disease. If that happens, it is important that next-line therapy is promptly initiated, and if the disease is limited to the bladder, that often means working with urology or radiation oncology to treat with either cystectomy or radiation. Finally, managing toxicity from any of the possible treatments for urothelial cancer is often a team effort, whether it relates to a cystectomy or to prior radiation, so it is important for all providers to work together to treat the patient.

As the field moves toward integrating circulating tumor DNA [ctDNA] or other molecular signatures into treatment paradigms for urothelial carcinoma, what threshold do you currently look for in the clinical setting to confidently pivot a patient from neoadjuvant systemic therapy to a bladder-sparing approach?

What I tell patients about this is that it is still evolving. As I mentioned, the way we define a clinical [CR] is stringently defined: MRI imaging, urine cytology, cystoscopy, and TURBT with biopsy, along with negative ctDNA testing. If all of that is negative, I would still counsel patients that we are investigating this strategy, but a bladder-sparing approach could be discussed after a risk-benefit discussion with the patient.

I will take a step back and say that the most important thing in all of this is a patient's values. Each of these data points, when favorable, increases the odds that the disease may not persist or recur, but odds are not everything; a patient's values are ultimately what matter most. If a patient says they are willing to take an increased risk of persistent or recurrent disease that may require further treatment, or that may even be potentially dangerous, in order to avoid the toxicity that comes with a cystectomy or radiation, then it is worth discussing a bladder-sparing approach. Ultimately, the best thing we can do as oncologists, or as a field of medicine, is to provide patients with all of the available data regarding their care and all of the evidence that has been collectively generated on this management, so we can jointly arrive at the plan that is best for them.

Considering the research landscape presented at ASCO 2026, where do you see the next major milestone for GU oncology, beyond current checkpoint inhibition or ADC combinations, to significantly improve durable complete response rates in these high-risk populations?

I am excited to see data on the next generation of ADCs and immunotherapy agents. Some of those include [the phase 2/3 Duravelo-
2 study (NCT06225596) evaluating] the Bicycle Drug Conjugate targeting Nectin-4, zelenectide pevedotin [BT8009], presented by Yohann Loriot, MD, PhD, which showed good data.⁶ The bicycle format of an [ADC] is meant to maximize the ability of drugs in development to target the cancer while limiting toxicity.

The definition of a cure for cancer is hard to pin down and requires long-term follow-up, but when we see the tail on Kaplan-Meier curves in immunotherapy trials, we see very durable responses. The next generation of immunotherapy agents, and hopefully the durable responses that will come with them, are also exciting. Those are the 2 directions I see us moving in: [ADCs] and immunotherapy. We still have so much further to go, and that is not even to mention all of the other agents under investigation, like radiopharmaceuticals, which can be paired with specific types of PET scans unique to urothelial cancer, with the expression seen on the PET scan helping to target the radiopharmaceutical treatment. There are a lot of different directions in which the field can advance in the coming years.

Is there anything else you would like to highlight that we were not able to touch upon?

We talked about a lot of promising drugs across a lot of different settings in urothelial cancer, from localized disease to the metastatic and later-line settings. These agents keep coming out and keep improving, and it is exciting to see how they can be incorporated as we work with our colleagues in radiation oncology and urology to provide the best possible outcomes for patients.

From seeing all of the data presented at ASCO, I am hopeful that we will see just as much improvement in clinical outcomes over the next 10 years as we have over the last 10. Immunotherapy and ADCs have been around for about 10 years now, and they have changed everything. I am excited to see what is next.

References

1. James ND, van de Wiel J, De Santis M, et al. Feasibility and safety results from RAD-IO: a multi-stage trial of durvalumab with chemoradiotherapy with 5-fluorouracil and mitomycin C in patients with muscle-invasive bladder cancer. J Clin Oncol. 2026;44(suppl 16):Abstract 4504.
2. Ye D, Lu X, Shen Y, et al. Perioperative SHR-A2102, a novel nectin-4–targeted antibody-drug conjugate, in combination with adebrelimab for patients with muscle-invasive bladder cancer: results from a phase 2/3 study. J Clin Oncol. 2026;44(suppl 16):Abstract 4506.
3. Powles T, Van Der Heijden MS, Bedke J, et al. Enfortumab vedotin plus pembrolizumab vs chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma: 3.5-year follow-up and response analyses from the phase 3 EV-302 study. J Clin Oncol. 2026;44(suppl 16):Abstract 4507.
4. Iyer G, Gao X, Wei AZ, et al. Initial results from NEXUS-01, a phase 1 study of LY4052031, an antibody-drug conjugate targeting Nectin-4, in participants with advanced or metastatic urothelial carcinoma. J Clin Oncol. 2026;44(suppl 16):Abstract 4508.
5. Galsky MD, Drakaki A, Basu A, et al. TROPION-Urothelial03: a phase 2/3 study of datopotamab deruxtecan (Dato-DXd) + platinum chemotherapy vs gemcitabine + platinum chemotherapy in participants with locally advanced or metastatic urothelial carcinoma with progression on or after enfortumab vedotin + pembrolizumab. J Clin Oncol. 2026;44(suppl 16):Abstract TPS4642.
6. Loriot Y, Reyes-Cosmelli F, Cutuli HJ, et al. Interim analysis results from Duravelo-2: zelenectide pevedotin (BT8009) + pembrolizumab in patients with previously untreated locally advanced/metastatic urothelial carcinoma. J Clin Oncol. 2026;44(suppl 16):Abstract 4516.