Precision escalation may define the future of high-risk NMIBC care

As clinicians explore ways to improve outcomes in high-risk non–muscle-invasive bladder cancer (NMIBC), several pivotal phase 3 trials of BCG plus immune checkpoint inhibitors (ICIs) have begun to clarify both the promise and the limitations of treatment intensification in this setting. Over the past year, data from the ALBAN (NCT03799835), CREST (NCT04165317), and POTOMAC (NCT03528694) studies have collectively reshaped discussions around the future of frontline therapy for BCG-naive disease, with some studies showing improvements in event- and disease-free survival with combination strategies while also underscoring the continued strength of BCG alone. At the same time, these studies have raised important questions regarding toxicity, patient selection, cost-effectiveness, and the risk of overtreatment in a biologically heterogeneous patient population.

In the following interview, Maria Carmen Mir, MD, PhD, of Mount Sinai Icahn School of Medicine, discusses how clinicians should interpret the evolving data surrounding BCG/checkpoint inhibitor combinations and why she believes the field is moving toward a more precision-based approach to escalation rather than universal intensification.¹

Urology Times: What were the key findings from recent trials of BCG/ICI combinations?

Mir: A lot has happened in the past year. The message is mixed—not uniformly practice-changing. There were 3 trials that came out, [with] a total of 2500 patients across these trials. Just briefly, ALBAN evaluated the addition of atezolizumab [Tecentriq] to BCG in the high-risk non–muscle-invasive population. It did not improve event-free survival vs BCG [HR, 0.98]. Toxicity was [approximately] 40% for grade 3 [or higher] complications. Overall, 40% of the patients included [had T1 disease], so it was a little bit of a lower risk [population].²

Then we had 2 more trials that were positive, CREST and POTOMAC. CREST [looked at] the addition of sasanlimab to BCG induction, or standard of care, and maintenance. It significantly improved event-free survival vs BCG [HR, 0.68], and it reported an approximately 7% [numerical] improvement in events [82.1% vs 74.8%]. [This was] particularly relevant in the high-risk population that represented around 60% of the group [HR, 0.63]. [Overall, 42.6%] of patients had [any-grade immune-related] adverse effects.³

The last trial is POTOMAC, which [assessed] the addition of durvalumab [Imfinzi] to BCG. The combination improved [disease]-free survival [HR, 0.68]. Approximately [21%] of patients [in the combination arm] had grade 3/4 [treatment-related] events, and 60% had T1, so it was a more high-risk population. Overall, the field has moved from giving BCG alone, which is what we had done for everyone, to thinking about intensification.⁴

Urology Times: Across these trials, one key takeaway was that adequately delivered BCG still demonstrated strong efficacy. How should these data shape the way that clinicians are thinking about BCG as a benchmark therapy in this setting? What level of evidence would be needed to change that standard of care?

Mir: BCG remains a benchmark therapy. With these trials, we have shown that modern BCG with appropriate induction and maintenance performs very well. Any new treatment would need to optimize those results. What I would need to change the field would be a clear improvement in end points like [progression-free survival], cystectomy-free survival, bladder-intact survival, and, of course, overall survival. That would be one of the things. The second would be to have an acceptable immune-related toxicity rate. These are patients with non–muscle-invasive [disease], which is potentially curable in most cases. Some of them may never progress, so we want to have a fair rate of events. The third one would be to be able to identify who benefits. Treating all [patients with] high-risk, non–muscle-invasive [disease] with systemic therapy would be overtreating patients.

Overall, BCG is not a weak comparator. It is very good. If we compare [these trials] with recent trials on BCG that we have—like the NIMBUS trial, which was a European trial that came out 4 or 5 years ago—the rates are very similar. We saw an 80% recurrence-free rate at 24 months. That's the same that happened in all the trials we're talking about. So BCG remains a strong standard of care, and intensifying will depend on a lot of things.

Urology Times: Your editorial¹ emphasized the biological heterogeneity of high-risk NMIBC and the risk of overtreatment. What role do you believe biomarkers will play in this setting moving forward? Are there any tools that are most promising for identifying the subgroup that truly needs treatment intensification?

Mir: As you mentioned, high-risk, non–muscle-invasive [disease] is very heterogeneous. It's a big pool of patients. It's not the same to have a patient who recurs from multifocal high-grade T1 with CIS [carcinoma in situ] vs having a single solitary high-grade Ta. This is all high risk, but we know it’s not the same type of high risk. There are a lot of promising tools. AI [artificial intelligence] pathology is an example. There is a platform called CHAI that stratifies high-risk, non–muscle-invasive disease as high [or] low. It might be able to tell us which patient would benefit from intensification. Another tool that we have out is MRI. Imaging upfront has the potential to help us better stratify patients overall, to make sure that they have muscle-invasive or non–muscle-invasive disease. This is ongoing. Bladder MRI still has a long way to go, because there are some issues with the technicalities [and] the protocols, and there is a learning curve for radiologists to learn how to deploy the results. But there is some potential with that. There are also other biomarkers. PD-L1 did not show a clear benefit in these trials, but other markers—for example, urine DNA or ctDNA [circulating tumor DNA]—that might play a role. These need to be prospectively validated, but we will probably have an add-on of tools that will help us risk-stratify much better. The key at the end is not only identifying high-risk [disease], but identifying [the tumors] that are biologically aggressive and [may need] intensification.

Urology Times: If checkpoint inhibitors ultimately gain a larger role in earlier-stage NMIBC, how do you envision multidisciplinary care evolving between urologists and medical oncologists, particularly around managing immune-related adverse events?

Mir: If checkpoint inhibitors move earlier in non–muscle-invasive bladder cancer, that will make [care] more multidisciplinary. Urologists, from my point of view, will always be central, because the TURBTs [transurethral resection of a bladder tumor], the staging, the intravesical delivery of the drugs, the cystoscopy surveillance—everything comes on the urology side. However, I think we need to learn from each other. It's not that medical oncologists should replace urology; it is about working together. We already have an example in urology about this. We have had an intensification in prostate cancer. It is on the metastatic side, not early disease. Still, we have had, over the last 10 years, urologists who were doing ADT [androgen deprivation therapy] for many years on our own, and then new drugs came in the field, and we intensified. We've been able to work together with the medical oncologists regarding the [adverse] effects of these drugs and how they should be applied. It should work the same way if intensification comes to non–muscle-invasive bladder cancer; we have to work together.

Urology Times: Cost-effectiveness is another major concern. How should clinicians and health systems approach potential integration of these therapies with the economic aspect in mind?

Mir: Economics is a major issue. BCG is very cheap. It is inexpensive but hard to [acquire] sometimes. But still, the checkpoint inhibitors are expensive. They require toxicity management, and there are a lot of costs associated with that. From my point of view, what we need to do is identify the ones that need escalation. That’s where biomarkers will help. Then we need to decide when we should escalate and the timing of escalation. Maybe we can start with BCG, and only some patients will need the intensification depending on their response. The other thing that will help in terms of cost-effectiveness is how long we should be escalating. Maybe some patients require 1 year, or maybe [some need] 2 years. In the trials, the duration of the immunotherapies was different. We don't know how long [patients] would need treatment.

In the end, the question is not whether these drugs actually work. We know that they work, but [the question] is whether there is an incremental benefit and if that is large enough in the right subgroup population that it would make a difference.

Urology Times: Your publication laid out 3 principles that should guide the next phase of development for these combinations. What are the key messages from those 3 points?

Mir: The [first] point that was highlighted is that patient selection needs to be improved. Future trials should not treat high risk as a whole group. They should determine who is going to fail BCG and is going to need immune intensification. The second principle would be the end points—they need to be clinically meaningful. We need to think about cystectomy-free rates, progression, overall survival, and quality of life, or how patients look at what they go through. They go through a storm of recurrences, TURBTs, cystoscopies, and follow-ups. That affects them, and it hasn't been taken into consideration so far. How patient-reported outcomes are studied needs to be improved. The third principle is that intensity has to be balanced with toxicity. Earlier-stage disease requires a higher safety and cost-effectiveness threshold than metastatic disease, and that is sometimes difficult to take into consideration in the whole picture.

I would say BCG plus immunotherapy is promising, but the future should not be a blank escalation for everybody. It should be precision escalation: right patient, right drug, right schedule, and right end point.

REFERENCES

1. Moschini M, Mir MC, Aning J, Volpe A. Immunotherapy escalation in BCG-naïve NMIBC: time for selectivity, not enthusiasm. Eur Urol Oncol. Published online April 2, 2026. doi:10.1016/j.euo.2026.03.020
2. Roupret M, Bertaut A, Pignot G, et al. ALBAN (GETUG-AFU 37): a phase III, randomized, open-label international trial of intravenous atezolizumab and intravesical Bacillus Calmette-Guérin (BCG) versus BCG alone in BCG-naive high-risk, non-muscle-invasive bladder cancer (NMIBC). Ann Oncol. 2026;37(1):44-52. doi:10.1016/j.annonc.2025.09.017
3. Shore ND, Powles TB, Bedke J, et al. Sasanlimab plus BCG in BCG-naive, high-risk non-muscle invasive bladder cancer: the randomized phase 3 CREST trial. Nat Med. 2025;31(8):2806-2814. doi:10.1038/s41591-025-03738-z
4. De Santis M, Redorta JP, Nishiyama H, et al. Durvalumab in combination with BCG for BCG-naive, high-risk, non-muscle-invasive bladder cancer (POTOMAC): final analysis of a randomised, open-label, phase 3 trial. Lancet. 2025;406(10516):2221-2234. doi:10.1016/S0140-6736(25)01897-5