ACE OncoCast

Expert Interview of Dr Guerrero: Optimal Management for NMIBC and MIBC Patients from a Surgical Perspective

• ACE Oncology • Season 12 • Episode 3

Share episode

Félix Guerrero-Ramos, MD, PhD, FEBU
Hospital Doce de Octubre
Madrid, Spain

The therapeutic landscape for urothelial cancer (UC) has undergone significant transformation in recent years, with the addition of PD-1/PD-L1 targeting immune checkpoint inhibitors (ICI) and novel targeted therapies and antibody-drug conjugates (ADCs) adding to the complexity of treatment options available for patients throughout the course of their disease. The optimal sequencing of treatments depends on an understanding of the relevance of different pathological subtypes of the disease and of the latest clinical evidence and guidelines that support the use of different therapies.

By this expert interview, you will receive a detailed grounding of the disease process and management from diagnosis through to salvage treatments of advanced disease. The course will enable clinicians who are involved in the management of patients with urothelial cancer to integrate the latest advances and use of novel therapies for advanced urothelial cancer into safe and effective patient care. 

How is intermediate-risk and high-risk non-muscle-invasive bladder cancer (NMIBC) defined in guidelines? Well, we know that it is essential to stratify non-muscle-invasive bladder cancer (NMIBC) into low, intermediate, high and very high risk, because every patient will have a different prognosis, and we have to tailor the therapies to the risk category. There are slight differences if you look at one or another classification. For example, the classical classification by the EAU guidelines considers high-risk as any patient harboring a high-grade tumor, T1 tumor, or CIS. For intermediate-risk tumors, those are Ta, low-grade, larger than 3 cm, multiple, and recurrent. If we go to the new version of the guidelines, some of these high-grade Ta tumors, if they are the first episode, non-recurrent, solitary tumors less than 3 cm, and high-grade Ta, would be classified as an intermediate-risk tumor. So, in general, there are some slight differences, but most of the guidelines agree on the classification. One important drawback of the classifications, as we have published in a systematic review in 2022 in the journal of bladder cancer, is that their external validity is not as good, their performance is not as good as it should be for both recurrence and progression. So in the future, we must try to improve how we categorize non-muscle-invasive bladder cancer (NMIBC), especially considering the use of artificial intelligence (AI), big data, or even including also some kind of biomarkers. What is the recommended adjuvant therapy for high-risk non-muscle-invasive bladder cancer (NMIBC) patients? How do you interpret the CREST trial presented at the American Urological Association in 2025 (AUA 2025) and the POTOMAC and ALBAN trials presented at ESMO 2025? Well, currently, the management of high-risk non-muscle-invasive bladder cancer (NMIBC) has a cornerstone. This cornerstone is BCG(Bacillus Calmette-Guérin). This type of therapy was first published in the 70s by Alvaro Morales, and we have been using this intravesical therapy for over 40-50 years. BCG for high-risk non-muscle-invasive bladder cancer (NMIBC) has to be given with an induction plus maintenance instillations up to three years of therapy, because this has better outcomes than if we give only one year. So recently we have had some results released from the pivotal trials with immune checkpoint inhibitors, which are administered systemically. The first one was the CREST trial, where there is an administration of BCG induction plus maintenance for two years, alongside with sasanlimab subcutaneously also for two years. This is demonstrated to be better, with a hazard ratio of 0.68, than BCG induction plus maintenance for two years. Especially in the CIS group, there's approximately a 25% difference in event-free survival (EFS) rates for the duration of complete response (CR) at three years. So in this group analysis, it showed that for CIS, it looks like it is a very active therapy. The other trial, which has been reported with positive results, have been the POTOMAC trial. This trial combines one year of intravenous durvalumab plus two years of BCG induction plus maintenance versus BCG induction plus maintenance alone for two years. The hazard ratio for disease-free survival has been exactly the same, 0.68, and both of these trials also include BCG induction-only arm plus an IO arm, which has not been significantly better than BCG alone. Finally, the third trial is the ALBAN trial, which has also been reported at ESMO this year like the POTOMAC trial.

The ALBAN trial had only two arms:

atezolizumab intravenously for one year plus BCG for one year versus BCG alone for one year. And in this trial, recurrence-free survival has not been better in the intervention group. And results show that atezolizumab plus BCG, both of them, for one year is not better than BCG alone for one year for these high-risk non-muscle-invasive bladder cancer (NMIBC) patients. So how would you define BCG-unresponsive, BCG-refractory and BCG-relapse patients in clinical practice? Well, first of all, we must highlight that the different definitions of BCG response were meant for clinical trial design. It is true that recently there is a beautiful paper by the group of Roberto Contieri and colleagues where they see that these definitions are accomplished with different clinical outcomes. So usually when there is a patient who cannot receive BCG due to toxicity, we call these tumors BCG-intolerant. We also have the BCG-unresponsive scenario, which is generally those patients who have a high-grade recurrence up to 12 months after finishing BCG if they have a CIS tumor, or up to 6 months after finishing BCG if they have papillary-only tumors, and of course, any recurrence during the therapy. In this BCG-unresponsive scenario, those patients who have the recurrence during BCG therapy have an even worse prognosis and are called BCG-refractory. There are also two new concepts: BCG-experienced, which is those patients having an experience in a high-grade recurrence after the timeline for BCG-unresponsive, I mean, six months for papillary disease or 12 months for CIS. If these patients experience a high-grade recurrence beyond that timeline, they will be called BCG-experienced. And finally, there are other patients called BCG-exposed if they have not received the minimum adequate therapy, which is 5+2, but less therapy and discontinued due to any other reason; these patients will be called BCG-exposed. There are some novel drugs approved or being developed for BCG- unresponsive high-risk non-muscle- invasive bladder cancer (NMIBC) patients. Could you please highlight these advancements? Well, we have four FDA approvals so far. One of them is systemic pembrolizumab, which was first approved in 2020. All these approvals are for BCG- unresponsive CIS with or without papillary tumors. Pembrolizumab yielded a complete response (CR) rate of around 40% at three months with a poor duration of response. After BCG, we had nadofaragene firadenovec, which was approved in 2022. This intravesical therapy reported 53% complete response (CR) rate at three months. And then in 2024, we had the approval of BCG plus N-803, also known as NAI (Nogapendekin alfa inbakicept), which is a superagonist of <i>interleukin-15</i>, with a CR rate of 71% at any time. So these were the first three approvals that have not been really used in real clinical practice in the USA. After that, we recently had another approval

in September 2025:

the intravesical device TAR-200, which provides a sustained release of gemcitabine in the bladder over three weeks and was approved based on the SunRISe-1 trial, reporting the highest response to date, with a CR rate of 82.4%. The duration of the response with this device is over 50% at 12 months. So this is a very significant achievement for this type of therapy, and these are the four therapies which have been approved so far by the FDA. There is also cretostimogene, which is CG0070. This therapy has a breakthrough designation and fast-track designation by the FDA. So probably in the future we will see this therapy approved for CIS patients with or without papillary disease. On the other hand, we have to highlight that 70% of the patients who are BCG-unresponsive harbour papillary tumors only without CIS. And for this population, there are several cohorts of the clinical trials reporting good and interesting survival outcomes. But there are no approvals yet. Probably these approvals will have to come alongside randomized clinical trials. And in this sense, there are only two randomized clinical trials

running currently:

the SunRISe-5 trial, TAR-200 versus intravesical chemo, either mitomycin C or gemcitabine by investigator's choice, which has already completed recruitment and we are waiting for the results; and the MoonRISe-3 trial, which is going to start soon, comparing TAR-210, which contains erdafitinib for <i>FGFR-</i>altered tumors, versus intravesical chemotherapy, again mitomycin C versus gemcitabine, up to the investigator's choice. In muscle-invasive bladder cancer (MIBC) patients. radical cystectomy (RC) is the primary treatment. How do you determine perioperative treatment strategies to manage this condition? Well, we know that for muscle-invasive bladder cancer (MIBC), radical cystectomy can only cure 50% of the patients. And regardless of radical cystectomy, there will be another 50% of the patients who will die because of their bladder cancer. Two years ago, it was demonstrated that the benefit of neoadjuvant chemotherapy, with an improvement in overall survival of around 5-8%. So this has been the standard of care for a very long time. There are several issues with neoadjuvant chemotherapy. One of them is low administration rates. There are many centers where they do not consider neoadjuvant chemotherapy. And one of the most important issues is that half of the patients who are going to undergo radical cystectomy are not candidates for neoadjuvant cisplatin-based chemotherapy because of any of the Galsky criteria. So recently we have seen the approval by the FDA and European Medicines Agency of NIAGARA trial, which combines neoadjuvant chemotherapy plus durvalumab and durvalumab as an adjuvant therapy after radical cystectomy. There are no other approvals in the perioperative setting. It is true that nivolumab was recently approved, about 1-2 years ago, as an adjuvant therapy after radical cystectomy for those patients at a high risk of recurrence, whether or not they had received neoadjuvant chemotherapy. And recently in ESMO, we have seen very promising data of the KEYNOTE-905 or EV-303 trial, combining pembrolizumab plus enfortumab vedotin (EV) as preoperative therapy, followed by pembrolizumab as an adjuvant therapy after radical cystectomy. So I'm sure that in the near future, we will have a lot of changes in the perioperative setting, and things are going to be very dynamic in the upcoming years. What is the role of surgery in bladder preservation? And how do you collaborate with other specialists in this setting, such as medical oncologists and radiation oncologists? Well, for bladder preservation, the classical approach has been trimodal therapy, which encompasses radiotherapy, chemotherapy, and maximal radical TURBT. When we're going to perform a bladder preservation approach in a patient with trimodal therapy, we need to have a very deep and fractioned TURBT. This is because we need also to rule out a possible T3 tumor. So we'll have to take the exophytic part of the tumor, then the tumor bed. Then we'll have to go to the muscle and send all the samples separately to the pathology department. Finally, with a cold-cup biopsy, we should take some biopsies of the perivesical fat to rule out T3 tumor. Also, we have to perform systematic biopsies, or even if we have any kind of enhanced imaging method like PDD (photodynamic diagnosis), we need to use that to rule out extensive CIS in the bladder, and also take prostatic urethral biopsies. And of course, all these patients have to undergo a very radical TURBT to remove as much tissue as we can. And as you were asking me, this is a real multidisciplinary approach, we have to discuss every of these patients in the tumor board, and we need the point of view of the radiation oncologist, the medical or clinical oncologist, and also the urologist to see which patients could be candidates for this. There is another marginal role of surgery in these preservation approaches, which could be partial cystectomy. However, there is not much evidence of partial cystectomy in these approaches. It remains more experimental or suitable for certain borderline cases, so this is not currently a standard of care. What about novel approaches to bladder preservation in muscle- invasive bladder cancer (MIBC)? Could these represent the future of treatment? Radical cystectomy has remained the cornerstone in the management of muscle-invasive bladder cancer (MIBC), with or without neoadjuvant or adjuvant chemo or other modalities, or even with radiotherapy. But now we are having these combinations of agents like the KEYNOTE-905 or EV-303 that were presented in ESMO with pathological complete response (pCR) rates up to 60% that we have to start thinking of avoiding radical cystectomy and ensure the future for muscle-invasive bladder cancer (MIBC) will be doing less radical cystectomy. After confirming a clinical complete response (cCR) to any kind of neoadjuvant therapy and then doing some consolidation, and in this sense we already have several trials with an adaptive design, where the patient receives a kind of neoadjuvant combination therapy. And when we assess the clinical complete response (cCR), if the patient has a complete response (CR), we can keep the patient preserving their bladders. And we can do a consolidation with any kind of systemic or even local therapy. If the patient does not achieve a complete response (CR) after the initial therapy, they will have to undergo radical cystectomy. One key here, and a very important concept, will be how to define clinical complete response (cCR). This is a very important concept because it will be the way to allow our patients for bladder preservation strategies. Generally, we are using cytology, cystoscopy, CT scan or MRI, and TURBT bladder biopsies to assess the clinical complete response (cCR). But I believe that in the future, we will have to integrate some more specific markers, for example, ctDNA or utDNA. So that if we have a patient with all these parameters, all these procedures that are negative, we can assess that the clinical complete response (cCR) is positive and the patient can still preserve their bladder. So as I said, and as a conclusion, in the future, I am sure and we should pursue performing fewer radical cystectomies and preserving more bladders for our patients, because of the toxicity of radical cystectomy being significant, and also the high rates of mortality in the postoperative period.