Expert Interview of Dr Enrique Grande: Highlights of the Evolving Therapeutic Landscape in Urothelial Cancer

Enrique Grande, MD, MSc, PhD 
Quirónsalud Madrid
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. 

Transcript

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Perioperative immunotherapy has been established as the new standard of care, which can effectively prolong survival in muscle-invasive bladder cancer (MIBC) patients Could you kindly provide your insights based on the NIAGARA and KEYNOTE- 905 (EV-303) trials? The systemic treatment of patients with muscle-invasive bladder cancer (MIBC) and the perioperative management have dramatically changed in the recent couple of years. We had the results of the NIAGARA strategy and the use of the triplet cisplatin/gemcitabine plus durvalumab before the radical cystectomy, followed by complete up to one year of treatment with durvalumab in the adjuvant scenario, which has impacted on the overall survival (OS) of our patients, with a hazard ratio (HR) of 0.7. So this is completely practice changing the first phase III trial to demonstrate overall survival (OS) with a systemic treatment in the perioperative management. Don't forget that just before we had the approval of adjuvant immunotherapy with the PD-1 inhibitor nivolumab based on the results of the CheckMate 274. And at this point of time, we still don't have a statistical improvement in overall survival (OS) with nivolumab. What is really new. At the ESMO 2025, we have seen the presentation of the KEYNOTE-905 or the so-called EV-303 trial, in which the novel antibody drug conjugate (ADC) enfortumab vedotin is combined with pembrolizumab, three cycles of neoadjuvant therapy before the radical cystectomy were offered with a pathological complete response (pCR) rate of up to 57% in patients ineligible for receiving, or refusing to receive cisplatin. After the surgery, patients completed up to six cycles of enfortumab vedotin and pembrolizumab (EV/P). And the most interesting finding, and the reason why this trial is practice changing and brings really a great news for our patients in daily practice, is that the impact on the overall survival, HR was 0.5, and the impact on the event-free survival (EFS), HR was 0.4. This is completely changing something, even better maybe than expected. The only concerns that we have are two. First, toxicity. Only 20% of the patients completed the entire schedule. And the second, financial toxicity. We will need to see how we are going to deal with, to be able to afford the cost of these very expensive drugs. The efficacy of adjuvant immunotherapy has been confirmed in high-risk muscle-invasive bladder cancer (MIBC). Considering the evolving treatment landscape and the availability of valuable tools such as liquid biopsy, how can we integrate these findings to make informed decisions for our patients? The use of adjuvant immunotherapy has been established since the approval of nivolumab, based on the data of CheckMate 274, after radical cystectomy in patients with high risk for relapse. Recently, we have seen the results of the IMvigor 011 trial, in which atezolizumab (Atezo) has demonstrated to improve the overall survival (OS) for patients who are ctDNA-positive after radical cystectomy. Very interestingly, if we take a look in deep at the design of the trial, the thing is that the screening period, the time when ctDNA could become positive, was in between, just after the radical cystectomy and up to one year after the radical cystectomy. So what does it mean? It means that we have two patient populations included in the IMvigor 011 trial: the patient population with positive ctDNA just after the surgery, and the patient population with initially ctDNA negative that became positive during the follow-up. The prognosis is impacted in the overall outcomes. The prognosis is impacted in the need to receive atezolizumab or not. Well, the hazard ratios (HRs) for both disease-free survival (DFS) and overall survival (OS) were pretty similar in these two subgroups of patients. In terms of safety, the use of Atezo in the adjuvant scenario is not really damaging in terms of immune-related adverse events (irAEs) for the majority of the patients. So this is something that we can really provide in daily practice. So we will have a new reference standard of care. And the most important thing is that we will be able to select molecularly those patients who are really in need of the adjuvant part. And lastly, and I think this is very relevant for daily practice, you know, the adjuvant indication is, I wouldn't say "old fashioned," but it's not the best indication that you may have. Because now, those patients in the muscle-invasive scenario should be discussed in the multidisciplinary team (MDT) before the radical cystectomy. And we know that for these patients with muscle-invasive disease, neoadjuvant approaches are impacting the overall survival (OS) from the beginning. So the thing is how many patients will we have shortly after radical cystectomy who have not used neoadjuvant approaches. And after the results of the EV-303 data, how many patients ineligible for cisplatin are not going to be able to receive EV/P but be able to receive adjuvant atezolizumab after radical cystectomy. The field is changing very rapidly, and we need to try to capture the new data and to try to translate it into daily practice. But we will have a lot of debate to identify the best patient profile for each of the alternatives that we will have shortly in the clinic. What are your expectations regarding potential developments in the perioperative setting in the coming years? More phase III trials will come. We have just seen the results of the NIAGARA trial. We have just seen the results of the EV-303, but novel drugs are under development. Here we have the combination of platinum-based chemotherapy plus pembrolizumab or plus nivolumab. We have also EV plus pembrolizumab for patients eligible for receiving cisplatin. And we will have also the combination of EV plus durvalumab and tremelimumab. So I think we will have new drugs in this topic. And hopefully, not only ctDNA to identify patients suitable for one or another option. Maintenance immunotherapy is crucial for first-line treatment, especially when avelumab is used after platinum-based chemotherapy without any progression. How do you perceive the value of avelumab in this approach? Avelumab in the JAVELIN Bladder 100 trial has demonstrated an improvement in the overall survival (OS) for patients who receive clinical benefit after a platinum-based induction chemotherapy. The results are pretty clear from both the statistical and the clinical perspectives. Median overall survival (mOS) was 23.8 months. And the hazard ratio (HR) for overall survival (OS) improvement was 0.76. So I think there is no doubt about how useful avelumab is in this scenario. Avelumab is also contributing to improving the quality of life of patients, or at least does not deteriorate the quality of life of the patients. Don't forget that, because of the schedule, the platinum-based chemotherapy is already having an impact by inducing tumor shrinkage and controlling symptoms due to the tumor size. So avelumab is contributing to maintaining this improvement in the quality of life. What has just been released recently? The results of the DISCUS trial. DISCUS is a phase II academic, randomized trial that compared head-to-head the quality of life of patients who received only three cycles of platinum-based chemotherapy versus the standard six cycles of platinum-based chemotherapy before starting avelumab. The results of this course are extremely interesting. Why is that? Because it is demonstrating that by diminishing the number of cycles we are impacting, we are improving the quality of life of the patients. And even more interestingly, it is putting the threshold, putting the benchmark of the expected median survival in the era of maintenance avelumab that we may achieve by including the entire population, which is about 18.9 months. So by reducing the number of cycles, we are contributing to a better quality of life without, it seems, without detrimental activity in the patients. You presented the DISCUS trial at ESMO 2025. Could you please provide further details regarding the study design and considerations? Additionally, what are the key findings that may have implications for current clinical practice? Traditionally, we have been using platinum-based chemotherapy to treat our patients in the last three decades. No matter if you were giving gemcitabine/ cisplatin or gemcitabine/carboplatin, we tried to go up to five or six cycles of platinum-based chemotherapy because we believed that the more number of cycles, the deeper the responses would be, and the longer the overall survival (OS) and progression-free survival (PFS) would be. In fact, we were considering that most of the patients with urothelial cancer were sensitive to platinum-based chemotherapy. The reality, or at least the experience that we had, is that the later cycles of chemotherapy were just serving to accumulate toxicity and really to progress the patients in most of the cases. So this is the background and rationale, because of the design of the DISCUS trial, we try to see that by diminishing, reducing the number of cycles from 6 to 3, if we have a better quality of life without a detrimental efficacy. With that design in mind, an international academic phase II trial was designed. It was conducted in three countries, the UK, France and Spain. We recruited 267 patients. 133 were recruited to the three-cycle arm; 134 were recruited to the six-cycle arm. Baseline characteristics were very well balanced, particularly for the stratification prognostic factors, such as liver metastasis or the investigator's choice of chemotherapy. And the primary endpoint of the trial was the quality of life of patients. Properly speaking, it was the mean change in the quality of life between the baseline and the completion of cycle six. That was the primary endpoint, and it was met statistically with a p value of 0.016, and the difference was -8.5 points in the health-related quality of life square of the EORTC. And the second primary endpoint that we used in this trial was the overall survival (OS). This was an interim report. And in this interim report, we didn't see any difference at all. The median overall survival (mOS) was exactly the same in the two arms, three-cycle and six-cycle arm. The median OS was 18.9 months, and the hazard ratio (HR) was 1.15. We cannot claim non-inferiority because of the statistical limitations of the trial. We would need to recruit thousands of patients to demonstrate the non-inferiority. But I think, clinically speaking, in this graph of overall survival (OS), together with a hazard ratio (HR) of 1.05 for progression-free survival (PFS), which curves completely overlapping, and no detrimental responses and no higher progression disease rate, I think, taking all this data into consideration overall, we can say that by diminishing the number of cycles of platinum-based chemotherapy before avelumab maintenance, we are improving the quality of life of patients without detrimental activity. The first-line treatment landscape for locally advanced or metastatic urothelial cancer has been transformed by the EV-302 trial and you led experts in identifying the criteria for candidates for EV-pembro globally. Could you share more insights and value regarding the EVITA criteria? The EV-302 and the combination of enfortumab vedotin and pembrolizumab is the current standard of care preferred regimen that we should use in our patients in first-line metastatic urothelial carcinoma. The impact in terms of efficacy is dramatic. I would say doubling the responses, doubling the progression-free survival (PFS), doubling the overall survival (OS) with a hazard ratio (HR) of 0.5 for survival. Very interestingly, and I think it is important to remark, 30% of patients who receive EV and pembro are achieving a complete radiological response, and the median duration of these complete radiological response was not achieved after more than two years of follow-up. So this is key. This is the new reference standard of care. However, the toxicity is high. And this is a little bit new. In what sense? Well, neuropathy is an issue. Skin rash is an issue. Hyperglycemia may be an issue. Pneumonitis is an issue with these new drugs. How can I identify in advance who will be the patients who will develop severe toxicity? There are no strict criteria. If you take a look at the package insert of the drugs of EV, pembrolizumab you don't really see contraindications, proper contraindications to these new drugs. But, you know, except that the patient is younger than 18 years old, the patient is pregnant, or the patient has allergy to the excipients. And I think that we need clinical factors to know the clinical factors. You can call them criteria if you want to, but clinical factors may help us to identify patients for whom maybe the administration of EV can contribute to high or unexpected toxicity. Who are these patients? Well, there is a consensus that was achieved among more than 200 oncologists spread across more than 30 countries, in which we show that ECOG 3, the presence of variant histologies different than urothelial tumors, and the presence of neuropathy were a kind of mandatory or major exclusion criteria to receive EV. On top of that, maybe you need to think twice before offering EV, or you may closely monitor patients who start EV. These will be patients with a creatinine clearance below 30 mL/min or under dialysis, or those patients with severe comorbidities in the skin, or those patients who have alterations in the cornea, or those at high risk of developing pneumonitis or with emphysema. Well, patients probably have hemoglobin glycosylated above 11%, so uncontrolled diabetes at the end. It means patients with comorbidities that could affect the expected safety profile of EV. The applicability of this EVITA criteria in daily practice needs, prospective data, or at least to demonstrate that in large retrospective series that we are working on. What is the optimal sequence of systemic therapy, starting from first-line treatment, in order to maximize the survival benefit in locally advanced or metastatic urothelial cancer? Well, the standard of care is enfortumab vedotin and pembro, and after enfortumab vedotin and pembro, it is supposed that platinum-based chemotherapy should be considered as a more accepted option unless you can go for a molecular testing of the patients. And if the patient is <i>FGFR3</i> positive, you can go for erdafitinib. If the patient is <i>HER2</i> positive, you can go for trastuzumab deruxtecan, according to the FDA labeling. Not yet in Europe. If you cannot afford it or the patient has contraindication for EV, maybe there is an option to start with platinum-based chemotherapy or the combination of gemcitabine, cisplatin and nivolumab, according to the data of CheckMate 901. And in my practice, I am comfortable using platinum-based chemotherapy. And those patients with a clinical benefit may receive avelumab in the maintenance scenario. And when the tumor is progressing after avelumab, you have the opportunity to go for erdafitinib if the patient is <i>FGFR3</i> positive, or you can go for EV, which has an impact on overall survival (OS), according to the data of EV-301. So, in the end, this is very good to have different options. The challenge that we have is the percentage of patients who unfortunately drop off from one line to another line of treatment. So these sequential strategies may be an issue in daily practice. So if you want to see or know which is the ideal patient, the ideal candidate to go for platinum-based chemotherapy followed by avelumab maintenance followed by enfortumab vedotin, maybe those patients that are a little bit older, I would say I wouldn't set a threshold for the age, but 80 years old with comorbidities may be the ideal candidate, or those patients with a very low tumor spread in which there are no symptoms because of the disease plus frailty. You don't really need a huge response on that patient population. So you are thinking in long-term quality of life with the use of a single-agent avelumab versus the comparator, which would be EV/P. Probably the quality of life in the long term is better if you are using maintenance avelumab than if you are maintaining EV/P because of the design of the trial and the schedule of administration. What the results from ESMO 2025 would you like to comment on regarding first-line treatment or novel therapies in later lines of metastatic urothelial cancer? Well, at this ESMO 2025, in beautiful Berlin, we have seen up to five phase III trials plus the DISCUS, another randomized phase II trial that are potentially practice changing. I think this is the most fancy tumor that we have today. There is a big excitement around the bladder cancer not only affecting the metastatic scenario, but also the muscle-invasive perioperative management, and non-muscle-invasive scenario. So we are in the right place to be in the first line of the metastatic setting where we have the results of the Chinese DV, disitamab vedotin plus toripalimab trial impacting the overall survival (OS) and progression-free survival (PFS) in the response rate in patients with first-line metastatic urothelial cancer with at least expression 1, 2 or 3 crosses by immunohistochemistry of <i>HER2</i>. I think this is a new step in the field of metastatic bladder cancer. We have a new target, <i>HER2</i>. And what are the concerns that we have? Well, it was conducted only in China. So we need to see the results of the DV-001, a phase III trial with a very similar design combining disitamab vedotin and pembrolizumab at this point of time in the Western world population. But hopefully, I am not expecting different results than in the Chinese trial. So hopefully, we will soon have a potential biomarker that we may use in daily practice to identify patients.