EG: Hello everybody and welcome to these ecancer debates that we have at ESMO in the beautiful Berlin 2025. It is my privilege to be here with all of these big experts in the field of bladder cancer. My name is Enrique Grande, I am a medical oncologist based in Madrid and together with me I have the pleasure to introduce you to Professor Syed Hussain from the University of Sheffield, Professor Patrizia Giannatempo from the Instituto Tumori de Milan, and Professor Félix Guerrero from the 12 de Octubre Hospital, urologist at this institution. You know, we had a lot of new things that are coming up to the field of bladder cancer, no matter if you want to treat patients in the advanced stages, perioperative setting for muscle invasive and also in the non-muscle invasive scenario. Up to five phase III trials have been presented, several of them in the plenary session, impacting in the armamentarium that hopefully we will have soon to use in daily practice. So let’s start with the metastatic setting. Dr Giannatempo, what has been presented in the plenary session, this phase III trial with disitamab vedotin, an ADC targeting HER2, plus toripalimab in this scenario. What are the main outcomes that we have?
PG: We have seen amazing data. This is the first randomised phase III result on HER2 positive patients in bladder cancer. They see that there is a huge advantage in terms of relapse free survival and overall survival as well. It was very curious because 50% of the patients had upper tract tumours and we know how difficult it is to treat these patients. Even the overall response rate is huge compared to standard of care that in this case was just chemotherapy without maintenance. Of course there is some doubt about comparison, we miss avelumab as maintenance, we miss enfortumab + pembrolizumab. We know in the Chinese population and in countries not really approved the combination of EV + pembrolizumab and avelumab as maintenance. But when we do… we can do, but if we hypothetically do a cost comparison with the use of EV + pembrolizumab and chemotherapy it’s still a good result. I think this is the first part. This is the first part to think that we have a new target and of course we have to include even Europe in this trial and patients with other characteristics like Caucasian patients, Black patients, not only Asian patients – we know their metabolism can be different – but I think they have done a very good job to explore a targeted therapy for this specific population. Maybe the rate of HER2 is higher in Asian populations compared to Europe and the USA but there’s a method. We still have, even in Europe, in the USA, patients with HER2 alterations.
EG: You mentioned two topics that I think are extremely relevant – patient characteristics, this is a trial purely done in a Chinese population. If we can extrapolate this data to the Western world population, because you mentioned they have a huge percentage of upper tract tumours in the region and molecularly speaking it could be different. The expression of HER2 can vary between bladder versus upper tract tumours. At the same time you mentioned the targeted agents. What are the key biomarkers, the key targeted agents that we already have in Europe? We have FGFR3, we have HER2 in patients, platinum and immunotherapy refractory, how do you manage these patients in your daily practice Patrizia?
PG: Thank you for the question. We already have a very good targeted therapy in metastatic urothelial carcinoma, it’s erdafitinib in patients with FGF3 alteration. So the main point in this case is check as soon as possible, so do the molecular tests at diagnosis because this takes such a long time to have the tissue first and then the results of the analysis. We know that some populations, some patients can rapidly progress and so we don’t have time to have the results. We should have already started erdafitinib in this specific population. Back to upper tract, even FGFR, the rate of expression in upper tract is around 50%, so I think we can really change the language, really prolong the life of these patients with FGFR alterations with erdafitinib. In my opinion, to receive a tablet instead of an injection is much better for the patient in second line. It’s easy, you can see once a month, they can go ahead with treatment, you don’t have to do a lot of access in the hospital. But the key is test these patients as soon as possible.
EG: I love to hear that because we are here not only to improve the responses, the overall survival, but also to improve the quality of life of our patients. In that sense the DISCUS trial was presented, a very good trial of course. But what are the main outcomes? Do you think we can de-escalate the amount of drugs that we are giving to our patients?
PG: Yes, thank you. I think it’s a very good trial. It’s very ambitious in my opinion because the primary endpoint was quality of life. So it is a trial for patients, not only for registration, the aim. What did they do? They compared three cycles of chemotherapy versus six cycles of chemotherapy plus avelumab and we know the quality of life is better when we reduce the amount of chemotherapy. Of course the overall survival data was too early to conclude anything now but we have already some data from the past, from other retrospective studies, that we know we don’t need six cycles for urothelial carcinoma. That means less toxicity and we know that avelumab is such a good drug, it’s very well tolerated when we give it after chemotherapy in this specific population.
EG: And do you think we can extrapolate this data to the EV-P era?
PG: Oh my God, don’t ask me that! I don’t know. I think in the real world, in the real world will happen something similar. We know the neuropathy, the median onset is six months, so even the median time of treatment is not so long with enfortumab. So in the real data, maybe with patients with low burden disease, with complete response, I think someone could go ahead just with maintenance pembrolizumab.
EG: And, Syed, I think this is very relevant because now EV-P is transitioning to the perioperative field. We saw amazing data coming from the EV-303; what is your overall view about the EV-303? Please tell us the design and the main outcomes.
SH: Thank you very much for the question. It’s a really exciting study because looking through, basically looking at EV plus P, this is a cisplatin ineligible patient population group who do not do very well. So this remains an area of unmet need so it was quite a timely trial really to look for improved outcomes for these patients. Again, a challenging patient population group, more elderly patients in terms of the median age, in terms of fitness and all. But I think the data is very convincing because what we are seeing is that there’s significant benefit in terms of the disease free survival, a hazard ratio of 0.4 and then looking at the overall survival a hazard ratio of 0.5. So these are really exciting trial data that we are seeing. I think at the same time when we look at that data we also have to look at the toxicity, efficacy has to be modelled around what Patrizia was talking about as well. This perioperative setting trial will be used because cisplatin ineligible patients are there. There are definitely certain things that we need to think about and debate more – patients who decline cisplatin-based chemotherapy, the definition of cisplatin ineligibility using Galsky criteria, GFR 60 and below. So I just feel that we need, as clinical academy colleagues across the… globally, we need to look at that data very carefully. It is very exciting data, the hazard ratio in terms of overall survival is very impressive. So this is bound to change the treatment landscape for these patients. Patients for cisplatin eligible patient population group, we’ll get that data very shortly as well. So I think these are exciting times but, again, if I may just mention about de-escalation trials, what you presented, Enrique, in terms of DISCUS, I think that will be relevant to what we are doing in both advanced settings with conjugated antibodies and ADCs as well to see whether de-escalation will be possible for those as well within trials.
EG: And Syed, I have a couple of questions. First is related to the patient profiling because there is a kind of overlapping population in between NIAGARA, supposed to be conducted in a cisplatin ineligible population versus the EV-303 supposed to be conducted in the cisplatin ineligible population, but NIAGARA recruited a subgroup of patients with a creatinine clearance between 40-60 that officially speaking these patients are ineligible by Galsky to receive cisplatin. So tomorrow in your office if you would have availability to choose between GemCis + durvalumab versus EV-P, in this particular subgroup of patients do you think we have data to recommend one or the other regimen.
SH: I think that’s a great question. It was a debate that we had after this presentation over the last few days over cups of coffee and discussions around ESMO in the corridors. NIAGARA has really shown that patients with GFR 40-60 they did benefit as well from perioperative durvalumab. So I think we need to be careful about it, that’s why I always like to look at the main paper coming out and looking through all that data as well – what was that subset of patients, for example, who declined chemotherapy and their GFR might be quite good actually. Similarly, the group of patients who are. So looking through all that bit will help us to make the decision. If I had all the drugs available to me tomorrow, which is not the case I’ll clarify, in the UK we’ve got EV+P in first-line setting, NICE has approved it a couple of months ago, we are delighted with that. But in the perioperative setting I would like to see the toxicity data, there were treatment-related toxicity and deaths as well which we need to be thinking about as well.
EG: My second question is in that sense do we, in terms of toxicity, quality of life of patients, do we really need six cycles of EV-P after surgery as an adjuvant treatment?
SH: I think that’s a really important point. That’s why I mentioned about when we talk about de-escalation we have to think about de-escalation not just in the metastatic setting but even in the perioperative setting because you may have had the benefit. We do see the toxicity accumulates as you move on towards more cycles. That’s why I’m just so keen to look at that data, a bit more follow-up, to see what happened to patients in terms of quality of life as well in terms of the outcome. Because if you are leaving a patient who has been cured of bladder cancer but comes with significant neuropathy or other toxicities and, remember, grade 2 neuropathy in itself is very debilitating – you cannot use your phone, you cannot text.
EG: And long-lasting.
SH: Long-lasting residual toxicities that can lead to a big impact on quality of life. So I’m a big proponent of waiting a little bit more for the follow-up to make sure it’s all… and seeing that in the print.
EG: What about the other phase III trial reported in the adjuvant scenario, driven by ctDNA?
SH: I think that is really exciting because sometimes less is more and it is so important to understand because as clinicians we sometimes are focussing on getting more treatments and adding more treatments and at the end of the day we see the patients who may suffer from toxicity. So IMvigor011 is such an exciting trial and such an important history with it, having IMvigor010 which was a negative trial and then there were subsets of patients who had that ctDNA. It was a very ambitious trial, IMvigor011, and that has shown some really interesting and exciting data, both disease free survival and overall survival. Numbers are significant who are basically ctDNA positive and if they were treated with atezolizumab there’s significant benefit in disease free survival and overall survival. With the quality of life in terms of the no new safety signals.
EG: And in the era of perioperative management, what is the role of adjuvant treatment only? Can we extrapolate the data of the IMvigor011 to the EV-303? So the need of adjuvant treatment based on ctDNA regardless of the trial?
SH: I think this is interesting because, again, ctDNA is likely to play not only a role in the perioperative setting but my view is that it will move into the metastatic setting as well, for example de-escalation where we could stop, really. But, similarly, if you remember with the NIAGARA trial when they looked at ctDNA or they looked at the pathCR rates, actually patients keep benefitting from it, irrespective of that. So it’s difficult to have that but I think IMvigor011 is a trial that tells us that if they are ctDNA negative there’s no need because the risk from disease recurrence is significantly low at one year and two years and further down the line. But if they are ctDNA positive this trial has significantly improved disease free survival, overall survival, with the toxicity which is very well manageable. So I do feel that this will change the standard of care in that sense. But in terms of adjuvant, these are the patients who some of them had perioperative chemo, high-risk disease and then they moved on to adjuvant trial.
EG: Let’s do the transition smoothly to the urological field because we have new data, the SunRISe-4, combining systemic treatment like cetrelimab plus intravesical devices like TAR-200. What are the main outcomes, Syed, Félix, in that sense?
FG: This year at ESMO they presented the final analysis of this trial where they demonstrated that the addition of TAR-200 in the perioperative setting significantly increases the pathological complete response rate. This is a non-registrational trial so further trials will be needed but another important finding of this trial is that there is a correlation between the utDNA clearance from week 0 to week 12 after completing the neoadjuvant therapy. There is a correlation of this utDNA clearance with a pathological complete response rate showing that utDNA might be a potential biomarker of response with regards to this therapy. What is important as well is in a previous interim analysis that was reported of SunRISe-4 we also demonstrated that those patients who were completing the four cycles of TAR-200 achieved a complete response rate of 50% as compared with lower response rates of those patients who didn’t complete the four cycles. So this highlights the relevance of the intravesical part of the therapy for these patients to achieve the best results.
EG: And you have presented here some data with the intravesical device?
FG: We have presented here, I was glad to present the poster of the biomarkers for SunRISe-1. Just briefly and to remind, SunRISe-1 is a trial for BCG unresponsive patients with non-muscle invasive bladder cancer. It has recently been approved by the FDA for CIS BCG unresponsive and here we present the biomarker analysis that we performed in this cohort of CIS patients. So we found that over 85% of the patients harbour some kind of alteration, the most common is in TP53 but probably due to the small sample we couldn’t find any association or any differences, correlation between the alterations, genomic and somatic alterations, and the outcomes of the patients.
EG: And what about the two phase III trials reported in the non-muscle invasive scenario that have been added today, already presented – CREST phase III trials. So we will have three options, one of them is not positive, the academic one, don’t forget about that, the academic one is not positive, but the POTOMAC with durvalumab, BCG plus durvalumab, is. Can you please tell us the differences in between the design of the POTOMAC and ALBAN trial and the main outcomes?
FG: First of all you can say that 2025 has been the year for BCG naïve, non-muscle invasive bladder cancer for sure – after 50 years there is something new. As you are saying, POTOMAC is positive, CREST is positive and ALBAN is negative. First of all, the main outcome for POTOMAC and CREST was disease free survival or event free survival, which have different names but are the same and only include high-grade recurrence, disease progression, cystectomy or persistence of CIS or death. On the other hand, the ALBAN trial included recurrence free survival even with low-grade recurrences, continence events. The hazard ratio for event or disease free survival for POTOMAC and CREST has been exactly the same, 0.68. There is a big difference between these two trials and it’s the great effect of sasanlimab plus BCG in the CIS patients which has not been demonstrated in the POTOMAC patients. There are also different incidences, there’s a different incidence of CIS in both trials and the definition of CIS patients, pure CIS versus any CIS, is likely different as well. Regarding the ALBAN trial we must highlight that it uses only one year of BCG and one year of atezolizumab versus two years of BCG for the other two trials which have been positive, both in the control and the intervention arm. So, for me, I don’t think atezolizumab is worse than the other drugs, it’s probably certain details in the design, population of the trial, that have led to ALBAN not to be positive. But, for me, this highlights the relevance of very old data that we’ve had for over 20 years and is that you need up to three years of BCG maintenance for these patients. In fact, we have seen how well BCG behaved in the control arm; nobody could believe that BCG was as good as that. So if we increase the awareness to urologists, because there are many places where BCG is not still prescribed, or at least well prescribed, I think BCG is still a very good weapon to treat our patients. In the future we will probably have to select some subgroups that may benefit from more aggressive approaches like using systemic IO. But anyway, in the future we are also waiting for the results of the SunRISe-3 trial which is the only trial with three arms with a BCG-sparing arm. They have TAR-200 alone or combo TAR-200 alone plus cetrelimab versus BCG. Here BCG is up to three years so we will see how BCG behaves in this population as well. I’m looking forward to the results of these trials.
EG: We can be discussing for hours with these experts. We had, as you saw, a lot of news and very good news for the patients in the field of bladder cancer, urothelial cancer, no matter if you are focussed on the metastatic perioperative scenario or in the earlier stages. A lot will come, a lot will come next year, in the next years, because we need biomarkers, we need head-to-head comparisons, we need to optimise the treatment, we need to align with the primary endpoints that we want to get in our patients, not only focused on the efficacy issues but also in patient-centric new endpoints that we have. So the field of urothelial cancer is probably the most exciting and fancy field that you can be in oncology. Professor Hussain, thank you.
SH: Thank you.
EG: Professor Giannatempo, thank you so much. Professor Guerrero, it’s a great pleasure and thank you all for listening.
