GU Debates 2019: Practice-changing developments in urothelial cancer (2/2)

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Published: 9 Apr 2019
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Dr Eleni Efstathiou chairs a discussion with Prof Thomas Steuber, Prof Peter Goebell and Prof Joaquim Bellmunt on the recent data presented at the 2019 GU Debates in Budapest, with a specific focus on patients with prostate and urothelial cancers.

In this video, the group acknowledge the sudden shift in bladder cancer research - which has resulted from genomic advances; including the use of The Cancer Genome Atlas Program (TCGA).

A more personalised treatment approach is anticipated in first-line metastatic urothelial carcinoma, along with checkpoint inhibition and targeted therapies; with potential applicability to the second-line setting.

The group also discuss novel data showing prolonged survival in the metastatic setting with immunotherapeutic agents; along with five phase III trials - in which the results are expected to be practice-changing.

They also conclude the discussion by highlighting the importance of patient communication in the clinic.

Watch part 1 of this video which covers the changing treatment paradigms for hormone-naïve and castration-resistant prostate cancer here.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

 

Dr Eleni Efstathiou – MD Anderson Cancer Center, Houston, USA
Prof Thomas Steuber – University Medical Center Hamburg-Eppendorf, Hamburg, German
Prof Peter Goebell – Friedrich-Alexander University, Erlangen-Nürnberg, Germany
Prof Joaquim Bellmunt – Beth Israel Deaconess Medical Center, Boston, USA


EE: So, gentlemen, I will start with you, Joaquim. There’s a shift, it’s happening in these past two or three years, we’re seeing some new data evolve. What do you think the bigger picture is going to be in the future with regard to understanding better the biology of the disease and to drive decisions with all the new agents that are being tested?

JB: Yes, you’re totally correct. We have been not getting any new data for the last thirty years…

EE: Platinum and platinum and platinum.

JB: We are watching prostate, kidney. Since 2014 when the first papers on immunotherapy in patients heavily pre-treated came up, it was published in Nature, a phase I trial published in Nature means something. And then, thanks to the TCGA, that we have been able just to get genomic information on bladder cancer and we need to remember that we don’t have any targeted therapy approved for bladder cancer. We know that there are targeted therapies for breast, for lung and so on, and now we are having immunotherapy as a new option and new targeted therapies, mainly for targeting the FGFR receptors and we are going to hear more about that but hopefully the field is going to change. Also new agents that are named antibody drug conjugates that are like a type of targeted therapy similar to the TDM1 that is being used in breast cancer. So with these three sets of agents the landscape is going to change so we’re going to discuss today about the clinical trials and they’re ongoing. I assume that in a year the landscape will be completely changed.

EE: So let’s take first line metastatic urothelial carcinoma treatment. You’re saying everything is going to shift very quickly; Peter, what do you think?

PG: I think, as you said there, there are two major directions. One is the development of new drugs and the other is the development of a new understanding of bladder cancer. So we are not treating bladder cancer, we are treating bladder cancers. All these various subtypes, and they haven’t been addressed in all these trials yet, so there will be a more personalised, as we see in kidney, as we may see in breast, we haven’t seen that in prostate, by the way. So not all these subtypes, despite the new endocrine subtypes. But I think we will see this shift towards a more personalised in respect of the subtypes in bladder cancer. That is one direction, the second direction is that we realise that checkpoint inhibition is one of the real advantage also for bladder cancers. In addition to that what we are now seeing in second line and hopefully moving into first line, because these alterations are there already in first line, that may be an interesting development towards targeting alterations.

EE: So tell us a little bit about second line, where do we stand?

PG: So FGFR, for example, for these checkpoint inhibition is one. As you said, the enfortumab, all these drug conjugates they are interesting new developments beyond chemotherapy which was vinflunine which is not licensed in the US but it was the standard of treatment in Europe. Looking at the data we see the checkpoint inhibition there but we also see all these more targeted drugs that are used there and they are beneficial for these patients. I think the development in second line needs to move further into the first line, as we see in all other cancers. So we start with first line development, second line development and then that moves into…

EE: But let me, for us who are not so much in the field of bladder cancer, understand it. You just mentioned earlier and we saw this beautiful data in prostate cancer changing the survival in hormone naïve with the addition of novel agents, we see this delay in metastasis. Are you starting to get a glimpse of similar effects in a disease that’s completely different, of course, with a very short natural history? Are you seeing such changes happening with the new agents?

PG: Yes. If you look at the landscape of current ongoing trials you see more and more neoadjuvant trials being executed and you see, basically, that that is a sign of moving into earlier treatment, so prior to cystectomy which still is the standard of care. But we are treating these patients prior to the operation and I think that is a good sign towards earlier treatment and a more complete picture, a multimodal treatment, where we start to do systemic therapy very early then add the operation, surgery, and then we may even continue. So it’s more a perioperative setting we are now aiming for and I think that’s a real change.

EE: And in the metastatic setting, Joaquim, do you see this change?

JB: Yes, so what we have, as of today, until recently we only had vinflunine, now we have level one evidence that immunotherapy is prolonging survival in our patients in second line. We have that data that these agents are useful in first line unable to receive platinum-based therapy. It’s based on the PD-L1 staining and we need more data on that. I think what we’re going to see this year is that we’re going to get the readout of at least three trials in first line that have completed accrual.

EE: That’s what I was going to ask you – we’re going to get data this year?

JB: At the end of the year we hope that we’re going to get the results of the KEYNOTE-361 that is with pembrolizumab combined with chemotherapy, so meaning immunotherapy plus chemotherapy. A similar design made with atezolizumab and maybe we are going to know about the trial that is combining a PD-L1 plus a CTLA-4. There are two other first line trials that are completing with nivolumab and also one with durvalumab and chemotherapy. So we have five phase III trials, three completed and these three and probably those are going to be practice changing. Also at the end of the year we’re going to know the results of the adjuvant trials with immunotherapy. So the IMvigor-010 that is the adjuvant atezolizumab trial that I’m involved with and this is what I know, hopefully we are going to get results on the role of immune therapy in the adjuvant setting, meaning patients that have failed neoadjuvant chemotherapy or patients who are not eligible for neoadjuvant or adjuvant chemotherapy and we’ll see if there is a survival benefit. So a lot of changes. And the last thing – we know that targeting FGFR alterations got breakthrough designation; it’s not only erdafitinib, it’s not only for the B-701 compound, So all these agents, despite not having yet phase III data, probably these compounds, because the benefit is clear, will move forward.

EE: And with that example you see they’re actually catching up and they’ll do better than us. We’ve reached a little bit, and you’ve seen it, a plateau in prostate cancer. We’re just hitting the mark for a lot of androgen signalling inhibitors and otherwise we’re in a steady state but we’re not moving forward with targeted therapies. Do you anticipate, and of course you gentlemen, anything in prostate cancer that will be ground-breaking this year? I know we mentioned before that we’ve got a press release and another on apalutamide again, we’re going to hear data, but ground-breaking, practice changing? Do you anticipate anything?

TS: I don’t know exactly on the time line but probably in the field of hormone sensitive metastatic where the addition with androgen receptor signalling inhibitors with chemotherapy but probably…

EE: The combination.

TS: The combination even...

EE: But still no other types of mechanism of action?

TS: No, I think when it comes to individualised medicine based on genome sequencing, let’s say the PARP inhibitors, the trials are ongoing but the signals are confused as to whether to use it in combination with or without a mutational status. I think it’s a long way to go.

EE: This is actually a segue to my next topic of discussion that I’d like to bring up to all three of you. So more and more data, more and more information, more and more genomic information and also we’re getting in our clinics germline testing, genetics and the like. Patient communication – it’s not just now about describing how chemo or androgen deprivation or what have you, now we’re introducing more ideas and thoughts. How difficult is that getting and how much should we be focussed on patient communication?

TS: Exactly, it’s getting more complex because we have, let’s stay in the hormone sensitive metastatic, it’s the most demanding field of patient communication because the patient used to be healthy and now he is sick and is faced with a deadly disease. We have concepts to help him, they are associated with good quality of life and they both work, so how to counsel in one or the other direction? I’m talking about chemotherapy or abiraterone. So it takes time to weigh the advantage or the disadvantage of each treatment option and to have to look a little bit downstream what will be the potential next drug that will be available. So we need to take more time and, of course, you need to be an expert, you need to know the data because the patients are demanding and they are going into the internet. They come with a lot of information, some is valid, some is invalid, it takes some time to sort it out. It’s very important to have relatives with them.

EE: That’s an interesting point.

JB: Well, I think that this is a topic that we are going to discuss today, the patient communication. Sometimes you are faced with three different types of patients – those that are not willing to know more than you are telling them, even they say, ‘Well, don’t tell me about that.’ This is more or less 50%. There are others, let’s say it’s 40%, that are coming with information from the internet, well-instructed patients that are asking really smart and clever questions. Then even there is this 5% that they are even providing you data that you are not even aware and you need to say, ‘Okay, let’s check.’ So patient communication is…

EE: But there’s nothing wrong with that, to say, ‘I haven’t looked at that.’

JB: Nothing wrong, absolutely. Absolutely. That’s the great thing, that open the door and not being paternalistic, that is the way that medicine was being done in the past. You need to sit beside the patient, this is something that in the US we know – there is not a table in between the patient and the physician, right now we are sitting together and let’s check the data and discuss what needs to be done.

EE: There are even companies out there, as we heard yesterday when we had an AI discussion, that are looking gradually and trying to pick up clinical trials for patients across the world. Peter, do you have a comment of all this advancement in technology and how patient communication will evolve?

PG: I think what is interesting, we are always talking about personalised medicine and we think it is linked to alterations, molecular alterations, and specific drugs for these patients. But what we are doing in prostate, for example, is already personalised medicine since decades. Personalised for me in this setting means that we talk to each and every patient differently according to his specific needs, his expectations, our possibilities to really treat this patient. I think if you look at ten, fifteen patients having prostate cancer you probably, although you have all these substances available, all these treatments available, you treat each and every patient differently. You do personalised medicine already in a more holistic way. Interestingly, with the possibilities we are adding now through all these new drugs, new availabilities, new possibilities, new imagings, new therapeutic things, I think it simply adds to the armamentarium we are having for these patients but we are doing personalised medicine already for decades.

EE: I think that this was an excellent summary of the whole discussion. We may not have biomarkers, words of wisdom – we may not have biomarkers, but we have a duty to listen to their needs and personalise based on the needs of these patients. Thank you very much and I trust we will continue to all do so.