Prof Heather Payne - University College Hospital, London, UK
Dr Neal Shore - Carolina Urologic Research Center, South Carolina, USA
Dr Eleni Efstathiou - MD Anderson Cancer Center, Houston, USA
Prof Nicolas Mottet - University Hosptial of Saint-Etienne, St Etienne, France
HP: Hello and a very warm welcome to this ecancer educational centre which is coming from sunny San Francisco at GU ASCO. My name is Heather Payne, I am an oncologist from London, England, and I'm joined by a very esteemed panel to discuss tonight hormone sensitive prostate cancer. So my panel is Dr Neal Shore who is resident here in the US, the rest of us have had to travel. Dr Eleni Efstathiou who is from both Houston and Greece, which one did you come from today?
EE: Houston, but I still travelled.
HP: Right, so that was easy. So you were a resident as well. And then Professor Nicolas Mottet who is from France. So it gives us great pleasure this evening to talk about hormone sensitive prostate cancer. I think we've all debated castrate-resistant prostate cancer for many, many years and this is still a relatively new topic. The last two or three years we've seen data giving an overall survival when docetaxel was added to ADT for hormone sensitive disease from the CHAARTED study and STAMPEDE. Then last year we saw that abiraterone can also improve overall survival when added to ADT in both the LATITUDE and, again, the STAMPEDE studies. So, Neal, how has this changed your practice? It's been amazing data; we thought we'd got hormone sensitive sussed, didn't we really, that we just gave ADT. How has this changed your daily practice?
NS: I think you raise a great point, it's only in the last couple of years, really, that we've had all the CRPC approved therapies and then now on the heels of that a way to be less nihilistic about patients presenting newly diagnosed with metastatic disease where we would only historically just give ADT. So the CHAARTED and the STAMPEDE data has been exceptional in telling us we can combine ADT with either docetaxel or ADT with abiraterone. Interestingly, today the FDA in the US just gave full approval for the LATITUDE data essentially.
HP: That's fantastic.
NS: So it has really changed it tremendously. For urologists, medical oncologists, in a multidisciplinary way, it's absolutely essential that a patient who presents now, newly diagnosed with metastatic disease, has that really robust physician-patient shared discussion. Of course we'll talk about, today, do you start with abiraterone or docetaxel, how would you sequence and I'm sure we're going to discuss also the nuances between high and low volume and how do you radiologically image for that.
HP: Thank you. Eleni, do you think it's a good cut-off, high and low volume disease?
EE: No. Obviously - you've heard me before complain about these simplistic approaches to life which is something that urologists are not to blame for. I think we appreciate these simple cut-offs.
NM: It was designed by the medical oncologists, don't blame urologists!
EE: I do, I just said. So unfortunately we have to rely, though, on some form of discrimination of our patients until we have more robust biomarker-driven data in a similar fashion like breast cancer does. That would be the goal and with that in mind I think we all agree, recently I was doing meetings that the word hormone naïve or hormone sensitive, what have you, is going to go away and we're probably reverting to the older, older terminology of advanced prostate cancer rather than anything else. But until the time, as you were pointing out, when we do have such biomarkers what are we going to do? High volume, low volume is an option; another option is to rely on features of the disease such as presence of visceral metastases, liver metastases would be a subset, a small one. Sometimes looking specifically whether there are markers within the tumours that we are familiar with - new endocrine markers maybe. So I employ in my practice all of these surrogate supportive markers that are not proven and they come mainly from post-hoc analysis to decide which of the two. I would not, at this point that we have both the data from docetaxel and abiraterone, say that if I have a patient with more than five mets with one of them at least being outside the axial skeleton I would go for docetaxel. More than likely I would go for abiraterone because the LATITUDE trial was all-inclusive, was a high risk trial, so it included a lot of such patients which are, arguably, the common type of patients you see in your clinic. So, I don't know, Nicolas?
NM: I agree and partly disagree.
EE: Always.
NM: As usual. Again, we have to realise this is based on trials, the subcategory of high volume and low volume is a subgroup category that was completely artificial, defined by CHAARTED, and the trial CHAARTED as a whole is positive. STAMPEDE - no stratification, positive again. So is really the volume, as defined by CHAARTED, relevant? I completely agree with you - not at all. But if you consider, again, for abi LATITUDE there was stratification based on Gleason, number of mets etc., again STAMPEDE no stratification at all and again positive. So it's probably completely irrelevant to stratify by disease volume. Second, it's a little bit counterintuitive, visceral mets we all agree that's poor prognostic, no question. But I remember that when the trial CHAARTED was presented the discussion showed very nicely a slide with bone mets, all the axial skeleton, that was low volume by definition and yet the opposite, full mets, one met in the ribs, by definition is high volume. Is it really that relevant? I'm not definitely convinced on that. And we must also remember, and that's a very important point of caution, all this is based on bone scan and CT scan, very old-fashioned imaging. Nowadays we're jumping to the new imaging modality PSMA or whatever, let's say PSMA, and we have absolutely no idea how to deal with this. The pre-defined low volume might be, in fact, very often a high volume based on the number of mets. Do we treat this guy as low volume or high volume if we consider volume? The M0, the previously M0 might be very often, in fact, M1 - do we treat this guy as an M0, that is local disease plus a systemic one or as an M1 disease which is systemic only with no local treatment? So we clearly have opened a huge Pandora's box just based on imaging. We thought it was easy, it's absolutely a nightmare to stratify on that.
HP: There are many challenges ahead, aren't there, and I think with new imaging techniques coming through it's going to change a lot of the ways in which we treat people. But generally, Neal, if you had a choice between abi and docetaxel, who do you think the ideal patients are for abiraterone and those for docetaxel? And we've heard from Eleni using biomarkers which we don't have the full data for, as yet, but for the majority patients of coming through the clinic are there features that would make you recommend one or the other?
NS: Yes, I think the things that we tend to look at are the tumour burden and the location of the tumour. So I'm also inclined if someone has visceral metastases, particularly liver, lung, I'm more inclined to start with docetaxel and get the six cycles in as opposed to a patient who might be older with just 'high volume' bone metastases or someone who would just not be fit for taxane based therapy. One of the challenges regarding selection is assuming that it's a toss-up, say they are both equally appropriate therapies. Most patients when you offer them the choice they're going to usually shy away from chemotherapy just for the notion of what chemotherapy is in their minds, which is not always necessarily appropriate. We know patients did extremely well in both the CHAARTED and in the STAMPEDE trials, the younger, better performance status, and the thing that's really unknown to us is if they get six cycles where would the subsequent sequencing of abiraterone come into play? We don't have that data. My feeling is that if were it me I think I'd be more inclined to want to take on that successive paradigm, that regimen. Of course we've got a lot of other trials that are going on right now looking at combining low and high volume with new therapies as well as existing ones. Enzalutamide has a trial called the ARCHES trial; the ARASENS trial with darolutamide is low and high volume combining with docetaxel. So it's an exciting time for clinicians to follow this data.
HP: It certainly is and I think we're going to have even more questions in the future, obviously, in making these decisions. Eleni, what has been your experience of people having abiraterone and docetaxel in this hormone sensitive state? What has their quality of life been like?
EE: So I'm going to get to that but I wanted to add a little something to what exactly you said, Neal.
HP: Please do.
EE: After reviewing very carefully the data from STAMPEDE and LATITUDE, both STAMPEDE arms that have been reported, one sees that the patients who are randomised on the treatment arm if you look at subsequent treatments you actually get more of the other active agent as well. So that is very interesting and if you look at what was the control arm invariably when they progress they get less of the alternate active drug and less of the original randomised drug. It's not like later they get it. So it turns out to be that consistently, with the exception of CHAARTED that I think didn't have that kind of follow-up, that you're seeing that the winner is the arm that got both. So I'm not really sure that sequence at the end will matter unless you go to the detail but it's just to give the opportunity to patients to have access to both, different mechanisms of action. So that's what I try, as you suggested also, to include in my clinic. I think what we've learned through this experience is to be very vigilant, not to just say, 'Oh, this is metastatic hormone sensitive, we can get away with not having any imaging whatsoever for three years,' which we used to see. Because now we have options and we can act even if the patients are not symptomatic. Because we used to be governed by an idea that there may be imaging progression but there's no symptoms, why treat? I think this culture is changing and that's the important part. So, coming to the part about…
HP: How patients tolerate these drugs.
EE: Well, the first shock is when you tell the patient, 'I think you need chemo,' because the culture, again, for a hormone sensitive newly diagnosed is, 'Chemo? Me?' And then you explain the breast cancer paradigm and it becomes more palatable. But you need to monitor these men, I think we all agree. It's not like in hormone sensitive we're seeing some toxicity, the same applies with abiraterone. I've had a lot of retraining and retraining to not drop that steroid. Patients don't understand it's not superphysiologic, you need to train them because you get in trouble. So I don't know, Nicolas?
NM: I fully agree with this. Almost nothing to add, except to be provocative with you.
EE: Of course.
NM: As usual. I fully agree that if you have visceral mets I would prefer to go for docetaxel except the evidence is very weak, almost non-existent, for that. We had patients treated with abi with visceral mets, they responded. Visceral mets equals poorer prognostic compared to no visceral mets. It's by no means strong evidence to suggest that giving chemo first is more effective than giving chemo later, provided they received all the drugs. Probably we all agree on that, probably, that the key message is give as much regimen as possible. So don't waste time using drug A then drug B then again drug A, at least four drugs, if not five nowadays, depending on country if radium is allowed or not allowed. You must receive all the drugs to have the longest survival. But visceral is a poor prognostic for sure, is it mandatory…
HP: It was out of LATITUDE, wasn't it? It was one of the three entry criteria for LATITUDE which I think made it quite surprising because chemotherapy you almost equate visceral mets with chemotherapy. I take your point completely but I think the choice is there. So perhaps we have too many choices.
NM: If I may. A question for Neal again. You said depending, senior adults, do you really believe age is a criteria for choosing abi or docetaxel? There's clearly a link between age and chemotherapy?
NS: For me personally, no. I think that I don't look to chronologically bias patients, I completely agree with you. It really comes down to performance status and it really comes down to having, and it's a bit of a hackneyed expression but I think it's actually pretty good, that we really do a better job of having that shared discussion and letting the patients decide. To your point, and you're absolutely right, the LATITUDE data the patients did remarkably well if you looked at the forest plot on visceral metastases as well. And maybe a part of it is just the historical biases that many of us have.
HP: I think, Neal, you've summed it up perfectly there because it all does come down to the multidisciplinary team and I thank my colleagues very much for being a great multidisciplinary team this evening. But most importantly it comes down to a discussion with the patient and I think that sometimes gives us very different views to, perhaps, what we would have thought initially. But ultimately we're a team, the doctors, the patient, their family, in making the right decision. I think we're sitting in a very happy place to say that we do have choices at the moment and potentially many more to come. So until we next meet, when I think there will be more trials available for this hormone sensitive setting, I'd like to say thank you very much for joining us.
