Prof Heather Payne – University College Hospital, London, UK
Dr Gero Kramer – Medical University of Vienna, Vienna, Austria
Prof Maria De Santis – Warwick Medical School Cancer Research, Warwick, UK
Prof Kurt Miller – Benjamin Franklin Medical Centre, Berlin, Germany
HP: Hello and a very warm welcome to this ecancer educational programme which is taking place at the twelfth Prostate Cancer Debate in Berlin. We’ve just finished what’s been a very interactive and extremely interesting meeting and I’m joined here by my colleagues to give you some of the highlights of our discussions over the last two days. So we have a good mixed panel of urologists and oncologists. First of all I’d like to introduce Professor Kurt Miller who is a urologist from here in Berlin, Professor Maria De Santis, who is my colleague in the UK but has also previously worked in Salzburg in Austria so has a very good understanding of the differences of management in different parts of Europe, and my final colleague, Professor Gero Kramer who is a urologist in Vienna. Thank you again for joining us. The first topic that I’d like us to discuss today has actually been the main theme of this meeting and this is centred around the information that we’ve had over the last two years and the very exciting data looking at the management of hormone sensitive prostate cancer. Perhaps I could start with Maria, would it be possible just to give us a very brief overview of the data for docetaxel given for hormone sensitive disease?
MDS: Yes, of course. We actually have three trials that were presented two years ago, one of which was presented a bit earlier. Our first trial was the GETUG-15 trial and this was a smaller trial and it was a negative trial for the addition of docetaxel to ADT. It did not show to improve overall survival but then came the two larger scale trials that both showed a significant improvement in overall survival when adding docetaxel to ADT. The first trial which was presented was the US CHAARTED trial; it was performed in patients that were basically primary metastatic patients and hormone sensitive. In this trial patients were divided into low volume and high volume disease patients. The trial by itself in the intention to treat population was positive and showed an overall survival benefit. This benefit was actually huge, it was many months and in the high volume population it was 17 months and this was unheard of in prostate cancer.
HP: It’s a really big difference, isn’t it, for any tumour.
MDS: Yes, so this was unheard of previously. Shortly after that the STAMPEDE trial was presented. STAMPEDE is a multi-arm and multi-stage designed trial and in the phase III part there were several trial arms that actually arrived at the phase III and among those was the docetaxel arm. Here again, the addition of docetaxel to standard of care which was, in most of the cases, ADT with an LHRH agonist. Again, docetaxel here showed to improve overall survival significantly but also secondary endpoints like the failure free survival were significantly positive in favour of the docetaxel. So these are the three trials and we have one negative trial and two large-scale positive trials. It makes sense to look at the meta-analysis which was done and also published recently. In this meta-analysis it was clearly shown that adding docetaxel improves overall survival and it is about a 9% improvement in overall survival when looking at the complete data. This was trial-based data, not individual patient data, but still a very solid and very reassuring result of the meta-analysis published by Vale and colleagues.
HP: In the last few years this evidence has really changed practice across the world. Do you think it was a good division having low risk and high risk with high risk being four metastases, one outside of the pelvis or spine, do you think that’s a good way to divide patients up? Because, certainly in CHAARTED, the low volume data didn’t show a difference in overall survival whereas the high volume data showed this very big difference. What are your thoughts?
MDS: I’m a little bit critical about this kind of division of patients. I know that in the US as the CHAARTED trial that actually divided patients into low and high volume disease patients liked to do that and it also became part of the guidelines there. However, I’m not entirely sure that this division is really the best way of choosing patients for life-prolonging treatment. The categorisation is pretty arbitrary because biological-wise it is not so clear if three, four or five metastases in the bone really make a difference. I think that patients with the primary diagnosis of metastatic disease in prostate cancer actually are at risk of dying of the disease and of developing problems, significant symptoms, from the disease and therefore I would recommend to treat them with life-prolonging treatment which is docetaxel in addition to ADT. To be honest, these patients will be in need of chemotherapy at one point in their course of the disease and the early addition of docetaxel actually improves survival by many months, 10-15 months, compared to the later use with only three months improvement of survival.
HP: It’s highly significant. Kurt, do you think that imaging is going to make a difference to how we look at high volume and low volume disease? Does it depend what scans we do?
KM: It would depend on the scans we do. However, as all the studies were based on bone scan and CTs we have no real clue if more metastases and PSMA-PET are predictive how treatment works. So it’s currently not really helpful for decision making in that specific situation. As Maria said, it’s really hard to make a selection where you say, ‘This patient does probably not benefit from the addition of docetaxel to ADT,’ that’s hard to sort out currently.
HP: It’s also very difficult because it’s just one factor, isn’t it? It’s counting the number of bone disease, we’re not taking into account the Gleason grade or nodal disease. So we all feel that there are certain problems with making this division between low volume and high volume. But we’re very happy with the docetaxel data and then, Gero, something else has happened this year.
GK: Yes, we are even more happy now because we have two large positive trials in hormone sensitive and castration naïve prostate cancer – one was LATITUDE and the other one was from the STAMPEDE trials. LATITUDE was including about 1,200 patients and that included high risk patients also in a kind of arbitrary inclusion criteria where two of three have to be met – one was Gleason score, one was visceral metastases and one was more than two bone metastases. This study was really highly positive with a hazard ratio of death of 0.6 and met also all secondary endpoints; that means that time to skeletal metastasis symptoms and so on were also prolonged. With STAMPEDE the inclusion criteria were a little bit different – about 60% had metastases, most of them bone metastases, but there were also 20% with only node metastases. There were also included high risk patients. Here we have the discussion again would we have a PSMA-PET, so the next generation imaging, probably also these patients would have metastases. So although this study was highly positive with a hazard ratio of 0.63 but with a broader spectrum of patients included. So the question, as it was an intention to treat analysis, if you could also include all the other patients for the future to give the combination of abiraterone plus prednisone in a dose of 5mg. So this will be discussed in the future. So, to sum up, a very positive two studies on abiraterone and prednisone and the next question is what we choose in the future – chemotherapy and androgen deprivation therapy, abiraterone and androgen deprivation therapy? The new studies in the future will answer this question.
HP: One of the questions that came from the delegates on several occasions was is prostate cancer going to become like breast cancer, so the high risk men will have chemotherapy and the lower risk men will have abiraterone? Of course, the LATITUDE study has completely gone against those thoughts that were in many people’s minds because in LATITUDE it was the high risk patients, it was the ones with the Gleason grades of above 8 and visceral disease and bone metastases who actually were getting the biggest… well, they were the population in the study, so they were getting the benefit. I think that has been a very interesting conversation, that it’s actually been the high risk ones in LATITUDE who have been shown to have this big survival advantage. Kurt, how do you think we’re going to choose? There has been some other evidence from STAMPEDE that was presented at ESMO.
KM: Correct, Matthew Sydes, who is actually the statistician of the STAMPEDE consortium, has presented data from a time period when patients were randomised to both the abiraterone experimental arm, so to speak, in the STAMPEDE trial, and the docetaxel. So that was no formal randomisation but it was, practically speaking, a randomisation. No statistical calculations beforehand but it was 560 patients so it’s the best sort of head-to-head comparison we have at the moment. The results show that if you look at failure free survival and both PSA failure and radiographic failure, or progression, there is an advantage for abiraterone which is understandable because you keep the patient on abiraterone. Then if you look at overall survival at the end, at maybe one of the most patient relevant endpoints, there is no difference. It comes down to the point if you start with the combination of ADT and abiraterone probably the majority of patients will get docetaxel once they’re progressing. So if you reverse the order and start with docetaxel then the majority of patients will get abiraterone once they’re progressing. If you look at it right now with a limited follow-up, still it seems to be that the effect is pretty much the same. That is not the point that we would base the decision-making on.
HP: So efficacy appears to be equal with both of the drugs?
KM: Yes, if you look at overall survival you can then discuss how important is failure free survival for the patient. Many patients are PSA addicted, they don’t like it if the PSA is going up. Actually in the CHAARTED trial, for example, it takes 18 months until the PSA goes back up again and in the LATITUDE trial it almost doubles the time. So is that relevant or is it not? It’s a subjective endpoint but it may be important and then we’re talking about side effects.
HP: So do you think choice is going to come more from quality of life associated with the two different treatments?
KM: It could be, yes. Side effects and quality of life, there is obviously some interaction between quality of life and side effects. If you look at the quality of life data of the abiraterone trials, specifically LATITUDE, in many domains it’s better in the abiraterone arm. We have some quality of life data also from the CHAARTED trial – we see that after three months quality of life goes down with docetaxel, which is to be expected, and then goes almost back to baseline after one year. So the overall picture for quality of life looks a little brighter for the abiraterone ADT combination than for the docetaxel combination but, of course, it’s hard to compare it, really, directly.
HP: I think for the future docetaxel has certainly changed all of our practices in that we’re treating men with hormone sensitive disease in this way and the data from abiraterone, obviously we’re waiting for licensing, but that’s going to have a big impact on our management over the next few years.
KM: The threshold to embark on the abiraterone plus ADT journey is a little easier than the threshold to the docetaxel plus ADT. It’s also all these patients are seen by urologists in a first step, also for urologists, even if some of them do docetaxel in some countries, it’s an easier step, they’re used to giving abiraterone now for more than three years and so on. So that’s a number of soft endpoints, so to speak, that probably this has a larger uptake than docetaxel plus ADT, but that’s just speculation.
HP: One of the comments that came from the audience yesterday was what if you don’t have access to abiraterone, and nobody has at the moment for this setting, but what if you don’t have access overall?
MDS: Here I think we can come back to the comparison that Matt Sydes presented showing that apparently adding docetaxel is similarly effective than abiraterone. Actually it’s reassuring and we can tell the patient also – ‘We don’t have abiraterone now, we have abiraterone if you progress and we will start the docetaxel now and the overall survival will most likely be the same.’ So this data is really important and reassuring for daily practice. We can explain to the patient that at one point they will get every drug.
KM: The question really is in the majority of patients docetaxel, ADT has gotten some continuous treatment with life-prolonging agents in the study. In an environment where you have no subsequent therapy that might again change the results you get because all the overall survival data are from all parts of therapy, not only from the first part of therapy. You must always keep that in mind, I think that’s important.
HP: I think that’s very important. One of the interesting discussions was actually going back to basics this morning, was looking at the side effects of ADT. I think it’s something that we often don’t discuss in great detail but obviously it’s the backbone of treatment for all men with metastatic disease and increasingly used in the neoadjuvant and adjuvant setting with radical treatments. So, Kurt, how do you manage your men on ADT? What do you do to try and prevent the toxicities because we’re seeing younger men, we’re hearing of men in their thirties what do we do for them?
KM: Yes. It’s probably not a really structured approach in the way that you use tables and nomograms and things like that. The easiest thing you can do, of course, you ask the patient in terms of how is he subjectively altered in his daily life in terms of side effects. That’s one thing, the other thing is about measuring bone density. To be honest, we don’t measure bone density. Sometimes in very elderly patients but that’s not the routine and it’s not the routine, I probably would say, in 90% of urologists in Germany that they measure.
HP: Do you think you should, or do a FRAX score just to pick those patients up?
KM: We don’t know. We don’t do DEXA scans, we don’t do this type of thing.
HP: But what about the FRAX index because that maybe would give you an indication you need to do bone density?
KM: No, probably not. We had the discussions repeatedly when these agents came into the equation and most urologists said, ‘Well, we don’t do this.’ It’s not a problem in their mind, it’s not a problem in my mind. So you can come up with a different opinion, of course, but that’s currently what I would see. Also we don’t do cognitive assessments like the guys from geriatric do, we don’t’ do this, we just ask the patient, ‘How do you feel? Do you feel that your daily life is a way impaired by this?’ Also I talk to the patient when I start ADT; we just can also switch from ADT to giving an anti-androgen. We have to see because it’s very heterogeneous. Many patients actually are not that much really influenced in their daily lives by ADT, that is my impression. Some are but not too many. Maybe they don’t report it when they sit in front of me.
HP: There are certain things that one can do to try and improve the overall health of men when they come to see you when they’re diagnosed with prostate cancer. So we’ve got an exercise programme that goes on at the moment and obviously exercise is perhaps the best way to prevent loss of bone density.
KM: That’s good. Yes, but the problem is to get the patient on the exercise.
HP: No, well…
KM: They have no choice in your setting.
HP: Yes, exactly, there are push-ups in the waiting room! I think it’s actually worked out extremely well because groups of men go off on an exercise programme and they actually give each other quite a lot of support in doing that so it becomes like a support group as well. Exercise is important to maintain bone density, measuring baseline cholesterol and blood sugar and, as one of our colleagues was saying today, doing a FRAX score to try and see those men and a lot of the older men, perhaps, do have a slightly lower bone density which, giving some calcium or vitamin D or bisphosphonate may be helpful. What do you think Gero, do you do anything?
GK: Yes, I’m doing more proactive management but also, as Kurt said, I talk to the patients. They have to change something if they do not any sport, so they have to exercise not only the body but also the mind.
HP: That’s good.
GK: I offer them to learn a new language, Chinese for example, so that they train. For me the most important work-up is before you start androgen deprivation therapy. I’m working together with a colleague from the internal department and he’s specialised in all these side effects. So we work together and every six months in the first two years these patients are going in this common evaluation of any side effects, also doing all this lab stuff like cholesterol and so on and so on. This works very well. It seems to be that if you start hormone treatment the first six months are probably the more critical ones which we didn’t expect at first. So in this time I try to see the patients more often and to have them in a more exact monitoring and then you can see if the patients complain about anything then you can directly try to solve this question.
HP: Because loss of bone density happens in the first six months, doesn’t it, so that it’s actually a lot quicker than we can predict. What about sexual functioning? Is that something that we just tell men when they start on ADT that they’re not going to get an erection again? Is there anything we can do to assist?
KM: There are two things – obviously it’s about erection, it’s about libido, both are significantly altered by this. There are some exceptional patients that can do something. With younger patients there are two ways to handle it, either, again, you think about giving an anti-androgen rather than ADT to preserve testosterone. Although the data are not so clear if it preserves erectile function, actually, over one year. That’s one thing to do or you get then counselling in terms of neurology and say what options do we have in terms of other drugs to do something about it. But at the end of the day this is a problem that is 100% associated with getting to castrate levels of testosterone.
HP: Do you still think it’s worth making an andrology referral? Penile implants and injects, do you think they help
KM: The question always is should you actively offer it or should you wait until the patient is asking it? Should you raise the awareness of the problem in the head of somebody who doesn’t have it before? So we rarely offer it actively but if the patient is asking you of course we discuss it.
GK: Yes, we are doing the same. I fully agree, also, with Kurt. The number of patients who have really a problem with this, because they are all overlaid about their disease, is not much. So I would say it’s below 5%.
HP: Do you think that’s because you don’t ask?
KM: Maybe, yes. Should you make a problem of it or not? That’s an interesting discussion. Maybe if we would ask more specifically we would stumble across more problems, you’re right, yes. But that’s of course also if we counsel a patient before we start it. This is a problem that is difficult to avoid, to put it mildly.
HP: It’s maybe something to think about for the future. I can feel a survey coming on here amongst patients. Now, just changing the topic a little bit, we’ve had some really great breakout groups. I just wondered if I could ask each of you to just summarise in a few minutes the sort of conclusions from each of the breakout groups? Gero?
GK: Yes, I was lucky to have the imaging group which is, of course, one of the most interesting upcoming themes because of the next generation imaging modalities – PSMA-PET and whole body MRI. To summarise, there were two things. First of all, all the studies were done with bone scans and CTs so all the answers were based on these two examinations. Now we have new imaging modalities which are, of course, more sensitive, which show metastases in different sites and earlier. So we learn a lot about the biology of the disease; we see metastases in the lungs or in the Verhoeff’s, lymph node very early. So what does this mean? Probably in the future we can stratify patients better, refer to the STAMPEDE inclusion criteria which are very broad. Interestingly, a lot more than we thought, I did that with Professor Badani, more people than we thought had access to these new next generation modalities. In the Prostate Cancer Consensus Conference in St Gallen about 50% were proposing these new methods for their patients but still we have no studies on that. We haven’t even good studies on the performance of these examinations concerning specificity and sensitivity but to tell you how the data, if you have a PSA level, for example, up to 0.5ng/ml after radical prostatectomy then you have a sensitivity of about 60% with the PSMA-PET which is pretty much, more than with other examinations. So that could help to make the right decision after radical prostatectomy. It makes a difference if you see a lymph node and you probably have to do a salvage lymphadenectomy or something else. So that will change the landscape.
HP: With that big change in practice for giving post-operative radiotherapy that if you see uptake in a lymph node that’s going to change your radiotherapy field completely. So that’s been a very good use of PSMA. Thank you, another subject that’s going to keep evolving over the next few years. Maria, you looked at the patients who were more difficult or with comorbidities.
MDS: Yes, indeed. We looked at patients that were elderly, patients with comorbidities and patients on long-term use of the new era targeted agents. Starting with the elderly, in the trials patients up to 90, 92 years were included. In daily practice the question is if we have cut-offs and if a patient of 90 would be treated or not. We discussed it in the group and actually, according to the guidelines, there is no cut-off. This was also echoed in the group and the international group of participants in the workshop, so this was pretty interesting.
HP: I think they’re right, though, aren’t they, because it should be the patient’s performance status and comorbidities rather than…
MDS: Yes, they are definitely right, because the way to assess the patients would be to look at the performance status, the biological age and not the chronological age. Also, due to the guidelines, to use a geriatric assessment but only with a tool that is called the G8 tool that is a pre-assessment and can pretty accurately tell you which patient would need more geriatric assessment and which patients would be fit to receive the same treatment as a younger counterpart. So this is also part of the EU guidelines.
HP: That sounds like a really useful tool.
MDS: It is useful, it is done in less than five minutes and gives you, actually, a good starting point for a treatment decision. So this was the first part of the workshop. The second part was on comorbidities and on assessment of patients before starting androgen receptor directed treatments. So, for example, cardiac assessment and internal medical assessment of the patients, which should be a standard but it is actually not in many practices. Some don’t have a good support in their practices and tend to do things themselves which is a big ask because our time is really restricted in clinic. Doing their own ECG and looking at blood pressure, etc., as a pre-assessment is a big ask.
HP: I think our multidisciplinary teams are going to get bigger as the future goes on as we need that support.
MDS: Yes, the MDT on the one hand and the other hand the set-up of the clinics where we follow those patients need maybe an additional person like an internal medicine colleague who would look after those patients and assess them. If they’re OK we can start the treatments but we would need to re-assess the patients. ECG would be a good baseline exam.
HP: I think cardiology is becoming more and more involved in the management of prostate cancer as we go on and I completely agree with you. I think also links with the care of the elderly doctors, perhaps, as we treat these older men to try and improve their performance status to allow them to have other treatments. Kurt, very briefly, oligometastasis, that must have been a very interesting session.
KM: It’s interesting in a way that is a lot of controversy. There is not a lot of data actually.
HP: That doesn’t stop us talking about it, though, does it.
KM: No, it doesn’t, quite the contrary.
HP: There’s more to talk about.
KM: You can discuss anything if there is no data and you can have any opinion on this. We’re pretty close, remember when we just discussed LATITUDE definition for patients’ inclusion – three or more metastases, at least an 8 or higher risk error set. Then you could decide either putting the patient on abiraterone plus ADT or taking the prostate out, which is kind of a totally different treatment. Also, should I irradiate on this metastasis. An interesting part of the discussion – there are some data, retrospective studies, showing if you use stereotactic body radiation you can have PSA responses ongoing for one or two years, is that good? You avoid ADT in that setting. So at the end of the day the message was don’t overuse this, do it in clinical trials whenever possible because we don’t have data and we need data badly. If you use local treatment there are side effects associated. The good thing about radiating bone metastases with a CyberKnife is there are almost no side effects associated so this can be handled generously if it’s available. However, the other things, keep in mind the effect is unknown but it’s pretty sure that you have some side effects.
HP: So we’ve got a lot to look forward to with trials that we hope are going to mature and give us some of these answers. I think the future is incredibly bright for prostate cancer at the moment. I just want to thank you very much for summarising and sharing your thoughts from the meeting and thank everybody very much for joining us in our discussions today. We hope this has been of some interest and we look forward to seeing you again. Thank you very much.
