Dr Neal Shore - Carolina Urologic Research Center, South Carolina, USA
Prof Karim Fizazi - Department of Cancer Medicine, Institut Gustave Roussey, France
Prof Kurt Miller - Benjamin Franklin Medical Centre, Berlin, Germany
Prof Nicholas James - Institute of Cancer and Genomic Sciences, Queen Elizabeth Hospital, Birmingham, UK
NS: Hello everyone, welcome to our programme today from ecancer. My name is Neal Shore, I’m the Medical Director of Carolina Urologic Research Center. We’re here live today in Chicago at ASCO 2017, today is June 5th. I’m truly honoured to have the opportunity to talk with my friends and my colleagues about some of the highlights that occurred this weekend at ASCO, some of the challenges that we still face in the diagnosis and management of prostate cancer and what is the future, what will it look like? What are some additional learnings that we want to attain? What are some of the newer trials that pique our interest? Most importantly today is that this is an interactive programme so you have the ability to write down and email in your questions. We want to have a very interactive discussion as well as a presentation of some really profound data which potentially should be very practice changing. I’m truly honoured and it’s a great pleasure to introduce to you to my immediate right Karim Fizazi, Professor of Medical Oncology at the Institute of Gustave Roussey in France. Next to Karim my very good friend Nick James who is a Professor of Medical Oncology at University of Birmingham in the UK and also my great friend Kurt Miller, Professor of Urology who is now at Charité in Berlin in Germany. So it’s really going to be a fun programme. I really would hope that throughout the programme questions that come up to any one of the individual panel members or to the entire panel, please send those in. We’ll try to address as many questions as possible.
So here are some of our disclosures, as you can see a lot of involvement for all of us with many different industry and with our government sources as well. Here are our objectives today. We want to discuss the current challenges that face you, whether you’re a medical oncologist, a urologist, a radiation oncologist, if you’re devoted to taking care of patients with prostate cancer. What are the issues around diagnosis and management? What’s particularly exciting today is we’re going to review two ground-breaking phase III trials. I’m so happy that the global PIs for both trials, Karim and Nick, are here to discuss them. Will this research change your practice management, that’s ultimately so important to why we do these trials? What does the future hold regarding ongoing and proposed trials and how will the learnings and the evidence that we have at ASCO in 2017, how will that shape our decision making?
Our first question for the audience is we welcome the European Asian audience today and, of note, on ecancer.org you’ll be able to after 24 hours get access to this live programme that you’re seeing today. But what are the greatest challenges today for prostate cancer management? Is it treatment of patients with high risk prostate cancer? Is it the management of castration resistant prostate cancer? Is it understanding the clinical utility of genomic assays, urine serum, tissue biomarkers? Or is it the interpretation and utilisation of diagnostic imaging? Of course all of these are important but we’d like you to just pick the one that’s most germane and interesting and challenging to you as an audience, a member. But let me first start with you, Karim, maybe you can opine a little bit, and they’re big topics. If you could take from the bottom the issues regarding utilisation of markers, whether they be genomic assays, protein and urine serum tissue and diagnostic imaging. A big ask of you but what are the things that just come front of mind for you?
KF: Regarding the last question about imaging, we’ve been living in advanced disease or even in localised disease mainly with bone scan, because metastatic prostate cancer is a bone disease mostly, and with CT scan because you might see some visceral metastases or lymph node metastases. We’ve done that for years and years. In the last decade, let’s say, this has probably evolved a bit with the use of whole body MRI and PET choline but there was still some debate. The next big question for the coming one or two years will be whether PSMA PET will totally change the field. It truly seems that PSMA PET is really able to identify tiny metastases that the other imaging are not able to do. If so, then really we might totally change the way we will treat these patients, not only locally but also systematically
Regarding the biomarker question, when you think about it amongst the four big cancers, at least in the Western world, breast cancer, lung cancer, colorectal and prostate, prostate cancer is the only cancer where we’re not using really precision medicine. So we’re not making our decision based on a given biomarker. Again, this is just about to change. We thought probably two years ago or three years ago that perhaps the AR-V7 variance would be the first biomarker to come to help us for decision making. I’m not totally sure about that, to be honest, and the biology of the AR is probably much more complex so there’s still much more work to do there.
Actually the first biomarker that may come out very soon is about DNA repair. This is because we now know that much more patients than we originally thought have DNA repair abnormalities, either germline or somatic, and also that we can target that. So I think this will really change quite, quite soon.
NS: You’re hitting incredibly important points, thank you. We’ll get back to that later on when we have some really interesting abstracts which are going to speak to exactly what you’re describing. Nick, you’ve been championing the STAMPEDE multistage multi-arm. It’s exceptional and once again you’ve brought some phenomenal information to us. It’s almost a semi-annual, annual event thanks to you and your colleagues. But let me ask you about the management of castration resistant prostate cancer, just the blue sky look. What are some of the things that you think about for a short answer?
NJ: The thing that is emerging in our practice, and it is being driven by PET imaging, just as Karim said; we’re currently using choline PET, we’re in the process of switching to PSMA. One of the things that we’ve seen which has been actually dovetailing in with the presentations that Karim and I have done over the last two days is we’ve seen spectacular responses to up front abiraterone. Then when these patients become castrate refractory the question arises is the disease different to the disease we saw before? I think the answer to that is yes and one of the things we’ve seen which we’ve been very intrigued by is we’ve seen patients starting with very extensively hot bone scans, getting PSA responses to undetectable levels then relapsing with just one or two sites of disease which we’re mostly imaging on PET because what we find is that some lesions are hot and some of the previous lesions are cold. So we’ve been moving towards giving radical radiotherapy to oligometastatic recurrences in previously polymetastatic disease. Talking to my colleagues, particularly at the Royal Marsden where they’ve got very good access to PET as well, this seems to be a theme that they’ve seen as well. So I think there’s going to be a whole new chapter in, if you like, the post-abiraterone CRPC space where they’ve had abiraterone up front where the treatment paradigm may actually turn out to be different to the CRPC pattern we have at the moment. Unravelling that is going to be really very interesting.
NS: So you’ve touched on great future learnings, controversies, oligometastatic disease and we’ll get into the STAMPEDE and abiraterone data as well as LATITUDE. Kurt, finally in treating patients with newly diagnosed high risk prostate cancer, what are your thoughts?
KM: Yes, it depends really if you’re on the metastatic side or on the non-metastatic side and somewhere in between is what just has been discussed, this oligometastatic disease. There’s a discussion on should we treat the primary in oligometastatic disease. Interestingly, you give one more metastasis and then it’s four and all of a sudden you’re in high volume metastatic disease and discuss chemo-hormone therapy or other combinations which we will discuss probably in a couple of minutes. So still it’s a pretty crude classification and we would need more differentiation here, as Karim has pointed out
NS: Gentlemen, thank you. A lot more discussion in front of us. Let’s get right to some of the really big highlights of ASCO. Again, awesome to have both Karim and Nick here to describe their presentations which were just jam-packed but, anyway, thank you for Karim to present the LATITUDE data.
KM: Thank you Neal. This is the LATITUDE phase III trial which was testing abiraterone and prednisone in patients with de novo metastatic prostate cancer. The data were presented yesterday at this ASCO meeting. Again this is really focussing on patients with de novo metastatic disease. The incidence varies a lot across countries; for example, here in the US it is thought to be around 3% but it’s rising, probably around 6% in Europe and Latin America but if you go to large countries from Asia such as China or India it can rise up to 60% of men who are diagnosed with prostate cancer. So it’s a big thing. As we all know, historically we’ve been using androgen deprivation therapy for these men and this is because it works, at least at the beginning, in almost 100% of them. Having said that, by a year these men have developed resistance to castration, at least for half of them; this is largely driven by reactivation of the AR signalling.
As we probably also all know, the field has changed two years ago and the standard of care has changed, thanks to three randomised trials – GETUG-15, CHAARTED and STAMPEDE – that could establish a role for docetaxel in terms of not only progression free survival but also overall survival with a hazard ratio ranging from 0.73 to 0.88 in overall survival
LATITUDE was about abiraterone, abiraterone is a CYP17 inhibitor so it’s preventing strongly the making of the androgens, not only from the testes but also the adrenal sources and prostate cancer sources as well. It was a quite straightforward randomisation and we selected patients with de novo metastatic disease who were really at high risk of dying from their disease. High risk was defined as men with at least two of the three high risk criteria: a high Gleason score, more than three bony lesions and visceral metastases. It was a classical phase III trial where men were randomised in a one-to-one fashion to get castration plus or minus abiraterone and prednisone given at 5mg daily or placebos for abiraterone and prednisone. Two co-primary endpoints: overall survival and RPFS. A big, large global trial and docetaxel was not used as a standard of care just because the trial was designed and completed its accrual before the trials establishing the role of docetaxel had read out.
A classical population of patients with metastatic high risk disease, I won’t detail that too much, many of them obviously had bony disease. Most of them had a high Gleason score and actually most of them had many bone metastases. So nasty cancers, obviously. This is the main, most important results about overall survival, one of the key co-primary endpoints. What we saw was a 38% reduction in the risk of death. The median in the control arm was what we were expecting, 34.7 months and it was not even reached in the abiraterone arm with a 30 month median follow-up. So at three years 66% versus 49% overall survival rates.
Across subgroups we saw a real benefit in terms of overall survival. This was true, for example, for patients in good and poor performance status and also, and this is also very important, those with and without visceral metastases. The second co-primary endpoint was radiographic progression free survival and here again, obviously, abiraterone wins. This was a 53% risk reduction in radiographic progression or death; median less than 15 months in the control arm versus 33 months in the abiraterone arm so this was more than twice improved.
This data came together with many other good findings in terms of time to PSA progression, time to pain progression, which is obviously very meaningful, time to symptomatic skeletal events, again very meaningful, and time to chemotherapy, time to subsequent prostate cancer therapy, which are meaningful, not only to patients but also to society in terms of use of resources and cost. Generally speaking, the benefit that we saw was truly related to abiraterone use up front and I’m saying that because most patients in the control arm received life prolonging therapies such as docetaxel, enzalutamide, abiraterone, cabazitaxel, radium-223, actually twice more patients received these drugs in the control arm. So we’re telling that the true benefit we see in overall survival is clearly linked to up front abiraterone.
In terms of safety we basically saw what we already knew from the abiraterone experience which is an excess in hypertension and hypokalaemia, slight excess in transaminase increase, which is really not an issue, and also a slight excess in cardiac disorders.
So, in conclusion, LATITUDE clearly established that for these men with metastatic high risk prostate cancer using abiraterone and prednisone up front significantly improves overall survival with a 38% reduction in risk of death which is obviously just great, and also a significant improvement in radiographic progression free survival. Safety profile was not really an issue, it was really what we were expecting. Based on that, I really believe that we have a new standard of care for these men with abiraterone prednisone being added on top of castration. The data were published yesterday in The New England Journal of Medicine which is just great.
NS: That’s fantastic, Karim, congratulations to you, your co-investigators. And what a great opportunity for our audience and for everybody at ASCO to have your phase III trial and now Nick’s very similar, some differences we’ll discuss, and looking at very similar populations, some nuanced differences. But really looking at that combination of abiraterone acetate with prednisolone and ADT. So thank you Nick.
NJ: Obviously great to be presenting these things back to back and the results are strikingly similar. As you said, they’ve got some interesting differences as well. So these are the survival results from the abiraterone randomisation in STAMPEDE. STAMPEDE has a number of different randomisations within it, so highlighted in yellow here are the patients we’re looking at today. I won’t go over the rationale because Karim has just done it. STAMPEDE includes a broader range, so newly diagnosed patients were 95% of the total into the trial and they had to be either metastatic, pelvic node positive or high risk locally advanced. All of those patients, the last ones, the T3/4s, got radical radiotherapy as well and about 60% of the node positive ones got radical radiotherapy as part of their base care. We did permit relapsing patients who had had prior surgery or radiotherapy but without significant amounts of hormone therapy but actually they only made up 5% of the total. Pretty standard inclusion criteria in terms of performance status, consent and so on. Stampedetrial.org is the trial website; all the protocols and everything are on there if people want to look them up.
We had a single primary outcome measure of overall survival and we also showed data on three of our secondary outcomes: failure free survival, toxicity and skeletal related events. A simple one-to-one randomisation, as with LATITUDE. Our target was a 25% survival improvement and we had three interim analyses which we haven’t published but which met their pre-set criteria. So we had 90% power and 0.025 1-sided alpha to do this analysis.
We recruited just under 2,000 men extremely quickly this time, [?? 18:17] is very efficient at harvesting patients, if you like, into trials, and randomised as indicated equally. Patient characteristics obviously differ from LATITUDE so PS2s were permitted but were only 1% of the total, 21% performance status 1, so just under 80% were PS0. Median age in the late 60s with a very big range, 39 up to 85. Just over half were metastatic and just under 90% of those had bony metastases so a slightly lower bony metastases proportion than LATITUDE. Then we have the other two populations, the node positive 20% and the node negative locally advanced 28% which obviously aren’t in LATITUDE at all. So there are some differences here. As I already mentioned, the ones to whom you could give radical radiotherapy in the main did have radical radiotherapy.
Our primary outcome was overall survival and we had 262 control arm deaths at the point of the data freeze versus 184 on abiraterone. That gives you a hazard ratio of 0.63 which is astonishingly similar to the LATITUDE one at 0.62. It means the data are really very convincing. So that’s a 37% improvement in survival. The curves you’re seeing here are overall survival for the entire population and then M0 and M1. For the M1 patients I didn’t show the curves but the median survival is about 40 months, so a little bit longer than LATITUDE, reflecting the fact that we’ve got all of the metastatic patients in the M1s, not just the high volume ones. So there are some differences in the metastatic patients. We’re projecting, the dotted lines you can see on here are the mathematical best fit curves so we can project those forwards. We’re thinking the median survival of the metastatic patients is going to come out somewhere in the region of 6½ to 7 years and given the hazard ratio is the same for LATITUDE I would imagine that will be similar, slightly shorter, reflecting the worse prognosis.
When we set STAMPEDE up we were anticipating the median survival of these patients was 2 to 3 years, so that’s a staggering improvement in a decade and a bit driven by obviously all the new agents that we have but in particular shifting them upstream. So the Forest plot, everything lines up, as with LATITUDE, over the point estimate for the trial. There’s no convincing evidence of heterogeneity by the various stratification factors we looked at. We did look at metastatic status in more detail and I’m sure this is going to generate a lot of discussion and controversy as to whether this is a dichotomous population and the two groups behaved differently. There’s not very many deaths here, which is obviously great news, but it means we can’t fully power that sub-analysis. But if you look at the way that the confidence intervals and the point estimates line up they overlie each other. There are more deaths in the M0 patients from non-prostate cancer causes which obviously dilutes your benefit because they’re not impacted by abiraterone. But the test for interaction by metastatic status is convincingly negative, it’s not borderline negative. So our conclusion, as already stated, was there was no evidence of heterogeneity so we feel these data apply to the M0s as much as the M1s. It was tested in the whole population, the whole population is positive and the test for heterogeneity suggests the effect is uniform.
Further evidence for the effect being uniform comes from the failure free survival data so we’ve got a lot more failure free events. A huge difference, as seen in LATITUDE, with a hazard ratio of 0.29, we have slightly different criteria. 61 leading zeros in the p-value of 71% improvement. The Forest plot here, again everything lines up over the point estimate, no good evidence of heterogeneity and in this case, if anything, the hazard ratio is more favourable for the M0s although we think there is no heterogeneity. So just skipping on to the skeletal related events, as with LATITUDE these are obviously extremely important and what we saw, this is focussing on the metastatic ones on this curve, is a 0.45 hazard ratio, a 55% reduction in skeletal related events, again mirroring LATITUDE. So the two trials are very consistent in their impact across all these key outcomes.
We also looked at new treatments and we looked at it in a slightly different way in terms of how we presented it. So from relapse time to life prolonging treatment is very similar but the pattern of treatment is different. Actually this is a point of difference between the trials because we are open label clinicians knew if their patients had abiraterone or not so we see far more use of AR targeting therapies in the control arm than we do in the abiraterone arm which is point of difference between the trials driven by the different design.
Safety outcomes, I won’t spend too much time on these. We saw almost exactly the same – increased cardiovascular hypertension, cardiac arrhythmias and ALTs. In principle these are grade 3-5 toxicities, in practice they’re not very hard to manage. Compliance, again this is a slight difference, we saw 21% stopping, apparently for excessive toxicity. We haven’t yet matched that to the reported toxicity in those patients. For the patients stopping at two years 70%, just about, got to completion of treatment.
So our conclusions are very, very similar to LATITUDE – abiraterone acetate and prednisolone improves survival by 37% across the population; failure free survival, on a slightly different definition, by 71%; SREs or symptomatic skeletal events, what we collected, go down by 55% which we think is clinically, and actually from the economic point of view, extremely important. It was well tolerated and the toxicity mirrors the CRPC setting. So, as with LATITUDE, we think this should be part of the standard of care for men starting on to androgen deprivation therapy, including the M0s. Now I appreciate that might be controversial but that was our conclusion.
NS: So all I can say to that… go ahead.
NJ: Sorry, that’s just the same slide. So added in The New England.
NS: Congratulations Nick, to you as well, phenomenal work. My response would be ‘Wow’ to both but I want to… Kurt, you’ve been involved in so many trials and you’ve seen so many things during your career and still actively doing so many great research projects and seeing patients. What do you think of this data?
KM: Yes, it’s still, as you say, at a considerable wow factor. It’s in the uppermost percentile because that is really, in terms of consistency and in terms of the dataset, it’s really unique I would say. For me there’s no question that it will be practice changing and Nick just opened Pandora’s Box in a way, I would say where’s the limit exactly? I wouldn’t discuss de novo metastatic disease, that’s pretty clear, but then again STAMPEDE has also M0 patients, patients with lymph node metastases, so where exactly do we stop with that and that will be the questions of the future, I would think. For me, in metastatic disease I think that’s going to be the future standard.
NS: Let me get back to you again, Kurt, on this. How will this change your practice tomorrow when you get back from Chicago and you see patients? You’ve been a believer and an adapter to the chemo-hormonal approach, what are you going to do now?
KM: We’re going to send up a letter because it’s not approved yet. We’re going to send up a letter for the insurance companies to try to get this financed because it will take about six months until approval is through the process and until that time most probably patients will ask for it. News is around very, very quickly so I think that’s the first practical step. We discussed this yesterday among German urologists and to get the patient to this treatment we would need to convince insurance companies. There is some financial toxicity in comparison with chemo-hormone therapy so that’s the only hurdle I would think.
NS: We are going to have a polling question and we’ll take the financial toxicity off the plate. I think it’s really important that the audience heard the data, the safety, the tolerability. When abiraterone acetate was first approved, as well as the androgen receptor signalling inhibitors enzalutamide and the newer ones that are out there, it was in the advanced CRPC setting, post-chemo then pre-chemo. I think many people thought at the time we can’t give these in the androgen sensitive state, there will be too much long-term toxicity. I’ll start with you, Karim, and, Nick, I would like you to weigh in too. Were either of you surprised with the incredible stability of in the safety adverse event profile? It's quite amazing for the duration of patients being on drug for so long.
KF: I guess you’re very right. Actually I had the same fear some years ago when we moved from [?? 27:59] 1 to [?? 28:00] 2, which was basically the post-PIVOT, post-docetaxel phase III trial when we know we were not using abiraterone for a long time to the pre-docetaxel setting where some patients who had received abiraterone for years and years. Actually I was quite reassured when I saw that even with long exposure to abiraterone prednisone there was no real increase in the toxicity burden. Actually it’s pretty much the same thing here, in order to trials in castration sensitive disease. Having said that we need still to be cautious - these patients need to be monitored very closely in terms of hypertension and kalaemia and also their liver test needs to be monitored. For specific patients who are at risk for cardiovascular issues we need also probably to take our time, refer the patients to the cardiologist, make sure we can really handle the cardiac problems as best as we can before considering the drug. But generally speaking this drug is quite well tolerated.
NS: A great comment regarding our patients who start off with ADT and/or now abiraterone, those who have baseline cardiovascular morbidities we have to be more careful with them and so on.
KF: I think so, yes. Actually we have a little time because in the trials the patients had the possibility to start with castration alone and then be randomised after a month or two. So this probably gives you a nice opportunity to discuss with the cardiologist in these specific cases.
NS: Nick, similarly a question to you regarding the AE safety profile and then a little addition to it. You used prednisolone 5mg daily, Karim in LATITUDE you used the same, so is that now your recommendation in the CRPC population too? What are our learnings from that?
NJ: To be honest I don’t know. The toxicity and safety profile is fine with 5mg, there is some concern because of the half-life of prednisolone that you’re only suppressing the ACTH feedback loop half of the time. That didn’t seem to matter very much and the differences are subtle, to be honest. Overall the toxicity, I entirely agree with Karim, was very manageable. We were concerned about long-term dosing so in the M0 patients we had capped the treatments at two years and actually capped the ADT at two years as well because we didn’t want to keep on dosing people, a lot of whom do extremely well, just to come back to Kurt’s point of how far to the left down the spectrum do you go. But basically it’s a very well tolerated treatment.
NS: Kurt, what do you think about that for urologists? Medical oncologists are extremely comfortable with steroid variation of preparation medications, maybe urologists in the beginning when abiraterone acetate first came out the notion of giving even low dose prednisone was a little bit of a new learning period, there was some concern and worry. Does this data resonate for you as well?
KM: As Nick said, I’m not sure if it really makes a difference in terms of 5mg or 10mg because with the 10mg you didn’t see much toxicity from the prednisone either. But in terms of urologists I would say after a couple of years getting used to prescribing prednisone in the meantime this is not an issue anymore. It will not be a hurdle for this type of therapy.
NS: We’re getting questions from the audience, here’s one for you gentlemen. Will this data impact patients who have just begun taking docetaxel as up front therapy based upon CHAARTED and STAMPEDE, the chemo-hormonal, assuming on appropriate inclusion criteria? Should they cross over from ADT and docetaxel to ADT and abiraterone acetate? Similar would be should they add abiraterone acetate? So two highly charged questions within that.
KM: May I take that one?
NS: Please.
KM: Okay. I don’t think a patient who has started already docetaxel and who has tolerated that well should discontinue. The benefit of docetaxel on overall survival and PFS is quite well established so if the patient is doing okay in terms of safety I would probably recommend him just to continue and complete the six cycles. Now, whether abiraterone should be added on top of that we just don’t know at the moment. We are actually randomising the question right now in Europe in the PEACE1 phase III trials where patients are actually receiving ADT and docetaxel as a standard of care and randomising the role of abiraterone and also that of local treatment with radiation therapy. So hopefully we will be able to complete the accrual in a year from now or even perhaps less than that but for now we really don’t have the answer. When we asked the question yesterday at ASCO to the attendees it was quite split in the audience as to whether people would be keen to combine already right now or wait for the data to mature and see whether we should do it or not.
NS: Nick, what do you think about Karim’s comments but then also a nuance to that question, there’s combining but then what do you do if you’ve just completed your six cycles of docetaxel to the androgen sensitive metastatic patient? Do you then at some point add abiraterone?
NJ: I’d have to agree with Karim, it’s tempting to infer that you might get the dual benefit and we know that you can give docetaxel and abiraterone and abiraterone is active post-docetaxel because we’ve got very solid CRPC experience with that. I would have to say you really need trial data because it will be a financial cost, as Kurt has pointed out. The other thing I would re-echo is within STAMPEDE the docetaxel and the abiraterone arms were recruiting for an overlapping period of time so we have about 600 men who, if you like, are randomised between docetaxel or abiraterone. So we’re going to run that comparison formally and present that, subject to it being accepted, at ESMO in the autumn. We’ve submitted a late breaking abstract place marker. But our take is that it looks, as Eric Small pointed this out in the discussion yesterday, that the CHAARTED survival advantage and the LATITUDE survival advantage in the same population look to be very similar. So I don’t think patients are missing out on survival gain by not having had abiraterone, given that they can have docetaxel. That is part of the answer as to what we’ll be saying in clinic this week when we go back is that actually you can have a treatment that will give you just as much benefit but with different toxicity, obviously.
NS: Kurt, here’s a question that’s saying, ‘In the future, going forward, I’ve been on abiraterone acetate and prednisone and ADT for my androgen sensitive metastatic disease,’ and now the patient has converted to CRPC. No new bone lesions but multiple bone lesions. What is your recommendation?
KM: Obviously this does not only change the way we treat hormone sensitive disease it will also change the way we treat castration resistant disease because so far I would say 80-90% of patients, at least in my country, have got either abiraterone or enzalutamide as first line therapy in CRPC. Now it obviously doesn’t make sense to give them abiraterone which they already had and it probably doesn’t make sense to give them enzalutamide with a potential 25% response rate for five months at best. So, yes, it will change the way we treat CRPC and probably docetaxel will now, again, move to first line CRPC treatment in these patients because that’s probably the best next step once you are under progression getting RB and ADT.
NS: Another question, both the LATITUDE and the STAMPEDE demonstrated highly statistically significant delays in SRE. By the way, both of your datasets had lots of zeros in those p-values, it was pretty darn impressive. Can you tell us about the use of antiresorptives in the trial? Do you have that information – zoledronic acid, denosumab?
NJ: In the up-front therapy previously in STAMPEDE we had shown pretty conclusively that up-front zoledronic acid added no benefit at all. Getting patients ONJ didn’t have an impact on bony outcomes or survival so we don’t think we have any antiresorptive therapy prior to relapse. There may be some post-relapse, it’s hard for us to capture that data but certainly pre-relapse there will have been no use, I don’t think, in the STAMPEDE population.
NS: LATITUDE?
KF: Yes, pretty much the same. The role of denosumab and zoledronic acid is already established in castration resistant disease so some patients received it in LATITUDE for castration sensitive disease with basically no data but it’s really a minority.
NS: Here’s a question about the cost of therapy and, Nick, you mentioned the economic utility. I’m sure you must have both in your datasets more health related quality of life outcome data to talk about. So as we move to this, throughout the world, value-based care can you comment on this issue of cost versus quality of life, toxicity and making a decision between taxane based therapy and an oral androgen biosynthesis inhibitor?
NJ: We’ve just analysed our quality of life data from the docetaxel but we haven’t published it yet; the paper is in preparation. The striking thing about that is that quality of life goes up if you have docetaxel, not down, overall. You obviously have a dip while you’re having it but once you’ve had it there is a QALI, quality adjusted life year, gain in the docetaxel arms, M0 and M1, compared to the control arms in our earlier data. When we looked at the health economics of that it turned out that up front docetaxel was cost effective, in fact it was cost saving in the M0 setting and very low cost in the metastatic setting. The thing that drove that was the reduction in SREs because SREs are expensive and really hit your quality of life. So preventing a lot of SREs is very cost effective. So although there is a cost to abiraterone we’ve seen bigger effects on time to relapse and SREs than we saw with docetaxel although it factors down to the same survival effect probably. So it probably will turn out to be cost effective. Crudely you have 18 months of abiraterone in the castrate refractory setting to give you maybe six months extra survival and that was cost effective. So in STAMPEDE we doubled that to 36 months, give or take, but we probably are bolting about three years survival on. So you’ve got 18 months extra buying you an extra several years. So it probably will come in under the cost effectiveness radar threshold.
NS: Karim?
KF: Yes, I guess the analysis will be formally conducted so we need to wait for that. But I quite agree with Nick, it’s really by lancing the cost with what you’re saving on the other hand. Also, at least in Europe, the cost of abiraterone really depends how many patients are receiving it, so it’s decreasing if you’re using it in more men. So we need the data and that’s very important. All the societies just can’t afford all the new drugs coming for cancer so that’s really key. Again, given the large efficacy benefit, the good toxicity and the fact that it’s very easy to give this drug, no IV etc. etc., I think the data will be reassuring.
NS: Excellent. We have a polling question for the audience. You’ve heard the synopses of these wonderful presentations and some discussion. Based on the data that we just reviewed, how would you now look to treat a newly diagnosed prostate cancer patient approximately aged 65 with presumed multiple positive bone metastatic lesions on bone scan? He’s got evidence of visceral metastatic disease, perhaps two small liver lesions, an ECOG performance status of zero. So your answer options are ADT only; abiraterone acetate and prednisone plus ADT, your choice of ADT, it doesn’t matter; ADT plus docetaxel six cycles or ADT plus docetaxel six cycles plus abiraterone and prednisone. Please assume that whatever country you are working and living in that there is no regulatory or funding or clinical trial restrictions, so you have access to all therapies.
While the audience is going through that, Kurt, what are your thoughts regarding the role for some of the other androgen receptor signalling inhibitors out there? Are you aware of any trials or data in this same population that could be compelling your interest in the near term?
KM: Obviously, and we just saw that with the poll, one of the questions popping up now is should we also combine docetaxel and abiraterone or other androgen directed compounds. Yes, there are trials underway like for combining ODM201 and docetaxel plus ADT versus docetaxel plus ADT and the like. That’s got to be the next question, obviously, is it okay to have a triplet or is it okay with the combination of ADT and ABI or docetaxel.
NS: Fantastic. Now let’s go over and have just a quick review of several really provocative abstracts. Karim, please.
KF: Thank you Neal. I selected two abstracts, one is the PLATEAU randomised trial that was presented Saturday by Gerhardt Attard. It’s really looking at an important question which is basically in patients who are progressing while on enzalutamide should we just continue enzalutamide when we’re using another drug as a salvage treatment? This is the design of the trial, many men were enrolled and screened, so they were men with castration resistant disease, metastatic castration resistant disease, who received enzalutamide. At progression they were randomised to receive abiraterone plus a placebo or abiraterone plus enzalutamide. So the key question again was should we continue enzalutamide when it’s failing. The primary endpoint was PFS and there were other secondary endpoints with a key secondary endpoint of radiographic progression free survival.
What the data show is that by the primary endpoint it’s a negative trial so PFS is pretty much the same, less than six months, when you’re combining ABI and ENZA in this manner and six months also when you’re using abiraterone alone. Now, for the key secondary endpoint there is a strong trend supporting better efficacy for ENZA plus ABI, ten months versus seven months. I wonder whether also this is clinically meaningful. If you’re looking at the PFS events it’s true that less patients are progressing radiographically when they’re receiving the combination, 38% versus 55%, but actually it goes the other way around. When you come into clinical progression, which are obviously meaningful, 25% of events in the combo arm versus 18% only in the abiraterone arm. So I’m not sure having an image worsening is really a signal that we should use a combination treatment when the clinical assessment is doing worse.
So the conclusion for this presentation is that it’s a negative trial. There is no good reason at the moment to support combining the two treatments at progression, at least when we’re using the sequence of ENZA first and abiraterone second. Again, regarding the signal in our PFS, I’m not that sure that it’s really meaningful given that the clinical progression went the other way around. I actually prefer having the patients doing well and imaging worsening if I have to choose. This is it for this abstract.
NS: Thoughts on the data from this abstract, Kurt?
KM: We would seldom stick to the sequence ENZA first and ABI then because what we know from admittedly very small datasets is ABI works not very well following ENZA. Then I’m not sure if that is really relevant for clinical practice, if we should continue giving ENZA in that setting. As Karim said, it’s a negative study so for me this is off the table.
NS: Nick, your thoughts?
NJ: Yes, I would agree with that. We’re not allowed in the UK to use… we have to choose one agent or the other then we have a three month window to switch if there are tolerability issues but after that we can’t switch. So this is a non-issue for us and none of the UK oncologists have felt it necessary to make much of a fuss about this. We don’t think the sequence is very good.
NS: There are some interesting things about the theme of is more necessarily better? So here ENZA ABI, theoretically maybe it’s more powerful, I guess it was trying to show that. But yet in the LATITUDE and STAMPEDE we’d combine to get a more powerful response. Different patient populations, different therapeutics but it’s in that concept of sometimes more is better, sometimes it’s not.
NJ: Yes, I think it’s in the context of adding things when you’re winning versus adding things when you’re losing, clearly the biology is different is what you’d conclude, isn’t it?
NS: Absolutely.
KM: The second abstract I selected is about, again, precision medicine basically because this is really something that we need more efforts and hopefully more victories about. We’ve been trying to identify biomarkers predicting for sensitivity or resistance to docetaxel for years in France and this is a report from two phase III trials that we conducted within the GETUG, so the French group. We were looking at various biomarkers that we hypothesised might have a role for prediction with regards to docetaxel efficacy.
GETUG-12 is in high risk localised disease and we randomised the standard of care of radiation plus ADT plus or minus docetaxel. GETUG-15 is an up-front metastatic phase III trial where we were randomising the role of docetaxel on top of ADT. So different situations but basically the same question – should we use docetaxel, yes or no. Regardless of the results we were trying to collect tissue and we looked at the expression of ERG, PTEN or PTEN loss, Ki67 and Rb. We were doing that by immunohistochemistry just because at this time we didn’t really have methodology to do much more than that and we didn’t really have access to frozen tissue.
The primary endpoint that we looked at was relapse free survival, progression free survival. What we saw regarding ERG is striking. We know that approximately half of prostate cancer have TMPRSS to ERG aberration, so the TMPRSS2 gene and the ERG genes are put together. Because of that these results see an increased ERG expression and ERG is an oncogene. So what we saw was that for patients with a high ERG expression docetaxel seems to work and that was quite clear across trials. For example, when you’re looking at time to relapse in GETUG-12 or relapse free survival 80% in men who received docetaxel, 68% in men who did not so quite a big difference for patients in high risk localised disease while for patients with negative ERG expression there was really no difference. The same pattern was seen in patients with metastatic disease in GETUG-15, for patients with ERG positive cancers basically their median relapse or progression free survival was almost double, 19 months versus 11. There was not much improvement in patients with ERG negative cancers.
So perhaps for the first time, and of course we are cautious in that, we still need validation, perhaps for the first time we have a gene or a protein that might help us for decision making, if this is confirmed, to try to better select men who are more likely to benefit from docetaxel. So we’re very happy about this data, of course we need confirmation to make sure that this is true.
NS: That’s excellent. Nick, Kurt, thoughts on this? Getting more precision based so we really know right therapy right patient?
NJ: As Karim said earlier on, it’s strikingly different between prostate cancer and, say, breast cancer where the disease has long since been sliced up into different subcategories by biological markers and it’s long overdue that we’d start doing it in prostate cancer. These data look interesting, for sure. It’s great work.
KM: I can echo this, that’s what we need for the future, to get better differentiation. Now we’ve got many more treatments and we need to know who is the candidate for this treatment, who is one for the other and that’s a step in the right direction, definitely.
NJ: So the two abstracts that I’m discussing, the first one was one presented by Maha Hussain. This is something we’re very interested in because obviously there’s an emerging story, as again already mentioned, around patients with certain DNA repair mutations, BRCA2 and so on, being susceptible to treatment with PARP inhibitors. This is a study that mirrors the TOPARP study which Johann de Bono’s group has been doing at the Royal Marsden which showed that if you had the right mutations you responded to PARP inhibition. This is a variant on that where the group were testing a PARP inhibitor, veliparib, plus abiraterone in a randomised fashion and then they collected and analysed the genomic data.
A straight randomisation, in this case looking at ETS status for stratification. The primary outcome was PSA response rate with a range of secondary outcomes – objective response, progression free survival and so on. On the primary outcome measure for the whole population, essentially this is a negative trial; the PSA response rate is a little bit higher with veliparib but not statistically significantly so. But the thing that was interesting really relates to the behaviour in the different subgroups. A number of the genes, PTEN, p53, PI3 kinase, were associated with different PFSs which is interesting, although oddly it appears not necessarily quite what we expected to see. But also the response rates differed according to whether you had the DNA repair deficiency or not. So basically with the DNA repair deficiency you saw a much bigger benefit with veliparib which mirrors the TOPARP study. Also various prognostic factors around biological markers, there was some debate as to whether these directions of effects were in the right direction but the bit that was interesting for me was the association between the DNA repair deficit and the PARP responsiveness going up which replicated the TOPARP study. That was the thing that was interesting.
NS: Kurt, any thoughts on the use in the trials, there are a lot of them out there now, on using PARP inhibitors and the landmark paper in The New England Journal, Mateo and de Bono’s TOPARP study? Now there’s really a plethora of all these trials.
KM: Yes. I think what Nick mentioned, that the direction probably in the future we’re going to test these patients. Actually I do see patients where I discuss this. PARP inhibitors obviously are not approved for prostate cancer yet but they are approved for ovarian cancer and the testing is also approved for [?? 54:29] cancer and that’s probably the next step. The interesting thing here was, if I get that correctly, also even for ABI alone you saw better results when the patient had this DNA repair deficiency which is a counterintuitive thing. So that’s something we need to clarify more, I think.
NJ: The trial was odd in that respect and the things that we thought should make you do worse appeared to make you do better in the data Maha presented. Also the second abstract that I’m going to talk about now, it has looked at some genes overlapping and saw the opposite directionality of effect. So clearly there’s an issue, I suspect, around validation of assays, how you’re doing the tests, what exactly it is you’re testing.
This is a sort of variant on one of the papers Karim looked at which is a crossover trial. Patients were randomised between receiving abiraterone and receiving enzalutamide and they then crossed over to receive whichever agent they hadn’t received and then you’re looking at the time to progression over the whole two treatments as the primary endpoint. So is there a better sequence – ABI-ENZA or ENZA-ABI? The short answer to that is no but the thing that is more interesting here was that they collected circulating tumour DNA and looked at the impact. There are two things interesting about this, one is that circulating DNA is a much easier thing to collect than circulating tumour cells and they were able to show that if you had DNA repair deficit collected from the circulating DNA you did substantially worse, so the opposite finding to Maha’s paper. But it’s the methodology that’s interesting here because this is a technology that’s replicable. Similarly for p53, AR mutations, Rb as well, they were all associated with worse outcomes from circulating tumour DNA. This is coming back to where we started around biomarkers; this is a technology that is easier to replicate in the clinic and will find its way into both selection of therapeutics, because you predict the DNA repair ones should be amenable to PARP inhibition. It also raises the possibility you can maybe use it for monitoring – does the circulating marker disappear if you give a PARP inhibitor, for example. That wasn’t obviously addressed in this study but it’s a very obvious extension from it.
As I said, in terms of the ABI-ENZA, ENZA-ABI there’s no difference, it doesn’t matter which way round you do it and I would argue just do one. But it was the circulating tumour DNA outcomes which were interesting because they both appeared to have prognostic significance but potentially predictive significance in relation to therapeutics that are now in clinical trials.
NS: Just closing in on time. We have the audience poll response and based on our polling question, here is our polling question, and here is the response by percentages.
NJ: Drumroll.
NS: Yes, a drumroll please. How would you now look to diagnose this patient who has high risk androgen sensitive metastatic disease with a good performance status? ADT only – 3%; ADT plus abiraterone acetate and prednisone – 79%; ADT and docetaxel – 3%; ADT, docetaxel, abiraterone and prednisone – 14%. Are those results surprising to you or is it…?
KM: That’s what you would expect. We just presented very convincing data so that’s how the mind works. What you heard last, that gets stuck in your brain.
NS: But didn’t you say in your session you thought it was still… did the audience get polled and it was about almost an even split?
KF: The question was more would you use just one treatment or would you combine? So more people were keen to combine already while probably we have a half or two-thirds, I can’t remember, were more keen to wait for data before combining. I’m not that surprised either, remember when you asked the question you told people this is assuming the drugs are available in your country, there’s no restriction. So basically if you try to compare the various trials the feeling is that docetaxel and abiraterone have quite similar efficacy or overall survival benefit, even if it’s not that easy to compare and people will obviously choose the less toxic compound. My answer would have been randomise C and D and this is actually what we are doing because at the end of the day we really want to know whether three drugs is really better. Hopefully we will have the answer in a couple of years from now.
NS: That’s very well said. I would like to give the panel an opportunity just to have some concluding statements, your thoughts on what we’ve discussed today, ASCO, the ground-breaking trials that you’ve both been championing. Let’s start with you Karim.
KF: Maybe I will come back to what Eric Small said during his discussion of my paper which was at the end of his talk he reminded people that basically we’ve been using castration alone for seventy years for these men with de novo metastatic prostate cancer with a long series of negative phase III trials. This changed back in 2015, so just two years ago, with a demonstration that docetaxel should be used at least in fit patients with a debate about how many metastases, all these things. But clearly practice changed two years ago and now in 2017 we’re changing again the field and the standard of care with abiraterone. So we’ve just continued changing the field like that and accelerating research that’s going to be fantastic for all the patients.
NJ: Absolutely, I can only agree with that. As always when you make an advance you create new questions and new problems. I think practice will change, clinicians and patients are mostly going to prefer abiraterone over docetaxel. There may well turn out to be a role for docetaxel and abiraterone and Karim’s PEACE1 study is going to be extremely important in answering that question. We will then be faced with quite difficult problems as to what you do if you’ve had docetaxel, abiraterone and then you’re castrate refractory, you’re kind of running out of options. So we will have a whole raft of new problems to deal with and, as always, you answer one question you create another one.
NS: Well said. We’re just trying to keep these folks, if not cured, alive as long as possible, out of the emergency departments, out of the hospital, quality of life.
NJ: If you did indeed prolong survival by 25% by bolting docetaxel on top of abiraterone you’re already at seven years or so for median survival with metastatic, another 25% you’re out at ten. So that’s starting to look pretty good.
NS: Thank you. Kurt?
KM: Yes, it’s kind of disruptive innovation, I would say. It’s like the iPhone but it’s a little bit easier to use. The good thing is really it took some time until the docetaxel thing was adopted, also for the urological community, this is much easier. So it’s a low threshold thing to get this in your daily practice and I think that’s what’s going to happen. As Karim said, it’s good for all patients.
NS: Great final comments, I don’t have anything to add other than to say thank you so much for your presentations, your participation, the leadership you’ve shown. These are not easy things to accomplish these large trials and getting the patients in. You have huge numbers of collaborators that I know you’re both incredibly grateful for and all the patients and the families. We’re doing so much better in prostate cancer, it’s really remarkable. You said earlier, Nick, what’s happened and the median overall survivals have changed significantly in the last few years, thanks to all this research.
I want to thank the folks from ecancer. If you want to watch the programme again you can go to ecancer.org and if you’ve got other colleagues who want to see this you can get to that as well, it will be on and archived for some time to come. So, again, gentlemen thank you so much. It’s been great to share this time with you at ASCO and thank the audience for listening.
