RJ: Hello and welcome to the 2019 ASCO annual meeting here in Chicago. I’m Rob Jones, I’m a medical oncologist in Glasgow in the UK and I’m here with Nick James from Birmingham, Ian Davis from Melbourne and Axel Merseburger from Lübeck in Germany. We’re actually going to talk about a concept which didn’t really feature much in clinical practice until five years ago and this is the concept of additional treatments at the time of first androgen deprivation therapy in patients with hormone sensitive metastatic prostate cancer. Nick, since those first data five years ago at this meeting, we’ve seen a plethora of other data in this area. Do you want to just summarise that for us in particular with emphasis to your trial, the STAMPEDE trial which, of course, has been a big part of those data?
NJ: Yes, it’s been a very exciting time, obviously, to be practising oncology.  Moving on from the CHAARTED data which Chris Sweeney presented 2014, wasn’t it, we obviously had the confirmatory data from STAMPEDE the following year.
RJ: This was docetaxel?
NJ: With docetaxel up front, followed quite quickly two years later by STAMPEDE and LATITUDE showing pretty much the same effect in terms of the impact on survival, different effects on failure free survival from up front abiraterone. Obviously the thing that has been added in terms of drug treatment at this meeting which is the ENZAMET trial, which Ian’s going to talk about I’m sure, and apalutamide. In addition for low volume disease STAMPEDE showed that radiotherapy to the primary improved survival by actually about the same amount as docetaxel and abiraterone if given at the start of treatment with or without docetaxel. So for low volume disease we’ve got a multitude of options – docetaxel, abiraterone, radiotherapy, enzalutamide, apalutamide.
RJ: There was also that curious comparison within STAMPEDE, this is relevant to the conversation we’re about to have, where there was a direct comparison, albeit an unplanned comparison, between docetaxel and abiraterone.
NJ: Absolutely. So the docetaxel and abiraterone arms overlapped to the tune of about 600 patients so although technically they were randomised against the control, effectively they were randomised against each other. What we saw was that the hazard ratio between docetaxel and abiraterone, obviously unpowered but planned, the hazard ratio was 1 for prostate cancer death. Abiraterone gives you a longer time to progression than docetaxel but, of course, you’ve used up comprehensively one of your therapies so that the CRPC duration post-abiraterone is much shorter.
RJ: So the conclusion from that really was that, the stage of the data before this meeting at least, was that you could pretty much choose between docetaxel and abiraterone, at least in terms of efficacy.
NJ: Absolutely. And it’s been quite striking in the UK, we can’t currently use abiraterone up front and there has been very little pressure from clinicians to have abiraterone adopted because we are comfortable with the idea that docetaxel gives you the same survival benefit.
RJ: So we’ve seen two new trials in this arena at this meeting, or the new results of two trials. The first one was the TITAN trial, Axel, do you want to just tell us a little bit about what that trial was and the headline data from that trial?
AM: Yes, thanks. So definitely, as Nick alluded to, we had some game changers in 2015 with the CHAARTED data and STAMPEDE data. 2017 another game changer with abiraterone and now 2019 I think this is another game changer is introduced in our armamentarium of the treatment of prostate cancer. So we have apalutamide which we know is approved in some countries in the EU and the US in non-metastatic CRPC, a selective androgen receptor inhibitor which has been shown results a couple of days ago here at the ASCO conference, a phase III trial. More than 1,000 patients and the primary endpoint, co-primary endpoints of overall survival and progression free survival were positive. So this resulted in a New England Journal publication, Kim Chi presented this data a couple of days ago. I think it’s a game changer, hazard ratio 0.67, I think we’ll hear the number in a couple of minutes again from ENZAMET, this is a coincidence. Then we have 0.48 for progression free survival. So really great data supporting the use of apalutamide in this de novo metastatic prostate cancer setting.
RJ: When you say game changer are there clear differentiators between this trial and the trials that have gone before? Apart from obviously being a different drug.
AM: Definitely. And let me give you an example. So in Germany we have some requests from urologists and also oncologists whether we have high volume disease, high risk disease, can we use or should we use docetaxel, should we use abiraterone. In Germany abiraterone is only licensed in high risk disease so what we know the risk factors are and docetaxel suggested to be used in high volume disease, however STAMPEDE suggests a similar thing. But this is an approval situation and here with apalutamide we have the all-comer indication which is a new thing and that’s why also I cued it in with the game changing.
RJ: We’ll maybe come back to the high volume, low volume thing in just a minute but, Ian, the other big new data we saw at this meeting, actually in the plenary session, were the data from the ENZAMET trial. Do you want to just take us through those key findings and, again, what makes that trial different?
ID: Thanks Rob. So we’re seeing some consistencies here and some extra pieces of information starting to flesh out the picture. So ENZAMET was very similar in design, it was testing the question of addition of enzalutamide to testosterone suppression in men with metastatic hormone sensitive prostate cancer commencing treatment. We found very similar outcomes to TITAN in many respects.
RJ: And it was all patients regardless of volume, regardless of risk factors?
ID: Correct, that’s right, yes. So we found very similar findings to TITAN in that respect. There was an overall survival benefit for the whole population with a hazard ratio of 0.67 and about a 60% reduction in the risk of progression when enzalutamide was added to the entire population. There were fewer distinguishing points from ENZAMET with TITAN and with ARCHES, which we heard about earlier this year. One was that the control arm in ENZAMET included a standard antiandrogen, so flutamide, bicalutamide or nilutamide. The second distinction which was brought in in the second version of the protocol after about 88 patients had been recruited was that we allowed concurrent docetaxel to be used at physician choice. That was not randomised but we did stratify for that.
RJ: But it was actually quite a large proportion of the patients randomised in the trial had had docetaxel, had they not?
ID: That’s right. In the end about 45-50% of patients received docetaxel, more in the high volume group but a substantial proportion in the low volume group as well.
RJ: So has ENZAMET answered the question about giving docetaxel and an androgen receptor targeted therapy?
ID: I’d love to say yes to that but no, it hasn’t. So we found some interesting findings. In men where a decision had been made that docetaxel was to be used we saw no additional benefit in terms of overall survival by adding enzalutamide. More than that, we saw some additional toxicity. We saw the expected enzalutamide toxicity but we also seemed to experience more docetaxel related toxicity and that’s still unexplained.
RJ: But you did show quite a significant effect on clinical progression free survival even in that subgroup of patients who had had docetaxel, did you not?
ID: That’s right, yes. So the benefit was most pronounced in the men who did not have docetaxel but in terms of progression free survival, which was the secondary endpoint, PSA progression free survival or clinical progression free survival, there was an additional benefit from adding enzalutamide there. So we need to see if that benefit eventually translates into a survival benefit and also whether the additional toxicity measures up in terms of the quality of life data that we hope to generate over the next few months.
RJ: Thanks very much. There are a couple of broader points that I think it would be really useful to tease apart here. So let’s just talk a little bit more about that sequential versus combination, should patients just get one drug, should they get chemotherapy and an androgen receptor targeted therapy? Nick, what’s your feeling on this?
NJ: Well my feeling is that actually your trial and taken together with TITAN and ARCHES does answer the question because, as far as I can see, there’s a very strong signal that you only need one treatment. There’s a very striking lack of any separation of the OS curves and, as you say, an increase in toxicity. And there was some evidence of harm if you had docetaxel plus apalutamide in the TITAN trial. You certainly dilute your failure free survival benefit and you’ve used up two of your salvage treatments instead of one. So I can’t see any particular advantage and I can see substantial disadvantages to putting two treatments in. So I would feel it just leaves us, you’ve got a choice of single agents but I would just very strongly think you should only have the single agent.
RJ: Axel, are there any patients you would want to give both docetaxel and an androgen receptor targeted therapy to in the hormone sensitive state?
AM: The combination, and that was clear from the ENZAMET presentation, I go along with Nick’s summary that besides adding financial toxicity I see no clinical benefit as of yet. This is different in TITAN which is a different trial design. We had 11% patients with prior docetaxel but this was prior and not concomitant like in ENZAMET. So this was like half of the patients had a combination, half of the patients had a sequence in ENZAMET while in TITAN, the different trial design, it was like a sequence and then the question derives what comes after progression. But I totally agree that the three combination backbone ADT and something else makes sense but not the triple combination.
RJ: And of course there are other data that we’re going to see in the near future, I imagine, which will give us more information about this. So we seem to be agreed that a patient should have either docetaxel or an androgen receptor targeted therapy, how do we choose? Your data have shown that there’s no difference in terms of efficacy. Axel again, maybe, how do you think we should choose which patient should get docetaxel and which patient should get whichever your choice of apalutamide, enzalutamide or abiraterone might be?
AM: That’s a big question now and in case we have all four approved now, approved and also financed, this is a decision we have to make with the patient according to side effects, according to toxicity. You know, the peripheral neuropathy and the hair loss in docetaxel which some won’t affect with it and some it makes really a difference in quality of life. This taking into account and on the other hand in apalutamide you don’t need the prednisone which you need for docetaxel, at least when you give it which you need for abiraterone which is different, with enzalutamide you don’t need it. So there are some factors that differentiate among the treatments but we don’t have head to head, for example, abiraterone, docetaxel as of yet. So given the data we have from TITAN, given the 33% risk reduction of death, I would feel very confident starting in this all comer situation with apalutamide.
RJ: Ian, any thoughts from the Australian perspective on this?
ID: The Australian perspective is pretty straightforward, we’ve only got access to docetaxel in this setting. But there’s another way of thinking about that. This is a fear of missing out situation and I don’t think anyone out there should feel that if I’ve been recommended to have this treatment and not this one that in any way that they should be missing out.
RJ: It provides reassurance?
ID: It provides reassurance, there’s no wrong answer here. I think any of these options individually is reasonable. So it comes, really, down to a discussion with the patient – what is their particular circumstance? Do they have other comorbidities? Are there financial implications? Are they happy to have a long period of treatment with an oral hormonal agent or a short sharp course of six cycles of docetaxel and get everything out of the way? Everyone has a different preference and every answer is a reasonable one.
RJ: So what about volume of disease, burden of disease, however you want to label it? Nick, what are your feelings on this and helping us make this decision to choose how to treat patients?
NJ: Yes, as you obviously know, I have quite strong views on this because I feel that the CHAARTED high volume, low volume thing is a bit of a manufactured distinction driven by relatively small numbers, underpowered, and it has changed on the two different analyses they’ve done. They came to one conclusion for the first and a different conclusion with the second in terms of the test for interaction and stuff. So in STAMPEDE we don’t see any evidence that docetaxel only works in one subgroup and we’re going to show further data on this at ESMO which obviously I can’t comment on in detail. But I think it’s a mistake to say that docetaxel doesn’t work in low volume patients, I very much think it does.
RJ: And I think we’ve fairly comprehensively seen that it makes no difference at all in terms of any of the androgen receptor targeted therapies as well.
NJ: Absolutely, yes.
RJ: What about radiotherapy to the primary?
NJ: We presented data at ESMO last year, Chris Parker presented it, and we published it obviously and we published a meta-analysis with the HORRAD trial. So very convincingly we saw pretty much exactly the same hazard ratio, rather than as we see with the androgen receptor targeted therapies, between two different trials testing essentially the same treatment, radical radiotherapy. So we are very convinced and the peer reviewers at The Lancet were very convinced it was a robust conclusion...
RJ: But that was just positive in the low volume as per the CHAARTED definition?
NJ: We used the CHAARTED definition just to make ease of alignment with other trials. We’ve actually done some sensitivity testing of the imaging thing and we’re not so sure the CHAARTED way of classifying is necessarily the best way but it’s a way that’s used so it’s easy to cross compare. But the survival gain was around the same, it was between the survival gain of docetaxel and abiraterone. So it’s a big gain from a really quite short, simple treatment.
RJ: So you’ve got a patient with low volume, newly diagnosed metastatic prostate cancer. You’re going to give them ADT, you’re going to give them radiotherapy.
NJ: I think so.
RJ: Are you going to give them another drug too and if so which one?
NJ: Until we saw the data here I would say for sure these are different classes of drug or different classes of treatment, you’d give both. Now, I was very surprised by the lack of the extra impact from giving two treatments so I maybe have to be a bit more cautious about saying that. But in the next arm of STAMPEDE the control is going to be treatment to the primary plus drug treatment of choice and we’re expecting that people will give abiraterone, docetaxel or whatever according to availability, not just ADT only.
ID: Can I expand on that point? It’s very tempting when a good idea comes along to say, ‘This is what we should do. That drug works, that drug works, we must get better bang for our buck by using both.’ So I’d really discourage people from going down that pathway and I think what we’ve seen here is we need the evidence to guide our treatment.
AM: I totally agree and we see some part, a sparse part of evidence in TITAN, 17% of the patients had local treatment, about 7% radical prostatectomy and 10% radiation to the primary. In the subgroup analysis benefit from apalutamide treatment we have some part of sub-analysis surely knowing that this is not the primary endpoint but I think this is where the trend is going to.
NJ: We have this data with docetaxel as well, I think it’s a very good point. So within the RTM1 around 10% had docetaxel and the hazard ratio for benefit from radiotherapy is the same whether or not you had prior docetaxel.
AM: So justified to give?
NJ: It was obviously underpowered but it suggests that it’s reasonable to give both.
AM: And still I don’t know about ENZAMET but in TITAN we had the time to initiate enough apalutamide, we could give six months’ ADT, in ENZAMET I think it was four months’ time until you intensified treatment. So you have some four months to half a year where you can discuss with the patient and look at the PSA what happens when you do treatment of a primary.
RJ: So I think we need to draw the conversation to a close now but I guess the good news is that all of these studies are coming back positive. It’s very clear that ADT alone is no longer the standard of care for anybody with newly diagnosed metastatic prostate cancer. You should consider other treatment for everybody, clearly there will be some patients not suitable. And actually there’s a choice out there and there’s no clear guidance, with the possible exception of the radiotherapy group, as to exactly how we choose. So we probably shouldn’t regret too much the choices that our patients make.
NJ: I think that’s a very important point, yes.
RJ: Well, thanks very much. It’s been great talking to you all here. We’ll just draw to a close now, the ASCO meeting is coming to an end and we’ve had a great few days.