Promise of personalised medicine for patients with prostate cancer

Dr Eleni Efstathiou - MD Anderson Cancer Center, Houston, USA
Dr Alicia Morgans - Northwestern University Feinberg School of Medicine, Chicago, USA
Prof Karim Fizazi - Institut Gustave Roussy, Villejuif, France
Prof Gerhardt Attard - University College London, London, UK

EE: Hello everyone. We are actually holding another round table of discussions regarding the GU ASCO updates and in general the ASCO updates in prostate cancer for the past two months. I think that ecancer has become a home to very nice and very exciting discussions and we’re always joined by rock stars in the field. So today our title is a little bit more sexy, about the promise of personalised medicine for patients with prostate cancer and I’m joined by people you know so, so well – Dr Morgans, Dr Attard and Dr Fizazi. I couldn’t understand who I should go first with when it came to the gentlemen, of course I went for the lady first. We’ve kind of prepared a little bit how we’re going to go about it, given that some of us are already involved in a lot of the trials that we’ll discuss. We’re trying to put on our independent hat, of course. As you know we’ve got quite a bit of disclosures but that gives us more the opportunity to understand what’s going on and give you the inside view of things. Then those of us who are not participating in those trials are going to give how we see it from the outside. So without any delay I’m going to turn to Alicia and she’s going to wow us about what happened during this last GU ASCO that’s going to make a difference with what androgen signalling inhibition, it’s kind of an oxymoron because we’re still used to using the enhanced androgen signalling inhibitors. But Alicia, your take home messages?

AM: Great, well thank you. Even though we’ve been investigating androgen receptor targeted therapies for well over a decade now and have been intensifying for a long time, there are still updates and things to learn and certainly there were some high profile presentations at GU ASCO focussed on this. The TITAN study update was presented and this was a four year median follow-up for patients who had metastatic hormone sensitive or castrate sensitive prostate cancer who were treated with ADT, with or without apalutamide. We saw that this clearly demonstrated a continued overall survival benefit related to that combination of ADT plus apalutamide in the metastatic hormone sensitive setting. Quality of life was maintained and really across subgroups there was a maintained and continued benefit. So this combination, this intensified strategy, seems to hold up quite well, as we would expect, and that was the update there from TITAN.

EE: I’m going to stop you there for a minute and jump into Dr Fizazi. Karim, I know you’ve been so involved with the development of darolutamide, the newcomer. We’re all anxious to get the data that’s going to come out of the trial, the phase III with darolutamide, it’s the only one that hasn’t reported. How soon should we expect them, what do you think? I know you can’t tell us exactly but where are we?

KF: Right, well I can tell that the accrual is completed and obviously events are coming. So I think we should see the data not in the too long future, so maybe this year or the next year. You’re right, this is the purest trial testing darolutamide on top of ADT plus docetaxel. There are two other trials looking at this combination with enzalutamide or abiraterone, namely ENZAMET and PEACE1. I also think that we will see data from these two other trials perhaps this year. So let’s say that maybe a year from now we should have a much better overview about whether three drugs is better than just two in men with M1 disease.

EE: So you said it, that’s going to be the big difference because until now we’ve been looking at ADT plus one, mainly, even though TITAN did have a few that had received first docetaxel then went on and ENZAMET did too. But Gerhardt, you also promised we’re going to see something from STAMPEDE coming soon through, your trial, I mean you’re the PI.

GA: Yes, so the comparison from STAMPEDE which hasn’t reported is the combination of abiraterone with enzalutamide plus ADT, of course, versus ADT. Therefore to ask the question about benefit over abiraterone plus ADT or enzalutamide plus ADT, an indirect meta-analysis approach will be required. Given the significant benefit with abiraterone or enzalutamide alone, hazard ratios of 0.63, 0.6, I suspect we will not have enough power to conclusively show a benefit for abiraterone plus enzalutamide plus ADT versus either alone. But let’s wait and see and I guess it’s all the more pertinent given the results from ACIS.

EE: Good, I like your approach. It’s like you’re preparing us for the worst so that we can be happy with what we get. Really, that’s a nice way to go. But joking aside, really it’s like the movie – when you say too many good things then everyone’s disappointed. So that brings me to the first trial that’s actually reporting positive and both Gerhardt and I have been really heavily involved – ACIS in CRPC. Alicia, back to you and get your thoughts on that first positive trial and how you view those results in mCRPC, of course, not hormone naïve.

AM: Yes, so this was a really interesting trial because these patients in the first line mCRPC setting had not received an intensified strategy in the metastatic hormone sensitive setting. So they couldn’t have had an AR targeted agent or docetaxel when they entered into this first line mCRPC ACIS trial. In the study they were randomised to abiraterone plus apalutamide or abiraterone alone and they were followed for a primary endpoint of radiographic progression free survival. Overall survival was a secondary endpoint; there were quality of life assessments. So what we saw in this study was, as you said, the primary endpoint of radiographic progression free survival was longer in the combination arm of abiraterone plus apalutamide by about six months. What I found most compelling about this was that this was investigator assessed radiographic progression free survival for the primary endpoint for the study but they did actually do a retrospective central review of the radiographic progression and found a high concordance and a consistent positive endpoint there with that central review of the radiographic progression. So that seemed to be a quite durable endpoint, was quite strong. There was a slightly higher rate of adverse events by the CTCAE criteria but although there was a slightly better quality of life for the abiraterone arm by patient report in the beginning, as the study went on, and throughout the study generally if we look at it overall, there were no real differences in patient reported quality of life between the intensified arm and the single drug arm, which is important too because if you’re going to intensify but people feel a lot worse that’s definitely something that you have to consider. Whether you’re in clinical practice or in clinical trials that can make a big difference when we’re making the decision to intensify. So it was positive but with caveats.

EE: I was going to get to that. You were very honest. The whole idea of making positive and important… I believe it was over 7 months at the end of the day, the final analysis, the difference is also to get a better quality of life. Sometimes the tools that we use are not the best and what have you but, in your opinion, the fact that we… if I understood that correctly, you are saying that the fact that we didn’t see yet in this secondary endpoint that difference kind of takes a little bit away. Forget the OS for a minute, it takes a little bit away from that rPFS, is that right?

AM: I would say not necessarily because I do think if you’re not making people feel worse you’re actually maintaining quality of life and prolonging progression, that’s a good thing. What I think took the wind out of some people’s sails related to this is that the overall survival for the trial, so a secondary endpoint, not powered for that, was not significantly different. That’s what took a little wind out. But the other piece is that, in the United States at least, when we have to get both of these drugs there’s going to be potential financial toxicity that was not recorded in the trial. It’s not something that we can measure when drugs are provided for free and so that is the other barrier that people think about when they’re thinking about the combination strategy. But if you have a better outcome and you’re not making people feel worse, that’s still a win on some levels.

EE: I’m going to take the European Union opinion by Dr Fizazi, making it very formal, and then the ex-European Union, UK, opinion from Dr Attard. Do you think there’s a future in these combinations because it’s like we’re looking again at the docetaxel plus but this time we’ve got a positive trial, regardless of comments. Karim?

KF: I actually quite agree with what was just said by Alicia. At the end of the day as doctors, and probably as patients, what we want is a treatment or treatments that can easily prolong life or make your life easier, basically. rPFS is something we’re using because the agencies like it, or kind of like it for approval, when we are not necessarily able to show overall survival improvement. Basically in the practice nobody really cares about rPFS. I’m not measuring rPFS in my routine practice and I’m pretty sure that you are not and patients don’t really care about it. We’re not necessarily counting the metastases.
So I think that it’s okay if a trial has a primary endpoint of rPFS because this is mandatory for approval reasons and because this is an objective thing, basically. But it has to show something on top of and on top could be, of course, overall survival but also pain control or better quality of life, I don’t know, lower cost – different, very important things to patients in society. And here this is not an example where we do see something on top of rPFS so I don’t think that this will fly due to that.
Now, having said that, I think that it’s still showing us, scientifically speaking, that the AR axis remains very key in this disease and that perhaps with super-abiraterone or super-enzalutamide or apalutamide or whatever we may be able to show more meaningful benefit to the patient. Basically, abiraterone and apalutamide very probably, like apalutamide or abiraterone or enzalutamide, share pretty much the same mechanisms of resistance, at least part of them. So the incremental benefit of apalutamide on top of abiraterone is there but it’s not super-big. Now, if ever we are able to invent other drugs that better target the AR axis when the cells are able to resist the current generation of agents, then we can really make a difference and probably this is what ACIS is suggesting, basically.

EE: Thank you for that, you can be also provocative at times, as I saw. ‘Nobody counts rPFS’ he said. So that was actually, to a significant degree, the reality. I was just thinking when you said that that what becomes important is the peace of mind that you have a patient who is not experiencing serious progression events. But it seems that these trials are not looking as much at skeletal related events because we’re early in the disease. But I’m going to take it to Gerhardt for one comment in the interests of time. You’re left now to defend ACIS, of course, and I truly believe and agree, and I’ve said it multiple, multiple times, we have to figure out subsets of patients who will get a benefit from the combo. But you’re also the person who presented the PLATO trial as a big trial in sequencing and you’re the person who prepared us for the next step in hormone naïve. Gerhardt, your thoughts or your wisdom on that – where are we going?

GA: I agree with Karim. I think what excites me the most is the potential biological message that blocking both androgen synthesis and AR antagonism appears more effective than blocking androgen synthesis alone. Potentially when you use abiraterone alone you salvage with subsequent AR antagonism, the trial is not going to tell us that, we don’t have the power. But I find that biological message, very intriguing. Hopefully that will translate into a much bigger benefit when started with ADT.

EE: So it could be that those feedbacks that we had reported from MDS [?] a while back might be a little bit true but may not really relate as much to across the board. So we’ll wait for more from you, Gerhardt. Back to you for one comment, Alicia. Finally we are getting a transition to even earlier in that high risk space which for the United States and Europe and the UK is an important unmet need with 70% of men being at risk of recurrence. Are we getting anywhere? What was the prospect within GU ASCO?

AM: There was a nice trial in progress presented. DASL-HiCaP is a study where we’re trying to intensify androgen suppression, both within the primary radiation setting where we’re using a combination of androgen deprivation in addition to radiation, of course, and in the post-prostatectomy patient population that’s so high risk that they still have a detectable PSA post-prostatectomy. In this study they’re using darolutamide to do that extra little kick of androgen suppression to see if that intensification can make a difference. That trial is in process and we will see. But it may be another trial from the ANZUP group, from Chris Sweeney, that ultimately ends up changing our practice, we will see.

EE: Karim, your thoughts? You’re the darolutamide master, master PI, tell us about it.

KF: I guess, regardless of the drug, I think that really I strongly believe that the concept will fly indeed. Eventually and probably not in the far future we will be using next generation hormonal agents in high risk localised disease. Actually I think that Gerhardt and his group in the UK and in Switzerland will really lead the charge, thanks to STAMPEDE. I think that abiraterone data because, as you know, there was an abiraterone arm in STAMPEDE including some patients with high risk localised disease, I guess the data will mature. I don’t know if Gerhardt can comment on that, maybe this year, maybe in the coming years. If I had to bet something I would bet quite a lot on abiraterone showing metastasis free survival and perhaps overall survival in this setting of high risk localised disease.
So I think this will very likely be the future for patients and then there will be, of course, questions around how long we should use these agents, the balance between the likely benefit and the toxicity. Of course also the cost for society, let’s say that if it’s abiraterone this will be a generic drug as opposed to enzalutamide, apalutamide, darolutamide which are not. So all these questions will apply but I strongly think that, indeed, these drugs will move in this space.

EE: Thank you very much and, again, we can’t give enough thanks to the STAMPEDE folks for starting all this and making a difference. But you just said something about the future and it’s been very elusive when it comes to immunotherapy in prostate cancer. So we’re going to move on to immunotherapy and where we stand. We’re not there yet, we know, but what did you, from your experience with the trials and what was reported during this GU ASCO, go away with? Do you think we’re closer to identifying subsets or enhancing somehow the impact?

KF: You’re very right, it’s surely something quite terrible, the history of immunotherapy in this disease. Because we basically know that some patients clearly benefit, sometimes fantastically, with a province of cures of metastatic disease like a decade after that. I do have those patients and that was reported. But, on the other hand, we haven’t been able to show this in a meaningful way. What we saw at this GU ASCO included data testing IOs in men with either neuroendocrine differentiation and/or what are called aggressive variants. Very small trials, very negative. The hypothesis made sense; you may remember we hypothesised that indeed these crazy aggressive cancers might be associated with a range of neoantigens so that IO might work. But actually it doesn’t seem to be the case. Actually probably the only patients who benefitted had an MSI high cancer.
Having said that, it was a mixed bag of mostly aggressive variants, ten patients, and only five patients with neuroendocrine differentiation. So we may have missed the signal; at least I think we need to be cautious when it’s really a small, small group of men. But it’s negative.
Now, in parallel to that two phase II trials tested IOs, nivolumab in one and pembrolizumab in the other one, together with chemotherapy of docetaxel chemotherapy. Here of course the data looked good, if you will, because there is efficacy. But, to be honest, even if I was deeply involved in one of the two trials it’s really hard to say whether we are doing better as compared to what we would have seen with docetaxel alone. Even in a population of men pre-treated with abiraterone or enzalutamide docetaxel works. What we saw was pretty much a 40% response rate, even by RECIST, and, say, 8 months progression free survival. So it’s probably in the highest range of what you would expect with docetaxel alone but whether it’s truly different I’m not really sure.
Based on those data, the two companies made the decision to start big phase III agnostic trials. So without selection on molecular grounds, which I don’t really like, to be honest, but I can understand the industrial decision, if you will. So we will see eventually whether there is a benefit. But I think, more and more, for immunotherapy we should design trials in subset populations of patients and test a given hypothesis. This makes much more sense to me.

EE: Well it’s going to have to end up to be investigator initiated big groups like STAMPEDE and the like that are going to push the agenda. Having said that, you guys know better than I that they are designing these big phase III trials from the standpoint that they’ve got approved agents on the market already so there’s not a lot of risk for pharma, unlike what has been the case for other agents such as satraplatin, for example, that we were discussing that lost it and other trials. In the interests of time I’d like to get a comment from you, Gerhardt, on what is the future of immunotherapy, especially when we see trials being transitioned to the hormone naïve space, such as the KEYNOTE, without even having the robust data that Karim alluded to. But then I want you to go into what must have been the most sexy presentation for the second time in a big meeting and that is, of course, the data that we have on theranostics, Lutetium-PSMA, and where we’re going with that. So, all yours.

GA: I agree entirely with Karim. I have my reservations on treatment of unselected patients with IO given the very clear response rate is less than 30%. So I think enough said on that. I think it’s even trickier to interpret when introducing these therapies at the start of ADT but time will tell. If nothing else, there’s a small group of patients who could benefit from that treatment, given the opportunity to take part in that trial.
So, moving on, this is a precision medicine session and beautiful work by Michael Hofman and Peter Mac in Melbourne. That follows on from I think it was the first prospective phase II trial of Lutetium-PSMA. There’s the follow-on asking the question about best treatment in patients progressing on docetaxel. More than 90% had also received an AR targeting therapy. About 200 men randomised between cabazitaxel after progression on docetaxel or PSMA-Lutetium. They screened I think it was 280 and the devil will be in the detail. This will become very interesting but clearly they have a robust or a biomarker that has been well thought through. Their eligibility requires PSMA positive disease, 20 or more at one site and more than 10 at the other with no discordance with FDG-PET. That’s interesting because I don’t think VISION, for example, has used FDG-PET. The bottom line: the trial used decline in PSA as its primary endpoint and it’s positive. So a higher response rate with PSMA-Lutetium versus cabazitaxel.
Of course that’s not an endpoint for regulatory submission and we’ll need to await the results of the VISION trial which was powered for OS and, I think, rPFS; they were co-primary endpoints. I know Karim was involved in that.

EE: So I wanted to go to Alicia but, for me, when they presented the most important was that little table that showed that 20% of men who got exposed to this treatment remained progression free for 12 months versus 3% with cabazitaxel. I’ll be honest, I’m one of those people who will re-challenge with cabazitaxel after six months and do it again and over and I’m very comfortable with the safety profile. But I want to take it to you, Alicia, I know it’s very late stage disease, I want to get your thoughts from your looking at the safety profile and with that prospect of getting men who will be treated not potentially needing treatment for a long period of time. Do you think that is a very important prospect? I know 20% doesn’t sound like a lot but we expect that it will transcend to a bigger percentage earlier in the disease. What are your thoughts?

AM: I actually think 20% sounds like a lot, that’s in one in five men who would be progressing and if I were in that group I would be very, very happy. We all have these men who, especially at this stage of their disease, are looking at feeling really poorly as each day goes by because of the complications of the cancer. Certainly if we can put those off, I think that that’s a win. The toxicity data also suggested that this Lutetium was very, very well tolerated and really the AE data suggested that it was at least as tolerable as cabazitaxel. The patient reported outcome data suggested at least as tolerable as cabazitaxel, although there was less of a difference there. There were definitely domains where the Lutetium seemed to win, like social functioning and some others that might be a little bit more impaired by cabazitaxel. I use a lot of cabazitaxel and so I agree with you, I feel comfortable with that drug. But I think when we have a new agent that might maintain quality of life and make one in five people potentially not require further additional therapy at twelve months, that’s pretty big.

EE: Karim, again, exactly Alicia says, I have a patient I have literally re-challenged seven times with cabazitaxel and he responded each time, now he’s not anymore. I don’t have Lutetium, is VISION going to be a big game changer? What do you think?

KF: I guess we’ll know very soon.

EE: There you go again being a sphinx.

KF: Well… No, what I would say also is that I think we all agree that cabazitaxel remains a good drug. Even if the Australian trial suggests that, indeed, Lutetium-PSMA has in this setting and in a very selected population of men based on PET and double-PET, perhaps a better safety efficacy balance than cabazitaxel, I think we will probably keep using these two agents sequentially. My gut feeling, and I hope we’ll have some more data, is that one drug can perhaps circumvent resistance to the other one which is not true for all drugs – we discussed already abiraterone/enzalutamide. That could be really fantastic for the patients if indeed it is the case. I share what you basically said. First, cabazitaxel usually is not very toxic, especially with a 20mg dosing and if you’re using GCSF. That’s really manageable toxicity as compared to many other anti-cancer drugs we’re using. Second, there are some patients with really fantastic taxane sensitivity; we all have them, when we recycle and recycle etc., for years sometimes. So it’s really great to have taxanes for these patients, especially cabazitaxel because we don’t see the cumulative toxicity that we used to see with docetaxel.
On the other hand, yes, indeed, I think it’s truly fantastic to see a new, or very likely newcomer with PSMA-Lutetium, quite non-toxic in general and quite active. Maybe one or two caveats, though, regarding the toxicity: one is about long-term haematological toxicity and VISION will probably tell about this. I saw some patients that required, really, transfusions again and again for platelets or for red cells. It was getting rarer to see this in my main CRPC experience. So let’s see if it’s the true finding or just bad luck. The second caveat is if ever VISION is positive and if we move it, or try to move it, in the clinical trial context, PSMA-Lutetium early in the course of a disease, there’s a risk for second cancers or myelodysplasia. So we need to be extremely cautious regarding this aspect before we make it ready for prime time.

EE: This is an excellent point because personalised medicine is a combination of things and we’re dealing with older men. So, you’re going to laugh but a urologist told me, ‘You know your personalised medicine starts in your clinic?’ It’s absolutely right, it’s that man that we’re talking to. It doesn’t have to do only with the targeted therapy or this or that, it has to do with everything this man is about. But, having said that, education for us, the healthcare providers, becomes very important and, Gerhardt, I’m going to take it back to you. We’ve come to the era where we’re actually inclusive of targeted therapies in prostate cancer so we’re not as behind as other cancers. But it’s taking a while and tell us what you saw and what your take-home message is from this GU ASCO with that in mind, from the perspective of more precision medicine-driven therapies.

GA: I guess the most compelling data continues to relate to detection of DDR mutations and specifically BRCA. We saw breakdowns of response rate by gene type in the PROfound trial, the high response rate maintained in BRCA2, big questions remain on ATM. We see that plasma is concordant with the original tissue sample in about 75% of patients in that trial. Of course, that proportion will be dependent on tumour volume – how much tumour is circulating in that patient. Of course it has to be above a certain level for detection.
Then the other very interesting area is AKT inhibition with the trial in CRPC, the IPATential150. For both these approaches at GU ASCO we saw trial in progress abstracts taking these approaches earlier. So the AMPLITUDE trial testing niraparib abiraterone plus ADT versus abiraterone in men starting ADT, M1 men, and the CAPItello trial that Karim is the PI for, testing capivasertib plus I think it’s abiraterone versus abiraterone in men starting ADT.

EE: So, it seems that we’re understanding more and more the importance of assessing the presence or not of DDR mutations and we’re still trying to find a place for other targeted therapies. We don’t have yet an approval for targeting PTEN loss and PI3 kinase pathway. My personal impression is that we might need to go earlier in the disease, beyond everything. Gerhardt, you pointed to the importance of actually kind of nailing the right assays and that’s going to be a bit part of it. It’s tedious but it’s going to be a huge part of it and we’re not there. Yesterday I was in a telemedicine with a European patient who was like, ‘This lab gave me a report of some mutations, then should we act on it?’ This is a patient who has been through everything and I’m trying to be nice and say, ‘Maybe in the future we’ll have confirmation of use.’ But it seems that there is now a plethora of such assays that have not been validated and we need to be really careful. We’re all privileged to be in big institutions, and I’m talking more to the people who are listening to us who are in smaller, so we’ve got to be a little bit sceptical, it sounds like.
So I would like to finish this discussion by thanking you all for your wisdom. I keep learning from listening to you and I do hope that in this coming ESMO, or ASCO I’m going to say too, we’re going to have more data that’s going to get us closer to having personalised medicine. Thank you all very much.