EE: So, to move on, very soon in Europe we will have approval and, I think it was already said, we will have availability of the first oral antagonists. I will be very clear, I was not involved at all in the trial and I don’t think you were either, but I’ve been using it consistently since approval and now 80% of my patients who have high risk localised, at least, disease plus they take this oral antagonist, plus of course an ARTA based on the STAMPEDE trial. But it’s an oral agent; it’s one pill a day, apart from the first day where it’s three pills. I’ve actually looked at the pills and I will tell you they are small, they are not horse pills. But we discussed it before and you’ve voiced some concerns because we’re starting to add more and more pills to our patients. So thoughts on that because we saw a very nice abstract looking at how this oral antagonist actually helps maintain more consistently, not just showing non- inferiority, even superiority to leuprolide – consistently below 20 testosterone which translates to potentially better outcomes even though in that we use ARTAs, we don’t know. So thoughts on how this will apply in the clinic?
NM: Two points: the first point is related to the testosterone level. I believe we have now very, very clear… well we have weak evidence that the lower the testosterone level, the better the outcome. The best one we have directly comes from the control arm of a randomised controlled trial of ADT – ADT continuous versus ADT intermittent at salvage after radiotherapy – there are one or two papers. If I remember well, Fred Saad published last year or two years ago in the JUrol an analysis on that showing that, indeed, when the testosterone level was not as low as expected the outcome was not as good as expected. We have also a very indirect signal that every time we combine we reinforce the androgen access suppression by either suppressing the biosynthesis with abiraterone or by strongly blocking the androgen receptor with enzalutamide/apalutamide/darolutamide, the outcome is better. So the lower the testosterone level, probably it’s of major importance. My issue is it’s a pill. It’s nice it’s a pill, that’s absolutely true. If you don’t take any medicine and you take one pill a day that’s perfect. We know that we are dealing with senior adults. The median number of pills they take in per day is far above one, it’s around 5-8. Okay, it’s just one more pill. And then there’s a major issue – are we sure that the observance of this pill every day will be there? We know, even for oncological drugs, that observance is an issue and if it is an issue it might be an issue regarding the testosterone level in real life. Not in trials when you have to bring back the empty boxes so the physician can know exactly, ‘Oh, you took all your pills, that’s good’; in real life that’s not the case. So that’s my only issue – lower testosterone, as low as possible – absolutely perfect. Just a question regarding the real-life observance of that.
EE: This is a great point and we’ll see how it adapts with each practice. There’s also the cost issue, obviously, that needs to be considered. I struggle every day with getting approved for insurances in the US, even with Medicare that’s our socialised programme. But there is another point I wanted to get your thoughts on. We know by definition in all the big trials that we’ve seen for localised disease that leuprolide was used. So what we do know from leuprolide, even though they didn’t look at the time to recovery of testosterone, what we call the U-gonad, is that once you start the leuprolide, and let’s say you stop in two years or three years, the period of recovery of testosterone is variable and in some patients it may never even come back. What we saw, which was a great thing, with relugolix is that it will come back and it will come back within a few months. It was a sub-analysis shown in the HERO trial for most patients, eventually everyone. Here’s the question…
NM: After a year, after a year. Only after a year.
EE: No, 50% came within a month. It was very interesting.
NM: Yes, but patients were only treated for a year, not for three years.
EE: For one year, yes, I agree. So we’ll have to see what happens later. But I have a question that’s actually inverse that came a from a urologist and it made me think about it. All the trials that we’ve done are with leuprolide so we don’t know when testosterone recovered. So, in effect, patients stayed castrate much longer. So now it’s a blessing that they will be U-gonad sooner but does it change outcomes? We don’t know that because what was three years was actually four and now what if three is going to be three and a half? Does that change? It’s an interesting question, to be honest.
NM: To go to that direction, I’m more and more inclined to check the testosterone level when somebody receives two or three years of agonist plus radiotherapy than is relapsing. Usually the testosterone level is not as low as the castrate level but very often, especially in the elderly, it’s low, far below the minimum normal. So it’s an absolutely relevant issue. But we know regarding intermittent it was not after one or two or three years, it was intermittent after 6-9 months. There might be something here to analyse and to check but we should have also the data with the injected antagonists, with the monthly formulation, where apparently also the testosterone recovery is quicker compared to the agonist.
EE: So these are interesting points to consider in real world practice. And with that in mind, all of a sudden we have a newcomer in the world of urology and uro-oncology which is PARP inhibition. It got the approval already but the uptake has not been… obviously with COVID years, I get it, has not been for those men with DNA damage response gene mutations, even germline or somatic. We’re not checking as much, we know that, and I’d like your comment on that. We know that in the US where we have germline testing available for all, advanced disease and beyond, only 15% of men are actually offered even though it’s cheaper, it’s essentially for free for almost all coverage, we still don’t get it. Now we’re talking about combining enhanced androgen signalling inhibitors, ARTAs, with PARP inhibitors in metastatic castration resistant disease. The abstracts we saw provide some level of comfort, some level of comfort within trials for tolerability but we know that real world patients are completely different. What are your thoughts there? Where are we headed?
NM: If 15% of patients in the US are checked for germline, I guess it’s far more than what we have seen in France, for example, where I know. One of the main reasons for that, we have guidelines, we have national guidelines as to when to refer for germline testing in prostate. We also have European guidelines on when to refer to germline testing. If you remember, currently most of them are weak recommendations except for the end stage; I will come to that just a little bit later. Germline, the main issue we are facing in France is that we need a geneticist consultation and very practical. The waiting list to get the geneticist consultation where I work is 1½ years. 1½ years – it’s absolutely forbidden to order any germline test without that, it’s not feasible and you might be sued if you try to do it on your own or if you suggest to a man, ‘Just go to the US and through there, to the internet, you buy the test.’ I know it’s done in some places, not with the doctor’s suggestion but patients know that. But that’s a major issue – for germline we need to have the geneticists. I must say I’m a little bit surprised that it’s so liberal everywhere because there was a talk at the EAU about it and ASCO who made the lecture on that was very clear – if we order a test and the test is suddenly positive the first thing is we need to be able to interpret what it means – not all BRCA mutations carry the same risk. Even though I have that in the back of my mind, I’ve never realised how different it is for various abnormalities of the germline for BRCA2.
Second, you need to be very clear and you need to explain what they call the CASCA test later on because the benefit might be for the patient but it might be even more important for the entire family because it’s not only about prostate but breast, liver, pancreas etc. etc. Here it’s only BRCA2 with all the other mutations that might also be there like the Lynch Syndrome, which is clearly underestimated. So I do believe there is some rationale that either the physicians are absolutely educated on that or it’s very correct to have somebody who is an expert, in terms of explaining what the results mean. This is for the germline but the labelling of the PARP inhibitors in prostate have nothing to do with germline. It has to do with BRCA mutation and, as you absolutely know, it might be germline, not so frequent but not exceptional that it might also be for somatic, that is for tumour mutation that’s completely different.
For tumour mutation we have a strong recommendation in the guidelines that once you become metastatic CRPC you must be tested for this mutation, again not germline but somatic. We know that once you’re a somatic mutation probably it might be wise to discuss do I need also to go to the germline mutation? It’s not 100% linked but at least it suggests something. I think the issue is the access to the test. The test must be of very good quality; in hospital tests must be checked to be sure they are correct, and that’s an issue. The test has a cost but, back to my country, it’s standard of practice for breast so if it’s standard of practice for breast it should become standard practice for prostate otherwise there is something I don’t understand. Even if you only have a 15% positive rate, let’s say you only have 15%, for these 15% positive we have a specific drug that has been shown, a specific class that has been shown, to improve the survival. So just ignoring it is not acceptable again.
EE: To add to that, we know from data that has presented by Dr Eeles and Elena Castro most recently, that these men, even with somatic, especially with germline, harbour a very poor prognosis. So you know my take, I would argue that I like to put my ducks in a row from the beginning and try to get that diagnostic biopsy, or prostatectomy specimen if I can, sequenced early on so I have it there in my archives and not scramble to find it later. I think that system-wide approach makes things easier because what you just described is so convoluted, you’ve already set your patient on a course and then you have to go back and forth. You can’t, of course, always get real time new biopsies and liquid biopsies are essentially for high volume disease – you can’t pick up when it’s just a little progression. Which brings me, in the interests of time, to the other topic which we’ve discussed between ourselves so many times and it’s really scary. Enhanced imaging is knowledge, right? We do PET PSMA but it’s not a panacea in any way. It’s a form of molecular imaging; it is not necessarily the best anatomic imaging. The best anatomic imaging would be whole body MRI with PET imaging combined and that would not even get you to 100% [inaudible], especially in low PSAs. So now all of a sudden we saw a very nice abstract looking at how treatment plans are changed based on the results of PSMA PET alone, especially in low PSAs, and it raises… all alarms go off. So you’ve got some guidelines, you’ve got men with high risk localised disease or intermediate high risk disease undergoing prostatectomy and just being followed. We know that if they had some adverse pathology features, once they’ve recovered most of their functions and PSA hits that cut-off of 0.2 and above, we had to consider salvage radiation therapy. All of a sudden now people are performing PSMA PETs and that abstract very nicely showed that even when you get a negative PSMA PET you downgrade your treatment all of a sudden. So we may be performing a disservice without having adequate data and that’s human nature. I could be guilty of that. What are your thoughts on that?
NM: The abstract was impressive because, the first one, it confirmed what we knew but that it’s done in a prospective trial and that’s always good to reinforce the message. These were patients that relapsed after a radical prostatectomy and they received a PET PSMA. The first point I want to raise with that, the overall positive rate of this PET PSMA was only 38%, so that’s the first point, despite the fact that the PSA was rising. If you read the abstract carefully you realise suddenly that the median PSA that was there when they used the PET PSMA was 0.3 with an interval between 0.2 and 10.3. Back to guidelines and, again, I’m a little bit oriented and biased with guidelines, but there’s no threshold anymore in the EAU guidelines regarding relapse after a radical prostatectomy. The threshold has gone almost two years ago. The rationale for that is we have now very clear evidence that the best outcome, even also for mets free survival, in when you treat a salvage for PSA that is as low as possible. It’s clearly been shown that if you treat them when the PSA is below 0.2 their results are better than if you wait between 0.2 and 0.3. So clearly it is an issue, at least it’s surprising to me. The second thing is, okay, they did it. Up to 10 let’s say there are some men that never come for follow-up and they waited for 10. The second message, and that was unclear from the abstract and presentation, if the PET PSMA is negative are you waiting for a spot before salvage radiotherapy? The message again should be very, very, very clear – if you believe that salvage is needed, if the PSMA PET is negative, remember i might be 60% of the cases, salvage immediately, don’t wait for a spot to salvage otherwise you will wait for a higher PSA and it might be a total mess.
EE: So the bottom line is, and I stand corrected with regard to the EAU guidelines, a negative PSMA PET CT should not stop you from acting appropriately based on what we already know from a long period of trials that we’ve performed. It should help you potentially understand and gather knowledge but not hold you up. Which brings me to the next topic, in the interests of time. We’ve seen the STAMPEDE trial look at high risk localised and it was outstanding to see that in men with high risk, very high risk, localised disease the combination of an ARTA plus ADT conferred an increased benefit in overall survival within a median of six years of follow-up. This is outstanding. But we know that…
NM: But it was unexpected, this huge benefit so early was unexpected.
EE: Which, whatever criticism you want to say about STAMPEDE pooling two arms together, whatever, it is what it is. The next step is going to hear data from industry-sponsored which is the more granular, more linear ATLAS trial which is going to come. My questions are two: the ATLAS trial being more granular is going to give a clear message and I wanted to see your expectations of how it can actually change practice. Importantly, I wanted to get your thoughts on whether PSMA PET will invariably affect that. Number two, how does it translate to combination with surgery, I know you’re going to kill me for that.
NM: No way, never. Let’s start with ATLAS. ATLAS is an industry-sponsored trial, that’s fine, which allowed to include a much larger population compared to STAMPEDE because in STAMPEDE you had very strict criteria – it was either cN1 on two risk factors between clinical, I insist clinical, that is DRE-based T3 or T4, ESOP 4 or 5 on a PSA above 40. You had to have two out of the three criteria to be in. While in ATLAS they accept patients with Gleason ≥8, that or Gleason 7 with a PSA above 20 and a stage equal or above clinical T2c. So a much larger population which, for me, makes sense. It’s a randomised controlled trial and I don’t really understand why they decided to go in the control arm for agonist plus bicalutamide. Okay, it’s just for flare prevention, I can buy it even if we’re not so sure that the flare prevention is absolutely clear. It’s clear that it has to be initially started with the hormonal therapy and after a few months you add radiotherapy so that you have a shrinkage of the prostate so you have a decrease in the prostate volume and so you have a decrease in the size. You might expect less side effects based on that. The primary objective is mets free survival, that’s absolutely fine because it’s a surrogate for survival. My only comment regarding what we have so far from ATLAS, and they just finished the inclusion, is that they only have 13% cN1 while in STAMPEDE we had 40% cN1. So it might confirm but the power for this confirmation might be less.
EE: [inaudible] longer too.
NM: Yes. The second point regarding ATLAS is that, as opposed to STAMPEDE, all the patients will receive prostate radiotherapy while in STAMPEDE that was not the case. It’s very surprising that for those who were cN0 in STAMPEDE 99% of those planned for radiotherapy received it whilst only 71% who were cN1 received the radiotherapy. Surprising, but that’s what was done.
EE: But that’s because STAMPEDE is real-world practice and it’s our fault as real-world practitioners.
EE: We [inaudible] maximise.
NM: So it will be an interesting trial; I would be very, very surprised if it would be negative. To be negative, I must say, I will not understand why because I don’t see any rationale for this trial to be negative because, as a whole, the apalutamide is not the same as abiraterone, the mode of action is different, but the end story is that they lower the activity of the androgen axis. So I don’t see any rationale to believe it should be different.
EE: So I think in this session that we discussed and I got your thoughts, I know I’m a little bit slow maybe on the uptake, but for the first time I see clearly a point from the guidelines coming to actually enhance the treatment and not limit it stating that now we have the opportunity to maximise treatment options for our patients and to not be led to downgrade or minimise or limit based on new data that are not confirmed and not validated. So PSMA PET, yes, a great imaging tool but not one that should deter us from what we already know with regard to combinatorial strategies, to adding salvage radiotherapy. A lot more to be learned but I really appreciate your thoughts and thank you for the pearls of wisdom, especially coming from guidelines that I know are in real-time updated, unlike what is the case for other guidelines or unlike what is NCCN that is more driven to insurance. So thank you all for joining us and I always learn so much from you, Nicolas, thank you.