Prof Karim Fizazi – Institut Gustave Roussy, Paris, France
Prof Axel Merseburger – University Hospital Schleswig-Holstein, Lübeck, Germany
Dr Kim Chi – BC Cancer Research Centre, Vancouver, Canada
Prof Amit Bahl – University Hospitals Bristol, Bristol, UK
KF: Hello everybody, this is Karim Fizazi from Institut Gustave Roussy here in France. Welcome to this ecancer event. So we will discuss the virtual ASCO meeting data for prostate cancer, mostly the data that was selected at the oral presentation and for prostate discussion. It was a very special ASCO this year, I have to say, but I think this was good to have and I think we saw important data that can change how we treat all our patients. So today with me I have the pleasure to have virtually, unfortunately, Dr Kim Chi from Vancouver, Canada, Dr Axel Merseburger from Germany and Dr Amit Bahl from Bristol in the UK. So let’s get started immediately and one of the most important things we’re currently seeing for the patients with prostate cancer is PSMA, both as a new way to image all the patients and potentially also to treat them. And actually we saw data regarding those two aspects at the oral sessions. Axel, would you mind discussing for us the data that were presented regarding PSMA-PET and how this can change the way we are imaging all the patients and potentially treating them? Axel, please.
AM: Yes, Karim, thanks a lot for involving me in this ecancer virtual activity. I’m happy to share my insights and I found a couple of abstracts on PSMA which really caught my interest. There were two prospective phase III trials, one was focussing on the aspect of prior prostatectomy usage of PSMA-PET and there is an ongoing discussion of what’s the best imaging prior to, for example, radical prostatectomy in order to find the positive lymph nodes in order to cure the men with high risk or intermediate risk prostate cancer. The multicentre phase III trial looked at the value of imaging, of PSMA imaging, and could show that within a high sensitivity and specificity more lymph nodes were detected preoperatively and also validated in the histopathologic report after surgery. So about 20% more lesions were found when using PSMA-PET imaging. In another question, whether or not PSMA is reliable and better in detecting nodes or the reasons for biochemical recurrence, another phase III trial, the CONDOR trial, was conducted and presented at this year’s ASCO also showing the higher sensitivity and specificity of PSMA-PET imaging in those men with biochemical recurrence. This is a very important question for us as surgeons, especially when it comes to the discussion of what’s the best salvage therapy. Guidelines will have to pick up this data to possibly recommend PSMA imaging in those two situations – on the one hand biochemical recurrence where we really think it’s of big value in order to decide radiation to the prostate bed, salvage lymph node dissection and also in the question where you have patients you want to treat for high risk or intermediate prostate cancer with radical prostatectomy or even radiation therapy. This trial has shown the value of this modern targeted imaging with PSMA-PET in order to find lymph nodes and define the clinical stage of the patient. This, in short, on PSMA imaging.
KF: Axel, thank you very much. I guess being a German urologist you have quite broad access to PSMA-PET for your patients with biochemical failure, as you just explained. But have you already integrated this imaging in the initial check-up of your patients with high risk disease, is that something you’re doing originally at your practice?
AM: It’s not supported by all the guidelines as of yet because of some issues in reimbursement in most countries. In Germany it is in wide use and a lot of patients will come to my practice with imaging, PSMA imaging, and it changes a lot. For example, when I do PSMA imaging in a high risk patient in about 15-20% I find metastatic disease. When it comes to Kim Chi’s data of TITAN to maybe discuss with a patient not radical prostatectomy any more but in metastatic disease then apalutamide or enzalutamide treatments. So it’s really changing a lot when you use or it has an implication on the further clinical course when using PSMA imaging, the same as when you have non-metastatic CRPC, it’s not advised, you don’t have to do a PSMA but a lot of patients present and then it’s, in some cases, not M0 CRPC any more, it’s metastatic. So PSMA, you have to choose wisely when you want to use it and in some indications, like for biochemical recurrence and also for finding mets in high risk disease I think it is of value and should be wisely included in the guidelines.
KF: Right, thank you Axel. Kim, PSMA is not only useful for imaging but it also potentially targets the treatments. This year at ASCO we saw data regarding the use of PSMA lutetium for probably the first time, comparative data. Can you elaborate on this study from Australia?
KC: Yes, so this was a very interesting study entitled TheraP. It was presented by Michael Hofman on behalf of the ANZUP group and really builds on their previous prospective single arm study of LuPSMA-617. But this time, for the first time, we’re seeing it randomised against cabazitaxel. This was an interesting study in that they had a very high bar, or a higher bar, for patients to get on in that they had to have an SUVmax on their PSMA scans of 20 and they had to have no discordance between FDG and PSMA. I think that’s why we’re probably seeing some higher response rates from the Australian group compared to perhaps other series that have been presented about PSMA therapeutic targeting. We can see that by 80 patients were actually not enrolled because of this PET scan exclusion, the PSMA-PET scan exclusion, while 200 patients were enrolled and randomised. Their primary endpoint was PSA response and it was substantially better than cabazitaxel – 66% PSA response versus 37%. The cabazitaxel response of 37% is about what we would expect normally from other trials with cabazitaxel. Toxicity was as expected and there are some preliminary data on PSA progression also showing an advantage for PSMA lutetium, although at the six month mark these curves are converging. So I think this is exciting data, it’s interesting data and adds to the known clinical activity of LuPSMA-617.
KF: Fantastic, thank you. Amit, do you think this is convincing enough? We saw preliminary data from Germany and then from Australia in a phase II supporting clear activity in patients failing everything, including taxanes, including next generation hormonal therapy with lutetium PSMA. For the first time we have comparative data so is that really exciting you? Do you think it’s compelling enough or do we need to know much stronger data? What do you think?
AB: I think the answer is it is exciting data and we do need a validation which will likely come from the VISION trial which is a randomised phase III trial of LuPSMA-617 versus best supportive care. But the interesting thing is that I think, apart from biomarker driven therapy, one can look at this as a biomarker driven strategy in theranostics. Like Kim mentioned, this was a very high bar for patients to enter this study so they had intensely avid, PSMA avid disease and there was no discordance between their FDG-PET and the PSMA-PET. This is important because in real life practice the average patient may not be a patient who will fit all these criteria because you are likely to get discordance. So this does not mean the end of chemotherapy in prostate cancer but it does meant the start of theranostics in prostate cancer. Perhaps the bigger rule will be bringing this therapy more forward in the treatment paradigm because the longer you wait with the disease, the more likely is there going to be different clones of disease emerging which would make this therapy less likely to be beneficial. So there are trials which are starting in the earlier spectrum of the disease pathway but I certainly believe this will be a big means of treating advanced prostate cancer in the not so distant future.
KF: Alright. Axel, regarding new treatments with data that we saw at this ASCO, obviously it’s the randomised trial about relugolix which is an oral LHRH antagonist, the first one we have comparative data regarding this family of agents. Can you elaborate a bit about this trial and the data?
AM: Yes. So the HERO trial was my personal hero at ASCO. It was surprising because it came along in an oral abstract presentation but with a New England Journal of Medicine publication which is always pointing towards some kind of game changer here. So the HERO phase III trial was presented with results comparing the oral GnRH receptor antagonist relugolix. So what we have with relugolix, we have as an injection and now we have an oral antagonist, versus Lupron for advanced prostate cancer. There were some key findings that I think are very important for us and for our patients. Relugolix achieved castration as early as of day 4 and demonstrated not only inferiority but also superiority over leuprolide in sustained testosterone castration throughout week 48. Also, and I think this is important, a faster testosterone recovery after discontinuation and, on the other hand, a 50% reduction of serious myocardial events. So it is somehow what we knew from phase II data out of degarelix cardio-protective compared to GnRH agonists.
KF: So do you… sorry to interrupt you. Do you already use LHRH antagonists in patients at risk for cardiac problems in your practice?
AM: Personally, yes, in severe cardiovascular conditions. However, we really have to await the phase III trial, PRONOUNCE trial, which is still recruiting with degarelix. The rest is more not the primary endpoint of the trials with degarelix but here we have prospective data of this oral antagonist showing that this is really cardo-protective compared to Lupron. So I think this is a good option for us.
KC: I think we need to be careful with this because we have to remember this was a secondary endpoint. As well, if you look at some of the cardiovascular endpoints, ischemic disease was actually numerically higher for the relugolix… I’m having trouble saying it as well, but for the oral LHRH antagonist. So we have to understand what are the major components or what is the breakdown of components for those major cardiovascular events. Although it’s very intriguing and I think it’s the reason why it was a The New England Journal of Medicine paper, because of that statistically significant difference. So I think we need to have more data.
KF: Yes. So, the story continues, it seems to go the right way and now it’s an oral drug which has pros and cons. I guess this is more and more compelling. But let’s move, for the sake of time, to the big thing at this ASCO meeting which is truly practice changing and I’m speaking about patients with non-metastatic castration resistant disease. Because we saw three large phase III trials with a very similar design looking at three AR antagonists and all three show overall survival improvement. Amit, let’s start with you if you don’t mind. You have experience with the enzalutamide trial, can you summarise the data and tell us what you think about that, please?
AB: Well, essentially all these three trials were very similar in their endpoints and metastasis free survival had already been established previously. The big debate that had happened was that people questioned that overall survival benefit was not there and hence is there a relevance in treating patients or should one adopt a strategy of waiting until they develop metastatic disease. Now we have all these three trials showing overall survival benefit in this setting with hazard ratios which go from 0.69 to 0.79 essentially. But there is a difference between the crossover rates and subsequent treatments that these patients received in the trials. So, in my opinion, the benefit is reasonably the same as seen from the three trial studies and the primary endpoint of metastasis free survival has been met and the secondary endpoints of delaying subsequent anti-cancer therapy and delaying time to skeletal related events has also been met, as has been the overall survival advantage. The quality of life data will be important, side effect profile will be important and the experience of the clinicians in the use of these drugs will probably guide practice in this setting. Just one point to make, however, is that this is no surprise that if you delay something, delay metastasis, then the likelihood is that you’re going to delay death. But we would always question that as being a surrogate marker for survival or not, which now these three trials have shown. But what is more important is that is nmCRPC actually a true entity or not. We’ve heard from Axel about the novel imaging techniques and more and more of these patients are unlikely to be non-metastatic as such but mostly micro-metastatic. And also whether one should start hormone therapy initially is a question because should one adopt the policy of reimaging and trying to identify oligometastatic disease rather than commencing people on LHRH agonist or antagonist, whichever one we prefer with the current data. So I think this is important data but probably in real life strategy not going to have that much of an impact in current practice.
KF: Okay. Kim, would you agree on that? You basically developed apalutamide, so any comment on that drug and about what Amit just said about the general field?
KC: I think with all three trials, as Amit said, there was a consistent benefit in overall survival and it’s very difficult to compare between the trials in terms of understanding the degree of benefit. For example, in the PROSPER trial they did do a sensitivity analysis looking at the patients that had crossed over and censoring them and showing a larger hazard ratio for the overall survival benefit. But just to show that there’s differences between the studies and that the overall survival benefit between them is probably similar. But I think what it does confirm is that earlier treatment is better and earlier treatment with more intense therapy is better, targeting the androgen receptor in prostate cancer. So I think we’ve seen this time and time again as we move our treatments earlier and it has a promising future for other trials that are looking at these more intense AR therapies earlier in the disease.
KF: Right. I really agree with you and just to support what you said, for patients with a rapidly rising PSA, either at the time of biochemical failure post-local treatment or even more importantly at this time of non-metastatic or minimal burden CRPC, if you want to call it, I think recognising that using a systemic treatment is associated with overall survival benefit on top of other benefits is truly important. I would agree with Amit that for patients with a slowly rising PSA, waiting, imaging patients, considering a second local treatment or a local treatment directed to the metastasis might be the good way forward. But for those patients progressing rapidly by PSA, using a systemic treatment, I think, is very important. Axel, any comment regarding the third drug, darolutamide, which came, basically, one year after the two others? Can you elaborate on that?
AM: Yes, I think darolutamide really nicely caught up and, as I remember, you were the one presenting this virtually here at ASCO, so a very nice presentation on the darolutamide data. What impressed me, besides the known MFS benefit and the now known OS benefit, but what impressed me a lot and moves me on to using the drug in clinical practice now, since we have it approved since a couple of weeks, is the basically no difference between side effects in the placebo arm, in the ADT arm, compared to the combination arm. So when looking at the details there was, but correct me if I’m wrong, not really a clinically relevant difference among the combination and the ADT arm. So I think side effects, I suspect, and I know it’s never fair to do a trial-trial comparison, however, side effect wise darolutamide seems to be the best tolerated substance even though we know the limitations in when the side effects and the quality of life was measured, this was different among the trials. But I still think the delta is there between the two arms and it’s very small in the ARAMIS trial you presented, so this is some difference. I also think, especially when you want to use apalutamide or darolutamide where you don’t have an indication further on the line, you should not do a PSMA-PET, like we touched on earlier, because this might mess up the M0 CRPC diagnosis and you have metastatic prostate cancer and then mCRPC you can only treat with enzalutamide in this indication or give chemotherapy. But I think you really have to choose wisely when to use modern imaging when having these results on hand which have been done with conventional imaging.
KF: Right. Regarding darolutamide, just to be on the safe side, what we can say is that basically the toxicity pattern that we’re seeing with darolutamide is very comparable to that of a placebo but, as you said, it’s very difficult to compare the three agents, given that we don’t have direct comparison from a trial.
AB: But even with SPARTAN you had the data with apalutamide health-related quality of life was comparable to the placebo arm. So I think, all in all, we are in agreement that improvement in overall survival and maintaining quality of life means that these patients who are in that setting should get this treatment. Of course, we have to remember that this is based on PSA doubling time which should be looked at in this group of patients. So it is not for patients with PSA doubling time more than ten months, in the trials they were less than ten months. And important that the PSA has to be above 2 than calculating this PSA doubling time for these trials.
KF: Right, absolutely. So let’s move on to the other good news that we saw in the last month or so regarding the development of new drugs, new targets and perhaps new concepts. I’m talking about the PROfound phase III trial that is now published in The New England Journal, it’s testing randomly for the first time a PARP inhibitor, namely olaparib, in patients with DNA repair defects. We saw data on quality of life at this ASCO from the trial. Kim, can you tell us a bit more? What the story is basically.
KC: As you said, Karim, with the PROfound study there is a large benefit in radiographic progression free survival that was reported in The New England Journal of Medicine in favour of olaparib for patients with DNA repair defects, particularly those with BRCA2 gene alterations. In a press release we also know that the overall survival became statistically significant for the overall study. We’ll have to wait to see some of those details as they get presented and published. But at this year’s ASCO the group presented on the quality of life data as assessed by FACT-P questionnaires. FACT-P questionnaires are pretty standard for quality of life assessments, patient reported outcomes. What they found was that there were fewer patients that had deterioration of quality of life when they were receiving olaparib as well as more patients that had improved quality of life when they were receiving olaparib. This is not surprising given the clinical benefits of radiographic progression free and overall survival, we typically see this, combined with the relatively well tolerated side effects of olaparib.
KF: Right, excellent. So with all this data with both quality of life, overall survival and all secondary endpoints being met, I hope that we will soon have PARP inhibitors approved and reimbursed for the patients. Because I agree with you, I think this really changes the field for these patients, some of them really having aggressive disease, patients with BRCA2 cancers. So I think for the sake of time we should terminate this ecancer event. It was really a pleasure sharing that with you guys. So, gentlemen, thank you very much. Hopefully next time we’ll be able to meet physically and to discuss some new data. It’s been fantastic. Again, we had three phase III trials reporting overall survival data, not speaking about all the rest, so obviously a very good ASCO for prostate cancer. So I would like to thank you for participating and thank you for attending virtually this ecancer event. Thank you very much.