Hello and thank you for joining us at ecancer. I’m Eleni Efstathiou, I’m a GU medical oncologist. Some of you know me as a person with a lot of interest in prostate cancer research but I’m pleased to say that I see a lot of progress across the board in all of oncology and specifically my preference – genitourinary medical oncology. So thank you for joining us to go over the recent results that we enjoyed seeing, even so virtually, coming from ASCO 2021. Currently I am the Chief or the Genitourinary Medical Oncology section at Houston Methodist and I’m looking forward to a lot of exciting research coming from us as well.
It was a thrilling ASCO. We would all agree that we looked at a lot of very, very fascinating clinical data coming from the field of metastatic castration resistant prostate cancer with, of course, the champion being the VISION trial that really is leading us to a new way to treat our patients. We hope that soon it will translate to an approval across the world with this new radioligand beta particle methodology of treating, let’s call it systemic treatment of our patients. We expect much more data to ensue; you can refer to a lot of the information that was presented during interviews and ecancer round table discussions, get the views of people who were actually part of the trial and have first-hand experience. But beyond that, we saw some very important clinical data ensue in the metastatic hormone sensitive prostate cancer field. Even though it’s a little early we got the PEACE-1 glimpse of the fact that potentially it would make sense to combine androgen deprivation with docetaxel and abiraterone. It looks pretty safe and the preliminary efficacy data is promising. We’re awaiting more from that end and actually to understand which patients this is appropriate for. So a lot to be expected from that field as well.
It was also fascinating to see how a small modification can make all the difference. I’m referring, of course, to the EORTC133/PEACE III trial that Dr Gillessen presented the initial data pointing to the fact that if you just add bone modifying agents you confer such a protective approach to your patients who are even on trial and, of course, definitely in your everyday practice against non-pathologic osteoporotic events. So something to think of at home when we’re treating our patients. Now she presented of course in the context of combining androgen signalling inhibition with the radioligand Radium-223, however, this goes beyond that approach. Importantly, her work and the work of her collaborators is pointing to the fact that maybe there is still an opportunity to pursue that treatment and opens up the doorway for other combinatorial strategies and you know I’m referring to Lutetium-PSMA coming forward.
So, further on, we were able to see in the second part of an oral a very nice dedication to minority populations that are not really tackled as much as we want in these trials. In this case ASCO focussed on African-American black population, it was a great thing to do, very timely, but you can think across the board, throughout your countries, of other minorities. Why is this population important to us in prostate cancer? We are looking at men, black men, who have a highly aggressive disease. They don’t participate as much in clinical trials across the world and they are diagnosed much earlier. So we saw some fascinating data about what PSA screening can actually do for such populations and I have to say I’m personally happy to see this data come forth because it’s putting a very simple approach to life, cheap, back in its rightful place as long as the treating physician knows how to act or not act accordingly so that we can avoid over-treatment.
So, again, as I said in the past, when PSA screening had gotten in trouble, it’s not so much about the tool, it is about how we use the tool. So it all boils down to the right education of all the physicians to actually contemplate on the right approach rather than overreact and cause the patient more morbidity. With that in mind, though, I want to make a little transition. In the past few years we have been privileged in prostate cancer to eventually start transitioning into what has been long anticipated which is precision medicine from the molecular determinant side of things. Now, let me put things in perspective. Sometimes when we say precision medicine we jump to the conclusion that we’re just referring to molecular determinants of disease but the word precision medicine should reflect this comprehensive approach to our patients that takes into consideration both the tumour and the host, the patient, who is very complex. In the case of the patient we’re looking not just as the simple thing as comorbidities and side effects of systemic therapies but also the whole composite of this man, in this case prostate cancer including variables that may affect how treatments work, his own immune response, that’s a big, big can of wonderful, not worms, that we’ll need to address in the future to intensify our treatments.
But let’s look at what happened this year at ASCO when it comes to molecular determinants. We do not see a lot of abstracts looking at the host, per se, and immune response, even though that’s our holy grail, but we did see a lot of abstracts, I counted more than 30%, that are tackling molecular determinants and that’s a wonderful thing. It means that we’re going to make progress and I want to remind you how ten years ago or twelve we were just starting our launching of new therapies in prostate cancer and we made great strides through the involvement of a lot of different investigators from different realms.
So let’s start with the oral that was presented. There was an oral presentation that was referring to molecular classifiers in high risk disease. It did something simple – it took the current clinical classification, in this case the NCCN guidelines and it looked how it compares in men such as men with known high risk disease – African American black population – as opposed to using the molecular classifiers. So it’s the NCCN guideline versus the molecular classifier and it actually uses a control – the population where these NCCN guidelines and also [?? 7:56] has mainly been focussed because of the unfortunate nature of more white population participating in these trials. It showed phenomenally that molecular classification actually identifies by a landslide a difference in the risk of the disease. So NCCN guidelines would actually characterise the disease as low-intermediate risk but per molecular classification it was high risk and it was in about 50% of cases. So it becomes urgent to start considering molecular classifiers when characterising the disease. This is just the tip of the iceberg because a lot of the abstracts that were presented were actually speaking to how different molecular determinants can help us, of course not in real time but hopefully in the short-term future, understand better the prognosis of the patient and subsequently help us understand how to treat correctly these men.
So there was one more effort from the SAG [?] group to look at molecular determinants as well with the DECIPHER classifier that was also, and I would urge you to go and look at that data. It also pointed to similar readouts.
Let’s look, though, beyond these predetermined molecular classifiers at a number, a plethora, of abstracts that were looking at sequencing and molecular characterisation of tumours. We saw that there was a lot of academia and industry collaboration that led to very elegant work. I would like to point out that in some cases we had analyses that were pertaining to over 10,000 patients. Now, are they conclusive? Are they telling us the way to move forward? Are they giving us a breakthrough change in treatment? No, they are not. But I want to bring up some very elegant presentations, posters, that I was looking at and impressed me. You know that a lot of us are challenged what to do when it comes to an ATM mutation. We’ve got PARP inhibition approved in the metastatic castration resistant prostate cancer space and we know that we can use it after a failure of a novel enhanced androgen signalling inhibitor such as abiraterone, enzalutamide, apalutamide, darolutamide. Mind you, I’m saying it in the order that they were chronologically approved, nothing else. But what happens next? Do you use a taxane or do you use a PARP inhibitor since the approval does include chemo naïve and was tested in chemo naïve as well?
There was a presentation that looked, retrospectively of course, at patients that harboured BRCA1/2 mutations versus ATM mutations. It was, for me, quite enlightening because it showed that it might make sense to look at those differently. A lot of you are thinking that maybe ATM is not even the right approach to select a PARP inhibitor but we do have the approval for that as well. For what it’s worth, there’s a lot of heterogeneity in the read-out of the data. So that specific presentation really suggests that for BRCA2 you should follow the approval as using an androgen signalling inhibitor first, then go on to using a PARP inhibitor and subsequently consider taxanes. That links very nicely with the CASTRA [?] data that was presented a few years ago at JCL. When it comes to ATM, though, the data – retrospective, need more data – but suggest that the idea of giving a taxane first may be the right way to go. Again, just something to look at in more depth. Go and look at that presentation and you can form your own opinion.
I want to also refer to a very nice dataset that came out of the Vancouver group that looked specifically at how the circulating tumour DNA fraction might be able to help as a prognosticator. Let’s just recapitulate that when we’re looking at the circulating tumour DNA fraction we’re referring specifically to the tumour derived proportion of cell free DNA. Now, they actually looked specifically at cut-offs and it looked like if the circulating tumour free DNA was more than 30% that associated with a more poor overall survival outcome. This is, of course, something that is in line with previous data that was reinforced during this meeting, that if you look at baseline circulating tumour cells, and in this case it was presented for hormone naïve disease, and they are over five, based on the classical approach to circulating tumour cells, the approved one, then you’re looking at a patient that likely with current approaches has not a favourable overall survival outcome. Something, again, that all points into the same direction.
This brings me to noteworthy data that have been promised and are starting to peak, to show up, from STAMPEDE. It was very nice to see two, at least, abstracts that I picked up on that are starting to look at molecular determinants of outcome. I really liked… you know me, I like to find ways that are not going to be extremely costly or very difficult in assay determination and actually Attard et al. looked at something that is very well known and validated and performed across the world – proliferation index, Ki67. They actually looked at these correlations and it seems to be something very valid and meritorious of pursuit – looking at how Ki67, proliferation index at baseline, may be associated with outcomes. Something, of course, that a lot of you are saying, ‘Well, duh, we expected that.’ Well, the next step will be which treatment should it help us pick as the beginning treatment for our patients?
They also looked, and this is a little bit more preliminary, they looked at more complex findings, such as copy number changes, in a separate abstract that was presented and there looks to be quite a bit of promise there too. But again preliminary data there – we need to look at the dataset in a more complex fashion, I would argue.
There was a very nice abstract that really identified the problem. The problem is what kind of assays should we be using. In that abstract they looked at tumour assays and liquid assays and pretty robust assays. We will actually list for you the different abstracts that I am referring to so you can look at them. You can see that assays are super-important because there was such a heterogeneity and lack of concordance between the different assays that really, for now, I would caution you to always select the more validated and approved assays to perform sequencing. As an overview, I would say that all the data is pointing to the importance of a real-time current integration of sequencing and molecular characterisation as much as is possible in our clinics. As a final example, I want to bring up that a lot of you are tortured of whether we should be using real-time biopsies to assess DDR status in the tumours or whether we should be going for archival. Well, there was another presentation that confirms the idea that if you go for an archival there’s definitely a very high percentage of concordance with the positivity that you would have in real-time biopsies so start there. Have that handy, integrated in your routine. Don’t forget germline testing – we’re going to have more and more data that are coming forth in that field soon.
With that in mind I would like to invite you to also follow us during ESMO that hopefully will be a hybrid meeting and we’re probably going to meet in person and talk more about all these important considerations that need to transition right now to our clinics. Because unfortunately the pandemic, amongst other things, set us back in that regard so I am expectant to also have the opportunity to discuss with you the data in the future that will be presented as to what is happening in the scientific and clinical trials world, as to what is required to happen in the real world experience so that we can take all this wealth of knowledge, practice-changing knowledge, and actually implement it easily in our clinics.
Thank you very much and I hope that soon enough we’ll be all meeting in person again and discussing these findings. Exciting times. Have a wonderful day.