ESMO 2024: Best practice in HRRm testing in patients with metastatic prostate cancer
Prof Karim Fizazi – Institut Gustave Roussy, Villejuif, France
Dr Anders Bjartell – Lund University, Lund, Sweden
Dr Niven Mehra – Radboud University Medical Center, Nijmegen, Netherlands
Prof Eleni Efstathiou – Houston Methodist Cancer Center, Houston, USA
KF: Hello, I’m Karim Fizazi, medical oncologist from Institut Gustave Roussy in Villejuif, France. I’m here at ESMO in beautiful Barcelona where we’ve heard quite a lot of good news, mostly, for patients with advanced prostate cancer. So we’ll try to basically make a summary of what’s been important here, probably focussing more on molecular data, DDR alterations, use of PARP inhibitors, but also with some other things. I’m joined here today with a great panel, I have to say. I’ll ask them to introduce themselves starting from Dr Eleni Efstathiou.
EE: Thank you very much, it’s a pleasure to be here. I’m Eleni Efstathiou, I’m a GU medical oncologist from Houston, Texas, enjoying Barcelona as well and enjoying the great news we heard.
NM: My name is Niven Mehra, I’m a medical oncologist from Nijmegen in the Netherlands and focussed on some precision medicine. I had a great session today also.
AB: I’m Anders Bjartell, actually a urologist from Lund, Sweden, but I’m so happy to be among oncologists because we work such a lot together taking care of our patients. So it’s really nice to be here in Barcelona and discuss with you.
KF: Yes, and it’s been great, honestly, in the last decade to learn how really to work as a multidisciplinary team that’s smoother and very important to the patients at the end of the day. So, first, one striking change in the last years has been the integration of individualisation of treatment based not only on clinical parameters but also molecular parameters in castration resistant prostate cancer. Also the use of PARP inhibitors in either patients with molecular selection versus others. This has been debated quite a lot in the last year and we are learning every year. But now that some of these agents are approved in all the respective countries I’d love to see what is your practice, again based on availability, and see how you’re really using these agents now that we have more habits about and a better feeling about how to use these agents. Eleni, if you don’t mind, can you speak about the situation in the US and in your practice?
EE: Yes, I was going to put on the US hat because something unusual has happened and our European audience may not be aware. But in the United States the FDA decided, based on a review of the data as they saw it, to limit the indication of the combinatorial strategy. We have approval for use of a PARP inhibitor with an androgen receptor inhibitor in the space of first line mCRPC but only for those men who harbour either germline or/and somatic events, DDR events. In some cases it’s just for BRCA2. So we are faced with a different problem than you are. You have a comprehensive approval then it is left up to the physician to decide what is appropriate. We would all agree that we saw most of the benefit coming in the BRCA2 population and we can go and tease in details that are forthcoming in the future about specific mutational events or co-events that may be happening. But when it comes to the other DDR events there’s a wide spectrum of benefit or not that cannot be fully teased out because of the limited numbers of cases tested. Finally, my take in the wildtype defined rest of the population, about 70% of our patients, there may be a subset in there that has a BRCAness signature that we have not unveiled yet. So I think that should be our focus.
KF: But right now in your routine practice you tend to test and to treat if it’s a BRCA patient?
EE: Absolutely.
KF: And if so are you mostly testing using ctDNA or tissue? How does it work?
EE: The answer is I test with anything I can get my hands on because we cannot be choosers. But my clinic specifically, because of the broad guidelines that we have in the US with regard to testing, allows me to incorporate systematic testing from day one. The patient does not need to be mCRPC. So that gives me the opportunity to get a hold of the tissue from the original biopsy or prostatectomy much faster which allows more access to the tissue. But I do resort into liquid ctDNA biopsy and obviously germline testing. So all these three happen and every six months we repeat liquid ctDNA testing or end upon progression. So it is a very testing dense environment.
KF: Okay, that’s a lot. And mostly the insurance agree or are you paying from your institution budget?
EE: We have 90% coverage from Medicare because our patients are older and most major institutions…
KF: For testing you mean?
EE: For testing.
KF: That’s nice.
EE: Because these are patients over 65 which is the most common, because it is in the NCCN guidelines and you can demand. When not we have found access for these companies that are conducting it to provide financial support, which is a great asset. So we get 100% coverage.
KF: Let’s move out from the US. Anders, what is your practice in Sweden with regards to the testing and use of the PARP inhibitors, either yourself or in combination with a medical oncologist? Tell us briefly how does it work.
AB: Well it started that a lot of men with mCRPC after all the available treatment then they were tested and see. That was mostly managed by the oncologist. But now the situation is different because we’re trying to identify men that we, at the urology department, diagnose, young men with an aggressive cancer. In our guidelines we are available to do the genetic testing. So that is where we now try to focus to make more testing in this group of patients.
KF: And again, same question, do you mostly test on ctDNA versus tissue, not even speaking about germline? How does it work?
AB: ctDNA was recently available everywhere in Sweden if we send the samples to Karolinska where they also have the ProBio study. So that panel will be transferred to all centres who will also be able to run the test there. So we can send for ctDNA, if it doesn’t work they will do the tissue testing. If it is possible then we should consider germline testing.
KF: Absolutely, that makes sense. And regarding treatment with PARP inhibitors, do you, and it’s a collective you, it can be yourself, it can be medical oncologists, whatever, but what is your policy regarding treatment use of PARP inhibitors? Do you focus mostly on BRCA patients? Do you integrate also PALB2, CDK12, some all comers? What do you do?
AB: We are limited to BRCA1 and 2, actually. We are so we don’t use… And especially the testing we have now, the answer we get is BRCA1 and 2 mutations.
KF: Okay, so you don’t have information regarding the other alterations? Got it, okay.
AB: No, we can get it if we ask for it but not in routine clinical practice. But, on the other hand, I see more and more men coming to my clinical practice after being tested and being BRCA2 positive. Then they ask if they have prostate cancer and that’s my job to look at that.
KF: Of course, and that’s another question which is key for the future, I agree. And how we follow these patients – should we do MRIs, PSA etc.
AB: I do MRIs and then I do examination. I don’t take biopsies if I don’t need to, of course not.
KF: That makes sense. Niven, I know that you’re quite lucky being a molecular medical oncologist in Nijmegen. I guess you have quite broad access to testing. But tell us, at your institution but also maybe in The Netherlands in general, what is the current situation for testing and for treating with PARP inhibitors CRPC men?
NM: Yes, you’re right, Karim, I have always been educated by my peers, so testing has always been on the forefront. But that’s not actually the case in The Netherlands everywhere. So based on the data which has been coming in the last couple of years that we should know the BRCA status when patients develop CRPC, so we need to know the status when we want to think about the treatment, meaning that we need to test early in the mHSPC setting for de novo metastatic. In my current practice I think some patients who are metachronous, where you have the time, especially low volume patients, I do not always test them in the mHSPC setting because these patients develop progression, sometimes there is ten years between their initial diagnosis and CRPC. Sometimes we tend to rebiopsy these patients or maybe use ctDNA. Maybe evolution is playing a role in some of these patients, especially if they develop high volume disease all of a sudden. So that’s what I do in my practice, so when a patient becomes CRPC and I’m thinking about their treatment decisions, if I know it’s a BRCA patient I would love to treat these patients as early as possible with a PARP inhibitor. So if they did not have ARPI in the up-front setting I would love to give them of course a combination.
KF: So do you mean that you’re using the combination of an AR pathway inhibitor and a PARP inhibitor mostly in your all-comer population or really restricting that to some genes? So what is your policy?
NM: At the moment still I’m restricting it to the BRCA genes, BRCA1 and BRCA2. I think I don’t have the possibility to give it broader yet.
KF: Would you? Would you?
NM: I would, yes, I would.
KF: In all-comers or would you select some other genes?
NM: No, I think there’s a hierarchy. We have, of course, BRCA1 and BRCA2 and then PALB2 next. Then we need to start looking at genes such as CDK12 but biallelic, which is half of the mutations are biallelic. Then I’m still a believer of ATM but also biallelic. I would not treat CHK2, especially in The Netherlands it’s a founder mutation, these patients do not respond to PARP inhibitor monotherapy.
KF: And patients without any DDR alterations?
NM: We were also chatting a little bit that there are some patients, about 10-15% of our patients, without mutations may still have homologous recombination deficiency but we don’t have signatures which we routinely use. So I think for the moment, now, I would not give my patients this combination because I think it’s toxic, we are seeing also that some patients develop myelodysplastic syndrome, leukaemia. So I do not want to give the patients without mutations these kinds of risks.
KF: That’s very clear. Actually, I probably do the same. I’m quite convinced about the benefit of PARP inhibitors for BRCA1 and BRCA2, obviously. I think something is probably happening indeed, even if the numbers are small, for PALB2 and biallelic CDK12 but really for the rest I’m really not convinced. I’d love to see a signature that would help us to identify which is the subset of other patients that may actually benefit but right now we don’t have it. Let’s stay with you, if you don’t mind. You presented earlier today at ESMO a beautiful study of combination nivolumab/ipilimumab in patients selected based on molecular grounds. We’ve clear efficacy for patients with MSI high cancers and more modest efficacy for others. So if, for example, you see patients with MSI high cancers and BRCA alteration, what is your current recommendation? Would you typically go, of course assuming drugs are available, would you go mostly for immunotherapy, for PARP inhibitor, for a combination? Any idea about those specific situations?
NM: Thanks for bringing up this point because I think this is a real important point to discuss and be clear upon. Because in the patients with mismatch repair deficiency we are seeing a lot of mutations so these patients have sometimes 20-50 alterations over the whole genome and you are finding mutations also in BRCA. But these are always monoallelic, passenger mutations, and I haven’t yet seen a patient respond to a PARP inhibitor. So do not treat these patients.
KF: So you would go for immunotherapy?
NM: Immunotherapy as soon as possible. In the US guidelines you can give pembrolizumab, in some European countries you can also give anti-PD-1. So I would try to do that as early as possible, preferably before taxanes. There are some data that taxanes limit efficacy.
KF: I think it’s an important message, even, of course, if we’re speaking about opinions because the numbers are small, but actually I fully agree with you.
EE: Yes, I do too.
NM: On the other hand, if I would have a very, very symptomatic patient with MSI, sometimes I would even… because these patients do respond to chemotherapy, it’s not that they are refractory to ARPIs with chemo. So a high volume, very ill patient, sometimes you need to get him to respond to allow the time to respond to immunotherapy.
KF: Sure. Again, we are at ESMO here so if I’m asking you one by one what is your most important message from the congress for advanced prostate cancer? Which trial was really important for your practice, for colleagues’ practice? What was most surprising or impressive? What would you say? Starting with you, Eleni, if you don’t mind.
EE: There were two trials that I think are important going back home. One quite surprising for me, and I will explain, the other one not surprising but needed. You probably already know I’m referring to PEACE III and ARANOTE. The reason why I bring up PEACE III and I say it was surprising to me, we, at least in the US, maybe not the case in Europe, had pretty much put to bed a little bit with the advent of Lutetium-PSMA the Radium-223 story. Of course we all here remember the ERA 223 that had to be closed down because of some issues with [16:17].
KF: Sorry, just for those who are listening to us, PEACE III is a combination phase III trial of enzalutamide plus or minus Radium-223.
EE: Correct. This is in mCRPC in men who have not previously been exposed to an RP. CLEAR, of course, may be a little bit outdated, one would say, because today 70% of patients get that exposure but, again, that’s not 100%. But it showcased from its results a very robust rPFS favouring the combination of enzalutamide with Radium-223 plus, an extra bonus, very nice OS survival that we have not, as of yet, seen with other trials such as PSMAfore, for instance, in a similar setting.
KF: With the caveat of an 85% crossover in PSMAfore of course.
EE: Correct, PSMAfore. That is why I am saying all of a sudden we’re put in this new question mark – should we honestly bring up front Radium-223?
KF: So would you, in your next to come patient based on the data that we were shown, if approved and reimbursed and everything?
EE: I will consider it because I did not consider it previously. So, yes, this is an eye-opening trial for me. That I had moved away, because remember for a lot of us the Radium-223 data came from one solo trial, the old ALSYMPCA trial, that was not a very robust trial, had only shown the overall survival, [17:43].
KF: Before you comment on ARANOTE let’s share opinions very briefly. Niven, Anders, would you go for enzalutamide plus radium if you see a patient with bone prominent disease not having received a previous AR pathway inhibitor tomorrow?
NM: Yes, for sure. I think we are underutilising radium which is an effective drug. So, yes, we now see that it’s well managed, there are no problems with bone or skeletal related events if you manage them well. So tomorrow I would do it.
KF: You would. Anders, do you agree?
AB: Yes, absolutely but I want to do it earlier, at the hormone sensitive setting.
EE: Oh wow.
KF: But of course in the context of a trial. We don’t have evidence right now so please don’t…
AB: But therefore we should do.
KF: Okay, good. And you mentioned ARANOTE which is a pivotal phase III trial for darolutamide in hormone sensitive disease as a doublet. So what do you think about the trial?
EE: I think the trial was important to be done, even though I did hear today the criticism regarding the control arm, that it was started in 2020 or 2019 and by that time we had a standard of care with a doublet already. Having said that, this was run in trials where that standard of care was not yet approved and we were not here to discuss the ethical considerations that some of our colleagues had, we are here to discuss the results. These initial results at an interim analysis with a short time of maturity, about 25 months, are in favour. The primary endpoint was met. We need a little bit more time to wait for the overall survival. I feel comfortable going back, not that I have not already been doing it, to now say clearly that the addition of darolutamide to ADT is equivalent to any of the other agents that I have available to me. So now, as of tomorrow, I have four agents clearly in my clinic for hormone naïve.
KF: Niven, your best of ESMO, just one trial? Would you agree or maybe you want to complement with something else?
NM: I enjoyed also the PSMA trials. I think it’s good to see that in the hormone sensitive setting we have now data that you can give supplement PSMA-Lutetium, two cycles.
KF: And just for those who are listening to us, this is a randomised phase II.
NM: A randomised phase II.
KF: We need to be careful, of course.
NM: Yes, a randomised phase II, so we need to be careful, but if you give two cycles of lutetium followed by six cycles of docetaxel and you compare to our standard of care, there seems to be some kind of benefit, maybe panning out on progression free survival and maybe on overall survival. However, it was only two cycles but I think more research is needed. We need to also look at the PSMA addition but I’m quite interested in seeing more of this.
KF: Okay, wonderful data. Anders?
AB: I would like to echo what you already brought up here and those are probably the most important news. Then looking into the future there was a very nice summary by Neeraj Agarwal about the T-cell engagers that may be coming along in the future. It’s very early but I think it was interesting to have…
KF: It is. We have radioligand, we have T-cell engagers, we have ADCs which are really promising, and new targets including STEEP1, HK2, which were not valid targets just a year ago or a year and a half ago. So I think we’re really making progress. I’d like to thank you, very clear opinions, very nice summary of the congress, and really I enjoy our discussion about best use of PARP inhibitors based on what we have now as evidence. With that, I’d like to thank you all for following this conversation today. Thank you very much.
