Understanding the use of PARPi combinations to treat patients with mCRPC
Prof Axel Merseburger – University Hospital Schleswig-Holstein, Lübeck, Germany
Dr Friederike Schlurmann – Centre Hospitalier Universitaire de Brest, Brest, France
Dr Elena Castro – Spanish National Cancer Research Center, Madrid, Spain
Prof Gerhardt Attard – University College London: Cancer Institute, London, UK
AM: Dear colleagues, friends and guests, it’s a pleasure to be here with this expert faculty reporting for ecancer today from ESMO 2024. Wonderful weather here in Barcelona. I’m sitting here with Elena, maybe you want to introduce yourself?
EC: Yes, I’m very pleased to be here with you today. I’m a medical oncologist from Hospital Universitario 12 de Octubre in Madrid.
FS: I’m Friederike Schlurmann, I’m a medical oncologist in France, in the University Hospital in Brest.
GA: I’m Gerhardt Attard, I’m a medical oncologist in University College London, UK.
AM: Thanks. So I’m very pleased and honoured to have you three here to support me and we are speaking on PARP inhibitors. There have been major, I would say, game-changing publications. So maybe, Friederike, if you could set the scene on where do we stand with PARP and PARP combinations?
FS: Sure, I can do that. It has been a really busy time, these two, three or four last years. We have three combinations that we have had studies. We had the TALAPRO-2 study and the PROpel study which were investigating PARP inhibitors plus RP, RC, how you want to name them, in this mCRPC setting for allcomers and they showed a benefit in those two populations, a greater benefit in patients that have mutations. Then we had the MAGNITUDE trial where we had only the benefit for mutated patients. So now this is what clinicians can do, we can prescribe depending on your country and reimbursement but on a scientific basis you can prescribe those doublets, talazoparib, olaparib, niraparib, with an RC in patients who have this mutation and patients who have not the mutation. There are still so many questions because those studies raised more questions than they gave us answers about who to treat and when to treat and do we really want to intensify all patients with PARP inhibitors even if we don’t find any mutations? And why is there this activity? I think we still have not really found out really the reason why we see this activity but we still have other studies, and we’re going to talk about this a little bit, that we still have other studies that show these results, that even if we don’t have any mutation we still have some activity seen there. But I think we still need to dig more into this topic and we still don’t know in which way we will use them. Do we have to use them up front or maybe in a sequence? I think Elena might be able to say something about that.
AM: Yes, I think this is the idea that we are discussing about. It’s confusing, as you said, because we have three different indications, labels, and we have a different situation in the US than the EU and Japan. We have different and conflicting recommendations from the guidelines that doesn’t go along with the label so it’s not so easy. So maybe put it down to an easier level for me, as a urologist. So should we combine or can you lead to the BRCAAway trial? It’s a small trial, it’s been published now, since a couple of days or so. What’s your take on that?
EC: Yes, so what the BRCAAway tried to demonstrate was whether for patients with BRCA and ATM alterations the combination of a PARP inhibitor was superior to the PARP inhibitor alone or whether the sequence really mattered, whether giving one RP or the PARP inhibitor first mattered or not. The study seems to demonstrate that for patients with BRCA alterations the combination is superior to olaparib in monotherapy. So at least for these patients this may work. What we don’t know yet is if patients have already been exposed to an RP whether the combination will still be relevant or we could use the PARP inhibitor in monotherapy. The study failed to demonstrate the question of the sequence because the number of patients that received subsequent treatment was very limited, it was eight patients in each arm, so we cannot answer that question from this study. But it’s very interesting that they see greater benefit from combining and that somehow may explain also some of the results that we have seen in the other combination trials.
AM: This is one of the most urgent questions I get – can’t we just give abiraterone and enzalutamide? No, it’s a mistake nowadays, we should go in triplet therapy. And the discussion is still going on, the elephant in the room thing with regards to HRR or non-mutated. This is a story from the four pillars, like the androgen receptor treatment, the AR-targeting agents and RPs, if they have an effect in combination with PARP inhibitor. What’s your take on that? HRR negative try out and test or only positive? I know it’s a very difficult question.
EC: No, for me we now have the possibility to identify who are the patients more likely to benefit from these combinations that are the patients who have BRCA alterations, according to the FDA analysis, PALB2 alterations and perhaps those with CDK12 alterations as well, we need to understand that. Other patients with HRR alterations don’t seem to benefit that much, such as those with ATM or CHK2 alterations. So now we have the opportunity to identify the ones that benefit and despite there seems to be benefit in patients without HRR alterations we do not know yet who are those patients but we know that the side effects are the same for all patients. Those include haematological toxicity, particularly anaemia. In some of these studies, depending on the PARP inhibitor, the frequency of grade 3 anaemia was quite high, almost half of patients presented with grade 3 anaemia.
AM: 40%, yes.
EC: That means they require a blood transfusion and then it’s fatigue, gastrointestinal toxicity. So my personal opinion is that for patients with BRCA and other alterations the benefit justifies these side effects. For patients without these alterations until we are able to identify patients likely to benefit, my personal take is that perhaps these side effects don’t justify the benefit.
AM: But, in summary, mutated men need a PARP and a PARP combination, I think we all agree. How do we test? We’re all fans of testing. I would call my Encyclopaedia Britannica or if I would get a slot in your office I would call Dr Attard, ‘How do I test and are there differences in mCRPC to mHSPC?’ You’d be really the one if I have questions for how to test and what’s the best method. So please share your expertise.
GA: Thank you, that’s kind. So to test or not to test, that’s the recurring question. Now, we’re having it because it’s not straightforward. Even implementation in clinical trials was a large and expensive exercise and trickling this down into everyday clinical practice remains challenging. The regulatory trials mostly used tissue testing and that’s where the strongest evidence is. The challenge with tissue is a high failure rate, especially when the tissue is older. That introduces the opportunity to use circulating tumour DNA, so that’s a blood draw. The chance of success from a sequencing point of view is very high, the DNA one extracts from plasma is very good quality. The challenge with plasma DNA is tumour fraction and tumour fraction can vary from very low and non-detectable to very high. In the earlier stages of the disease, so that’s mCRPC, the development of mCRPC, those tumour fractions are low and often, or not often, but can be undetectable. So there are several posters that have looked, several studies that have looked at plasma versus tissue and there’s a couple of posters here at ESMO. The key message is there is discordance and the discordance is primarily driven by the absence of tumour in the plasma sample. The take-home message is if you’re trying to set this up and you’re doing testing test tissue, because that remains the gold standard, but if you cannot obtain tissue or tissue fails then try and do plasma testing. But do not label someone as BRCA negative based on a blood test because it can be a false negative.
AM: So you would urge if it’s negative go into tissue testing, I understand this. If I can request this situation of mHSPC, do you expect more tissue or more signal than in mCRPC?
GA: The prevalence of BRCA alterations is consistent in mHSPC and mCRPC. It’s the same patients, they’re just diagnosed three or four years earlier. The BRCA mutant patients have mCRPC presented with mHSPC and, unlike localised disease, they’re not diluted by good prognosis cancers so the prevalence is the same. The big difference with mHSPC is that tissue is more recent so the success rate is going to be much higher. ctDNA is going to be lower because you’re a urologist so you probably see patients before they’ve started androgen deprivation therapy. In my clinic, as an oncologist, the vast majority have 4-8 weeks of hormone treatment. This is highly effective, tumour fractions have plummeted. So ctDNA testing for HSPC is not very efficient, it’s going to be a game of diminishing returns as hormone treatment continues. The last thing I’ll say is germline and half of BRCA mutations exist in the germline. If you’re thinking about the cost effectiveness you’re missing half but, again, if everything has failed then forget germline and ideally we do germline up front together with the other two.
AM: Which has an implication on the families.
GA: Correct.
AM: If you have, the genetic counselling makes sense. So, yes thanks. So you already mentioned mHSPC where we don’t have a label for the PARP triplet, the combination. This is mCRPC triplet therapy, in mHSPC we speak about doublet and triplet like chemo. Is it primetime already for PARP combinations in mHSPC, so hormone sensitive prostate cancer?
EC: I think we still need to wait to see the results of the phase III trials that have been conducted in this scenario. The AMPLITUDE trial and the TALAPRO-3 study and there is a third one with the new class of PARP inhibitors, saruparib, that opened very recently so we will have to wait a little bit. But at ESMO this year…
AM: There’s some data, yes?
EC: There is some data based on a phase II trial led by Joaquin Mateo with the combination of talazoparib and enzalutamide. It seems to be superior to enzalutamide in terms of radiographic progression free survival. It’s a small series, 52 patients, but still I think it is aligned with the results that we have seen in mCRPC and perhaps it’s a hint of what are we going to see in the other trials.
AM: But, if I remember correctly, it’s also in line with regards to the treatment related adverse events which were transfusion rates within 40% which we don’t really want to have in mHSPC when we have data we discuss tomorrow on ARANOTE and TITAN and ARCHES. So toxicity, maybe Friederike you can share from your clinical experience and also being involved as an investigator of PROpel, you were co-author. So how do you deal, how do you treat, how do you monitor adverse events?
FS: I think that there is this toxicity, there is anaemia, we see it in all of those clinical trials. It differs a little bit in between TALAPRO, PROpel and MAGNITUDE; the PARP inhibitors are not the same, the [RCs] are not the same so we don’t have the same rates. It depends really on the combination and I hope that the new classes like saruparib will hopefully be less toxic, that would be really great, I hope so.
AM: Is there already published data on this toxicity?
FS: No, there is no published data. There’s like phase I, phase II data which is promising.
AM: It’s a promising signal.
FS: Yes, that’s why we have the phase III trial that just started, EvoPAR 01 just started. I really hope that this is going to be better but on the other hand I have to be really honest with you. I’m a medical oncologist, we see patients, we treat them with chemotherapy, we do one, two, three, four lines. We are capable and able of managing those toxicities so it’s not really the PARP inhibitor that I would be the most afraid of when talking about toxicities, seeing patients that we treat with Lutetium-PSMA where we have anaemia too. Docetaxel we have quite a lot of anaemia too. So this is something that we have to monitor, that’s for sure, and clinicians that are going to prescribe PARP inhibitors for the first time, they have to be really aware of it and how to test it and test it really often in the first month because we know that the toxicity is coming in the first weeks. The first 2-3 months you really have to be aware of and really see the patient pretty often and do blood tests and everything. But once the patient is really on PARP inhibitor normally it turns out to be pretty good and well tolerated. I think it’s just a question of time that clinicians will get used to that.
EC: May I add something to that? I think you are absolutely right but we need also to be vigilant even when patients have been on treatment for quite a long time because of the risk of long-term toxicities. One of the things in this study that we commented earlier that was a bit remarkable was the event of two cases of acute leukaemia in the study. So it could be just by chance or it could be patients have been on treatment almost for three years. But I think it’s something we need to take into account, particularly now that we are going to use it more and more and for longer.
AM: Just for me to cure in this triplet in mCRPC, maybe Gerhardt, yesterday we saw Silke present the PEACE-3 data. I still have some questions, I have to say, with regards to statistical significance and if it’s really changing the guidelines and how it’s influencing. So how do you see how you would…? Radium may already also… like we have radioligand therapy, PSMA, so how would you see PARP triplet and radium quadruplet that has been presented yesterday?
GA: Interesting. So I think it’s going to be challenging to combine radium, PARP, enzalutamide in a quadruplet therapy. Probably the line one mCRPC RP naïve space is relatively restricted so PEACE-3 yesterday, that was presented yesterday, is a population who are RP naïve. I found the data very convincing, it’s true there are some statistical questions were asked but I understand the numbers at that start of the follow-up KM curves is very small, five or six patients, and curves can flip either way. I agree with Karim Fizazi who did the discussion that when you look at those curves this is an effective treatment. Radium is improving rPFS, it’s improving survival. We need to settle a bit, we need to see the full publication, we need to see the side effects, and then it’s going to be a balance between these different treatments. But I didn’t see a role for combining radium with PARP inhibition.
AM: Maybe I phrased the question wrong. So what’s the winner, the combination of a PARP or the new introduced somehow standard by Silke yesterday? It’s a renaissance of the radium-223 which was off-shelf somehow. What’s your opinion on that?
EC: Well, coming back to your comments earlier, perhaps for patients with HRR alterations it will be very clear that the PARP and for those other patients in which we do not identify an HRR alteration, the addition of radium could be an excellent option.
FS: It’s like you said, it’s a study that was designed eight years ago with the GETUG group so the setting really changed and those patients are disappearing, we don’t see those patients anymore. I don’t see a lot of those patients in my clinic. As you said, when you have a mutation then the question is just not there, you will put him on PARPi. If we really reuse radium it’s quite a difficult drug to manage, it’s not that easy to do that in the clinic and you need nuclear medicine. We have other trials now coming with PARPis and the Lutetium-PSMA, for example, so I think it’s going to be difficult to find the space really to put this combination in the real-world setting, I’m not sure that’s going to come.
GA: Yes, I agree. With my cynical hat on the combination of PARP inhibitors and RP has far more win than marketing and its sales. Radium is the ugly duckling, I guess. As you said, it was forgotten, sitting on the shelf. There is logistical intricacy and in fact the take-up of radium globally was limited, which I think is a shame. A lot of that efficacy may be driven by cancers with DNA repair deficiency, this being a radiation plan treatment. So I am a bit hesitant to select out the BRCA mutants for radium because we may lose that benefit but we’re going to need some more time to think through that data. And having options is great.
AM: More time [??], yes. I fully agree. So I also liked Karim Fizazi’s comment on some are building a war machine and they are having a peace machine.
GA: I loved that, yes.
AM: Kudos, really, to the authors and the group for this, in getting this academic trial run. So I can only say thank you Elena, thank you Friederike, thank you Gerhardt, for supporting me here for ecancer. Thanks a lot.
