PARPi combinations to treat patients with mCRPC
Prof Axel Merseburger – University Hospital Schleswig-Holstein, Lübeck, Germany
Prof Karim Fizazi – Institut Gustave Roussy, Villejuif, France
Prof Laura-Maria Krabbe – University of Muenster Medical Center, Muenster, Germany
Prof Gerhardt Attard – University College London: Cancer Institute, London, UK
AM: Dear colleagues, friends and guests, it is my pleasure to be sitting here at ESMO 2023 with this very expert multidisciplinary panel. On my left I have Laura Krabbe, Laura, do you want to introduce yourself?
LMK: Sure, thanks Axel. My name is Laura Krabbe, I’m a urologist from Berlin, Germany.
AM: Gerhardt Attard.
GA: Gerhardt Attard, I’m a medical oncologist in University College London, UK.
AM: Last but not least, Karim.
KF: Karim Fizazi, medical oncologist from Institut Gustave Roussy in Villejuif France.
AM: No need for introduction but I think it’s just good to set the scene of what we are going to talk about today. We are going to speak about metastatic castration resistant prostate cancer, especially on the topic of PARP inhibitors and combinations. We have learned a lot, especially yesterday at Sunday’s ESMO session, on also selection of patients and if biomarkers play a role. I’m just looking at you, Gerhardt, because I know you’re the expert in biomarkers in mCRPC. So you presented some data, would you somehow summarise this and how this has clinical implications in our daily work.
GA: So to summarise more broadly, we can define BRCA status and really we’re focussing primarily on BRCA although there are a number of less common genes. We can define BRCA status either by testing germline, and that’s saliva white blood cells, but that captures only about half of the total alterations, half are somatic only. The second way we can ascertain BRCA status is testing the tumour. This comes with a number of challenges – finding the tumour and then a high failure rate because these samples are old, poor quality. The third way is using plasma or circulating tumour DNA. The poster we presented here was a comparison in the MAGNITUDE trial of patients who were selected based on tissue or based on plasma. The trial allowed either test to be used and the majority had both of them but there were patients who only had plasma or only had tissue. The bottom line is that there is a small number of patients, just under 10% of the total BRCA population, who are BRCA positive on plasma but not on tissue. That is probably because we know there is a false negative rate in tissue due to the poor quality, that would probably be germline mutations that are then detected in plasma. Now, the flipside, when we look at plasma versus tissue in a line one mCRPC, a significant proportion of patients will have low circulating tumour DNA. In fact, there is about 30% of patients who are positive on tissue but not on plasma. The message there is plasma is helpful, quick to take, gives a good result but if a patient is negative and you’re not certain there was tumour in that sample, do not label your patient as BRCA negative. He could be BRCA positive and that’s a false negative result from plasma.
AM: To be curious, could this be the reason why in these trials of the all comer populations the negative had an effect?
GA: I think there are many explanations for that, this could be one of them. Clearly there are false negative rates but it’s going to be a small proportion overall. In fact, most of the analysis in PROpel and TALAPRO-2 have utilised tissue not only plasma.
AM: And plasma, would this be applicable, for example, in our German setting? Is it readily available or is it just specific to your lab?
GA: Yes, I’ll tell you what was exciting at this meeting was we had a presentation on the ProBio trial, which we may well discuss in a few minutes time, which was an academic trial and showed the implementability of transnational plasma DNA testing and using that to select patients. So clearly being done in an academic trial. In the global industry-sponsored trials plasma has been implemented in several of them. So certainly that is here and here to stay, plasma testing.
AM: Thanks a lot and thanks for sharing this data and also pointing out the ProBio which we can definitely discuss later. But just coming back, we have those large big trials looking at niraparib, the MAGNITUDE trial, there’s the PROpel trial with olaparib, we had TALAPRO-2 trial, I know Karim you are deeply involved in this trial. Here at ESMO you showed also some selection criteria and efficacy and safety data you were involved in as an author. So would you share those news from ESMO 2023?
KF: What we showed here at ESMO was a correlation between those received doses and efficacy and/or safety. Indeed, in general, PARP inhibitors have quite a narrow window of efficacy. So, in other words, if you give just too much you’re toxic, if you give too low you’re not efficacious and this is quite well known and well recognised. For talazoparib we had to be cautious in the development from TALAPRO-1, TALAPRO-2 and now TALAPRO-3 which is in metastatic castration-sensitive disease. Indeed, when you’re treating a man as a single agent you would typically use 1mg as a starting dose. But in combination with enzalutamide, because of other drug-drug interactions, you need to lower the dose up front to 0.5mg. This was actually clearly identified in the lead-in part of TALAPRO-2 and then we did the big phase III trial, actually two trials because one is for all comers but the other one is really for BRCA or DDR patients. So what we tried to analyse in this paper, or these two papers, was really the correlation between the received dose and what happened to the patient. Not surprisingly, but I think it’s good to have, we could show that, indeed, patients receiving higher doses had greater efficacy but also greater toxicity. Which is telling us probably in the clinic that we should try to go to some safety signal to get the efficacy but just not too much so that the patient can tolerate it. Of course, it probably has to be an individual decision, not all patients are made equal, we know it very well. Even within the same patient, depending on the time, we may actually have sometimes to lower the dose and sometimes to make the dose higher. Which is not making our life easy as medical oncologists but it is as it is and I think it is very important to recognise that.
AM: Thank you. I think this is really important data. Does it mean for the audience if you have no side effects, there is no efficacy? No, that’s not the case. It can be both, right?
KF: No, of course not. This is more a general statement. If someone is developing some side effect, of course we’re not happy for the patient but it perhaps means that the exposure, the tissue exposure and the cancer exposure is probably good enough to induce efficacy. I’m not saying that we should do our best to get toxicity of course.
AM: And you mentioned TALAPRO-3 in mHSPC, so hormone sensitive prostate cancer. To my knowledge, this has not been published yet. When might we expect the data?
KF: I’m not going to provide you a time because this is obviously event driven. But the good thing is that this trial and some other trials in metastatic castration sensitive disease could complete their accrual. Those are very important questions. I’d love to know whether, especially for BRCA patients, I’m more on the fence for others, obviously, but for BRCA patients I’d love to see whether an earlier intervention with a PARP inhibitor and perhaps a short duration of PARP inhibitor, short meaning probably one or two years, not necessarily lifelong, can make a difference in this setting when hopefully the disease is less complex to target and hopefully to cure. So those patients remain rare so I’m glad that we were able to complete the accrual and, of course, we need the follow-up. On the other hand, I’ll be also happy to know whether we are not toxic when using PARP inhibitors earlier in the course of the disease. This is why it is so important to do that in the context of clinical trials. I’d hate to see secondary leukaemias or myelodysplasias, especially if this is something we don’t know because people are doing it just outside trials.
AM: Thank you for this great work you are doing in this PARP combination area. I’m really looking forward to the data. We have to discuss how this competes with radioligand therapy where we’ll see the data today, so exciting times in mHSPC and surely also in mCRPC. So, PROpel aside, the TALAPRO trial, we have seen data on the MAGNITUDE trial and yesterday Kim Chi nicely showed an update on the MAGNITUDE trial. Laura could you see or share your views on this update?
LMK: Yes, of course. Kim Chi presented the final OS analysis. First of all it’s important to note that overall survival was a secondary endpoint here. We know that the MAGNITUDE trial is a little bit different from the other PARP inhibitor combination trials as that we’re looking from what was presented at a biomarker positive cohort. We know that in this cohort the primary endpoint, radiographic progression free survival, was positive. So the question was now does this translate also in an overall survival benefit because there we come back to the discussion what is most important to our patients, to us in clinical practice? Is it already enough to see a significant delay in progression, is that what’s already sufficient to start to utilise a drug or do we really need to see OS benefit every single time. Also, what are the possible confounders? So here we saw that from the analysis there was, I would say, a numerically modest overall survival… I don’t want to say benefit but it was longer in the median by about 2½ months for niraparib abiraterone versus abiraterone plus placebo. We can ask around, I think maybe most of us would have wished for this difference to be a little bit larger. They also shared a preplanned multivariate analysis which adjusted for certain risk factors where the hazard ratio was better, about 0.66, so about a 35% reduction in risk of death. So this alludes to the principle of this working and to the efficacy but maybe it wasn’t as large of a difference as we would have hoped for. The question is obviously are there possible explanations for this and Kim Chi alluded to the subsequent treatments, that a significant proportion of men, one third, received a PARP inhibitor at time of progression when they had been in the placebo arm. There were also at least some patients who received a platinum-based chemotherapy. So the subsequent therapies might have muddied the water here for OS.
AM: Thank you. Nicely summarised, this data, and the PFS was the primary endpoint that was met, it was a positive trial and led to EMA approval. I liked your point, what Kim also alluded to yesterday, that you had one third of the patients that were all known BRCA positive in the control arm getting a PARP at some point. Ethically-wise I think this is fair, how are your thoughts on that Gerhardt?
GA: So clearly PARP inhibition works for the BRCA mutants. As Karim said earlier, for the others we’re probably still on the fence for the other genomic alterations. The question here is should we use this line one or should patients just get NHA and then monotherapy when they progress? Using it line one comes with probable increased toxicity because they’re going to be exposed for longer but can we improve survival? That’s where the question, I think, remains. We don’t have a definite benefit in survival from MAGNITUDE. There’s a clear indication, there’s a trend, as Laura just said, not a statistically significant and definite benefit. So I think we’re still on the fence here. There’s that balance between maybe increasing efficacy but clearly increase toxicity, are we going to improve survival? We’re not sure.
AM: So definitely for HRR mutated men PARP needs to be integrated into the treatment. So the question is, and this is always the elephant in the room somehow, this old mCRPC derived out of ADT monotherapy, we don’t have it anymore. We have doublet therapy, we have triplet therapy, we have therapy intensification in mHSPC. So I’m asking you, Karim, how do you interpret this data or can this be extrapolated in the old mCRPC times? What are we doing now?
KF: The question is whether this is the truly old CRPC times or not. I think we believe it is because we are treating all the patients, probably the four of us, for mCSPC with at least a second generation AR pathway inhibitor and sometimes a triplet. But this is not the case everywhere, very, very clearly. Many surveys are showing that, indeed, many patients with mCSPC do not receive treatment intensification. So for these men, obviously, the data we just discussed may actually apply with their protein counts. But I’m with you otherwise, we’re missing data for all the reality which is mostly patients developing CRPC after they have failed abiraterone, enzalutamide, darolutamide or apalutamide. For those patients there’s no clear indications that if they have, for example, BRCA alteration we should go for a doublet with an NHT and a PARP inhibitor. Perhaps a PARP inhibitor is very sufficient, we just don’t know.
GA: In fact, that’s where the evidence is, isn’t it. For a patient progressing on NHA it’s PARP inhibitor monotherapy. All these combination trials for patients who are NHA naïve, a very small number had received NHAs previously so I think that’s really important. I’ve heard some people discussing say, ‘I’ll use it for all patients.’ No, if a patient is progressing on NHA why would you expose them to the additional toxicity of a combination when the indication is monotherapy.
AM: I fully agree. Even discussing ADT sparing in the future, there are trials looking at that, not in the setting of CRPC but possibly. So looking at the sequencing, when you have an HRR mutated man, maybe starting with you Laura, would you go PARP first and then docetaxel or docetaxel first and then PARP.
LMK: If I have someone with a mutation, obviously BRCA1 and 2 being the ones we know best on how to act, then we know from this last year from the TRITON study that the progression free survival is longer when these patients are exposed to PARP as opposed to a second new hormonal agent or docetaxel. So we’re trying to come to a place where we give more individualised treatment and if you have something that’s actionable, like BRCA1, BRCA2 mutation and you have a study like the TRITON study in your hand, even though that might not be the specific drug that you can utilise as it might not be on the market, but the principle stands. So I think someone who has had intensified therapy in mHSPC gets a test, has a BRCA mutation then that patient should be exposed to PARP.
AM: Thank you. I can only echo you and I think this is a clear statement here. I think this is a big take home of the rucaparib data, monotherapy data. Maybe we’ll have a final comment and maybe get a final comment on the PARP combination story and then, Karim, you and then we thank the audience for the interest.
GA: I think the decision, agreed, monotherapy then docetaxel. But after today the decision is going to be a bit harder because the lutetium-PSMA FORE trial for chemo naïve patients will be presented. In the abstract there’s a clear indication that this is strongly positive trial. So the decision is going to be PARP monotherapy or PSMA lutetium.
AM: So we have to meet again in this group.
GA: We have to meet again in six months’ time.
AM: Sounds good. Karim?
KF: That’s very true and just to support what Gerhardt said, it appears that patients with BRCA alterations may actually be those who benefit most from lutetium-PSMA treatment. So there will be some fine-tuning there and maybe combo for some patients will be the solution, we’ll see. Of course we need data. But, very importantly, I’d like to remind the audience that we should probably stop speaking about HRR and for sure all comers, at least in my opinion. We have quite clear data now in all these three trials indicating that BRCA2 patients are different patients, probably BRCA1, even if numbers are small, are quite similar. They clearly benefit from PARP inhibition by PFS and likely by OS. Of course we can argue on that but, across the board, this is fair to say. Now, for other patients it’s a totally different discussion. This is true for non-DDR patients but it’s also true for DDR non-BRCA patients who actually behave, in general, quite similar to non-DDR patients. So we should stop pooling these patients together with the BRCA patients in all the discussions and, most importantly, in all the decision making.
AM: Thanks a lot, a clear statement. I thank the expert panel for discussing this with me and thank you, the audience, for the interest in PARP combinations here from ESMO 2023. Thank you.
