Update on the latest in PARP inhibitors for prostate cancer

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Published: 11 Jul 2022
Views: 2841
Prof Axel Merseburger and Prof Bertrand Tombal

Prof Axel Merseburger (University Hospital Schleswig-Holstein, Lübeck, Germany) and Prof Bertrand Tombal (Université Catholique de Louvain, Brussels, Belgium) discuss the latest in PARP inhibitors for prostate cancer.

Initially, Prof Tombal comments on the phase III PROpel trial which investigated the tolerability of abiraterone combined with olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC).

Prof Merseburger and Prof Tombal also discuss the health-related quality of life and pain in the MAGNITUDE study of niraparib with abiraterone acetate and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.

They discuss what this data could mean for the future treatment of prostate cancer.

Prom Tombal then gives practical guidance on testing for HRR mutations. They also cover other subgroup analysis studies from EAU 2022 that investigated BRCAness and PARP inhibitors.

They conclude by talking about the PRESIDE trial.

Comments on the phase III PROpel trial
BRCAness and PARP inhibitors
Discussion of the PRESIDE trial



This programme has been supported by an unrestricted educational grant from AstraZeneca.

AM: Dear colleagues, welcome, welcome to ecancer. My name is Axel Merseburger, I’m a urologist and Professor and Chairman of the Department of Urology in Lübeck, Lübeck University. It is my great honour and pleasure to sit here together with Professor Bertrand Tombal, no further need of introduction – a well-known, world-wide respected expert in the field of advanced prostate cancer, also a urologist. So we are here at EAU 2022, face-to- face, live again in person. We saw a lot of data this year, starting at GU ASCO. Bertrand, maybe you can set the scene about PROpel and MAGNITUDE and what’s the story about? I just saw Noel Clarke today in the morning at breakfast, I know it’s his so-called EIGHT story that set the basis on all this. So please tell the audience, the viewers, what the news is about PARP and abiraterone.

BT: Thank you for being here, Axel, it’s a pleasure. You know that PARP are already considered a standard of treatment for patients that are progressing on abiraterone and enzalutamide. It’s slowly making its way in Europe as this, with urologists being educated about looking for DNA mutations. But then there were basically two very important questions: should we wait? That actually the patient is progressing on abiraterone or enzalutamide. Should we combine them from the beginning? And that’s very important as a, I wouldn’t say huge but a very strong, rationale that they improve the efficacy and they change the mode of action of each other, there is a good rationale that actually they could work in everybody and not only as it is registered in Europe in the subset of BRCA1 and BRCA2.

The problem is that you cannot marry any PARP with any hormone therapy because there are a lot of drug-drug interactions. So for abiraterone there were two trials with similar… it’s abiraterone in both arms which is one of the commonest and one of the big advantage is abiraterone coming generic soon, it’s a very easy, cheap drug. Then there were two trials, the PROpel trial that was with olaparib and the MAGNITUDE trial with niraparib. Already one big difference because of this interaction – in the MAGNITUDE trial they couldn’t use the full dose of niraparib which is 300mg but they chose 200mg. So that’s important when we discuss. In both they started with a broad group of patients, very interesting and provocative. In the PROpel trial the patients were started on the treatment and then the test was obtained.

AM: No testing before for HRR?

BT: Not testing before so it’s really a test-agnostic trial which, to me, is very provocative and makes in some way the study very simple and pragmatic. Then, as we all know by now, big provocative surprise that is raising a lot of questions.

AM: A positive surprise.

BT: A positive surprise that we have to admit there is a very significant improvement in radiographic progression free survival. Then when they analysed the subgroups, when they analysed the DNA repair subtype, a big surprise again – it seems to work in everybody. If you are the devil’s advocate you would see it works better in BRCA1, BRCA2, as we know. That’s a big surprise for PROpel. For MAGNITUDE this is a little bit different. They knew the status up front and they had an interim analysis and they stopped the trial because of not missing the futility endpoint in the group of patients that were not harbouring DNA repair mutations. Then, for the rest it’s positive. So for both trials we will now wait for further overall survival. But we had here several posters that basically confirmed what we know. You mentioned you were discussing with Noel this morning and I think you can now tell us that quality of life, actually, is very good.

AM: Yes, definitely, I’m just coming back to the trials just to inform the audience. So the backbone is ADT for both trials, putting on top abiraterone, and in one arm it was just abiraterone and ADT and in the other arm it was niraparib and the combination or olaparib and the combination. So a modern treatment where I never thought this would add some benefit. But we saw the results and they were really convincing PFS-wise. OS-wise not yet. The curves trend to separate. Just pretend we would have an approval of this situation, would the PFS convince you? And then we come towards the topic of subgroup analysis and what we saw here at ASCO and EAU now. Does this ASCO GU presentation and the publication which is out now convince you to treat like this?

BT: I would say yes and no. Yes, surely that if I know the DNA repair status of my patient and it’s BRCA1, BRCA2 and many of these patients we know them earlier on, know that we’re trying to do genetic testing much earlier. I think that for that subgroup of patients it is clearly practice-changing; we have to start the combination up front. Then for the group of patients who don’t have BRCA1, BRCA2, it will take a little bit of time but I must say, and we will discuss the EAU quality of life results, there is nothing bad so far, as I may say. The toxicity is acceptable because anyway we may have to use these drugs later on; the toxicity is acceptable. The tolerance, the easy to use, the convenience, so I’m not yet fully convinced. In Europe it’s easy, the EMA is quite tough. So I think that we are emotional, we treat patients, we want to do the best for our patients; if the EMA say yes then we’re going to be reassured that on a population level it’s a yes. Then maybe once again, always the same thing, for the frail and that… But let’s take 65-70 guys who progress after a bad story, we know they fail prostatectomy, radiotherapy, no, I think that honestly this will be… Because if you try all the other combinations have failed, we try to combine with radium, it doesn’t work, with apalutamide it doesn’t work. So we would be happy with a trend in overall survival because for the rest we have nothing.

AM: So just to be a little bit provocative, and I know I can ask you this because we have been chatting about this topic since ASCO GU, just as a word [inaudible] the trial I presented at ASCO GU. We were discussing will this be the new backbone, like having ADT and NHT or possibly abiraterone, and then adding on top something like now we have seen PARP inhibitors. As you alluded to already very nicely, quality of life and side effects – a little bit more side effects, definitely, in the combination but quality of life, as we have learnt here from a poster at EAU, somehow is better. So what’s your explanation or can you say something about the data we just saw here at EAU on the combination quality of life data?

BT: Yes, because people tend to forget – what do you do when you measure quality of life? People always link toxicity, tolerance, side effects and quality of life. No, that’s wrong. Quality of life is not directly linked to toxicity, it is linked to the quality of the life, meaning how the patients may actually live a normal life. This is always a result between the effect on the cancer and the side effects of the treatment. When you are treating more advanced patient cancers, it’s not new, if we look at older studies we’ve done – COU-AA-301, COU-AA-302, and especially I’m still a big fan of the effect of the prednisone on quality of life – these patients improved, probably because you have an effect on the cancer which is more important than the toxicity of the drug. So these results are absolutely encouraging and that’s one other brick for… I’m always very critical and I must say that we discussed that, we’re waiting for these results, okay, I have to admit I’m surprised – it’s not bad. The good thing, also, of quality of life it’s real-life evidence because it takes into account patients who had dose reduction, so it’s really how the drug works in the patients. So very, very encouraging.

AM: Yes, I fully agree and this has been discussed at EAU and we discussed this on our course today in the morning with Eleni Efstathiou. So it’s just a hot topic for the first half year of 2022. Any other subgroups or analyses you are interested in or you saw that caught your attention also in ASCO? Like the combination, BRCAness, the rationale of why it will work, any words on that?

BT: A big question. I remember already 18 years ago in the lab with John Isaacs, people were looking at the interaction between ER manipulation and DNA repair mutation. It’s true that there is that so-called BRCAness which is making that when you give abiraterone or enzalutamide or any of the hormone, actually. If you remember, the mode of action, DNA repair mechanisms are involved into the mode and you’re making the cells more sensitive to this hormone. Everybody believed we would see that in animal, everybody said, ‘Yes, we have no proof in human.’ It sounds a bit like the abscopal effect of radiotherapy – everybody speaks about it, we have very little clinical data to look at it. Here, we must admit, we have data. So because I already know in my country, in Belgium, they probably won’t say yes to everybody because that’s expensive. So I try to look at the precise DNA repair mutation. It’s true that once again the biggest effect is in BRCA2. I think why BRCA2 because BRCA2, in the end, it’s the most frequent one. All the other ones it still remains a kind of… and also BRCA2 is the one which is linked in the mechanism of BRCAness. So for all the other ones, I must admit, except for a few rare mutations, we haven’t seen a group where it doesn’t show a benefit. So keep in mind also that’s important. I’m not sure that the tests we use, they give the whole picture. So that’s where we have to be careful about precision medicine – there is a big imprecision in precision medicine, meaning that it tells you what gene you have found. For the urologists it’s important. It’s like prostate biopsy in a guy who has a small cancer. So it’s like when you have one single Gleason 7 you don’t know what’s in the rest of the prostate. That’s one of the big advantages of the PROpel trial, it’s close to reality. So so far I haven’t found any subgroup where we can say no, it’s not going to be for that one. So that’s very encouraging.

AM: So the hazard ratio convinces you in both trials, in the testing part?

BT: Yes, to be honest, let’s be honest, you’ve got olaparib full dose, well tolerated, a big hazard ratio, no need to decrease the dose, quality of life reassurance, toxicity significant but manageable. Niraparib it’s going to be more complicated because it’s a low dose of niraparib; many people, through my connections at EORTC, many oncologists say that’s a reduced dose, it explains most of the small differences. So I think that the standard of care will be…

AM: But an increased dose would be probably more toxic and you have the potential for anaemia and that sort of thing.

BT: Yes, it is known that they haven’t chosen that dose like this, they had to reduce the dose from scratch. No, the big question, and I would like your opinion because I’ve been doing a lot of advice in Germany, in Germany it’s going to be hard to find somebody who has not received abiraterone or apalutamide yet when they progress. So what’s your opinion on these patients? Let’s assume somebody is progressing on apalutamide, what are you going to do?

AM: This is a good question and I was about to expect to get it from you. This is something we need to gather more data; I think we need to have real-life and registry data then with patient reported outcomes, health related quality of life and, as said, I would say hopefully about 90% get treatment intensification, let’s say, in mHSPC and not the traditional mCRPC. So they start with apalutamide and ADT and once it comes to progression what do you do next? I personally would say testing, yes. You need to do testing to know if you have a label for olaparib which is approved now. If we have the doublet approved we have to discuss and then we don’t know yet if the doublet brings a benefit after a doublet or even a triplet when thinking of ARASENS data just published and discussed. So what’s your opinion?

BT: I think that we discussed that before, the PRESIDE trial was an important trial because we do two strange things: the first one is we don’t do a lot of combination, except with ADT but that’s an easy one. Usually when a patient is progressing on a drug we stop the drug to start the other. If you think about the reason, it’s mostly because this is the way the trials were designed and the regulation and pricing that followed. Then, at least now, we started having trials with docetaxel, your trial, PRESIDE, and a Spanish trial with abiraterone. They both showed that actually it’s a little bit better if you keep either enzalutamide or abiraterone when you give the docetaxel. So that’s a concept David Crawford coined ten years ago – layering. I know that we have all this PSMA PET technology, whole body MRI technology, actually we realised that the progression is absolutely heterogeneous. Sometimes it’s two or three lesions that progress and the rest is well controlled by your abiraterone or enzalutamide. So a good way would be doing a PRESIDE with abiraterone and olaparib, that would be the first one.

But I think we’re going to need this combination because the patients who progress on apalutamide, enzalutamide, they need more than apalutamide and enzalutamide, that we know already. If it is to switch, you know that if the patient is on enzalutamide and you want to give olaparib you cannot do that, there will be some incompatibility between the drugs but why not combine. So these are very important questions. Something I like, because this is a urology meeting, is that the urologist must be embarking on this also because these are oral drugs. So they need to learn to do it properly, it’s important. So I think that’s very important that we teach our colleagues very well how to manage and do like we do with all the questions in real life is to find real life solutions.

AM: Thank you. I think the viewers, including myself, learnt a lot from you so really thanks a lot. I’m looking forward to continuing the discussion and it’s always a pleasure to see and hear your insights. So, Bertrand, have a good EAU 2022.

BT: Thank you, you too.

AM: Take care, bye-bye.