ASCO GU 2023
Latest in PARP inhibitors and combination therapies for prostate cancer
Dr Dan George – Duke University School of medicine, USA
Prof Noel Clarke – The Christie NHS Foundation Trust, Manchester, UK
Dr Friederike Schlurmann – Centre Hospitalier Universitaire de Brest, Brest, France
Prof Eleni Efstathiou – Houston Methodist Cancer Center, Houston, USA
DG: Welcome to our round table discussion on PARP inhibition combinations in prostate cancer. I’m Dr Dan George and I’m happy to present today, with my guests here who I will introduce in a minute, on behalf of ecancer. Why don’t we start with you, Eleni?
EE: Hi, I’m Eleni Efstathiou, I’m a GU medical oncologist from the Houston Methodist Cancer Center, pleasure to meet you.
DG: Thanks for coming. Noel?
NC: Thank you Dan, I’m Noel Clarke, I’m a urological surgeon and Professor of Urological Oncology at The Christie in Manchester.
DG: Fantastic. And Freddie?
FS: Hi, I’m Friederike Schlurmann, I’m a medical oncologist. I’m coming from France, I’m from the beautiful region of Brittany and I’m happy to be here today with you.
DG: Thank you so much. We’re here from San Francisco at GU ASCO and we’ve had some fantastic updates in some of the data that was presented earlier this week. Noel, do you want to start us off by just giving us a background around the rationale for these phase III studies of combinations of PARP inhibition with novel hormonal agents?
NC: Yes, so one of the big topics of the meeting has been PARP inhibition and particularly PARP inhibition combined with androgen deprivation, that’s novel androgen deprivation. The background to this is that PARP inhibition, which is well established in late stage castrate-resistant prostate cancer as an effective treatment, is enhanced by the addition of novel hormone agents, whether that be with abiraterone or with novel hormone therapies. There is a good deal of pre-clinical data to support that. We know that homologous recombinant repair is a mechanism of DNA repair which is ubiquitous and PARP inhibition inhibits that binding of the PARP to the DNA and that enhances the DNA damage. Now, the double strand break is the critical thing and the use of androgen deprivation with a novel androgen deprivation agent enhances that DNA damage. That, in turn, enhances the DNA double strand breaks and increases the cell kill. The phase II study which we ran with olaparib in an open label manner, that’s to say without homologous recombinant repair definition before randomisation, showed that there seemed to be an effect across the piece, whether there was DNA damage repair defect or not. That then led to the conduct of trials, three essentially but two that looked at this without randomisation based on HRR deficiency. The data, which we are going to discuss, looks really quite promising because there is an effect which seems to occur irrespective of HRR mutation status but with some key differences.
DG: Great. So just as a hypothesis here, we’re thinking that these novel hormonal agents are working, in addition to all of their effects downstream of testosterone inhibition, at also destabilising, to some extent, this DNA repair, sensitising, if you will, these tumours to PARP inhibition in this context.
NC: Yes, absolutely. So there’s an effect on the androgen receptor from the novel hormone agents, part of which is associated with the repair process. If that’s inhibited along with the PARP inhibition then there is synergy in that process.
DG: Fantastic, and this is separate, or perhaps additive, to the effects that homologous repair defects might have in this same mechanism?
NC: Yes, absolutely. We know if an ADT has failed, in other words late stage castrate resistance, then it’s important to have some form of homologous recombinant repair defect to get maximum effect. But given further up and in synchrony in first line, it’s clear there is more than just a monotherapy effect, there is a synergy in what is happening.
DG: Now, Eleni, there have been three studies done now, three phase III studies conducted in this space based on this rationale, following this study, the Study 8, that Noel laid out for us, the preliminary data, if you will, for this in patients. Can you walk us through, just top level, what those three studies were and any differences between them in the drugs?
EE: The three studies that we are referring to are the combinatorial, just to reiterate, that are in the early mCRPC space, meaning right after we’ve failed with the initial treatment. So, in that sense, all three studies are similar. But then we go into the details and, as we’ve repeated over and over, the devil is in the details, and we look at the specific design. So, the three trials were PROpel, which is the most mature and you presented wonderfully the outcomes. The second one is MAGNITUDE, in fact, last year we heard in parallel the data being presented, and the third one is a newcomer, TALAPRO. Now, when it comes to the specific study cohorts the PROpel was the trailblazer, saying ‘We’re going to put all early mCRPC on, regardless. We’re not even going to look at HRR status in the beginning,’ correct me if I’m wrong. ‘We’re doing it on the back end of things, we will do some extra analysis on it and we’re just randomising the patients regardless,’ you didn’t even use strata of HRR since you didn’t do it up front, ‘to either having abiraterone plus prednisone plus placebo or abiraterone plus prednisone plus olaparib.’ You had rPFS as an endpoint on the study but that was based on investigator assessed rPFS as a primary endpoint with secondary endpoints key central review, we can report on that, and other key secondary endpoints lining up to overall survival. So that was it in a nutshell and, again, correct me if I’m missing something.
NC: No, that’s correct.
EE: So then we go to MAGNITUDE which had a little bit of… and I want to take a minute to explain what happened there because I was heavily involved in the steering committee from the beginning, we were all like, ‘That’s it. No, we’re going for HRR. No…’ And then you get on the stage a few years ago and you show that data and we’re all just sitting there like, ‘Oh, he’s showing something in HRR negative…’ And then we go back and we started arguing – ‘What are we going to do? What are we going to do?’ Then we said, ‘Okay, we’re not going to just go back and do agnostic but we’re going to create two cohorts, one that’s going to be HRR positive that we’re going to follow through as we planned and randomise to get niraparib, in that case, plus abiraterone plus prednisone versus abiraterone plus prednisone plus placebo. We’re also going to start a cohort in the negative HRR group that we’re not going to fully accrue but when we reach those 200 patients we’re going to halt, do a futility analysis.’ So that was the big difference there – the a priori definition of HRR positivity versus negativity. So MAGNITUDE had two cohorts and, just to fast forward, once we reached those 200 patients in the HRR negative we did the futility analysis based on PSA progression, rPFS, and we’re like, ‘Well, we’re not seeing anything.’ And you can judge and criticise but we stopped it. So we can’t really speak to HRR, that’s it. And then TALAPRO comes along, and reproducibility here is key, which is more similar than dissimilar from PROpel. They’re like, ‘Well, we’re not going to listen to all the investigators freaking out about not putting only HRR positive but we’re going to have all comers as well. We’re going to figure out who is HRR positive, who is HRR negative, but we’re randomising one-to-one regardless of status on, this time, enzalutamide plus talazoparib versus enzalutamide plus placebo. So this is, in a nutshell, the differences: so two trials abiraterone, one trial enzalutamide; three different PARP inhibitors, all of them PARP1/2, some data pointing to potential differences in the DNA trapping mechanism. So I think we would agree talazoparib a little bit more similar to olaparib versus niraparib. Finally, a little bit of a lower dose on the niraparib plus abiraterone arm versus the equivalent that you would see in olaparib or talazoparib. These are the differences.
DG: Basically, yes. I think that’s a really good summary, thank you Eleni. That really helps us.
EE: I hope it made sense.
DG: It is. It’s complicated but I think it does make sense. There are subtle but really important differences in these trials. Then we have the top level efficacy results, the PFS and the OS. Noel, can you walk us through what we’ve seen now from the three trials to date regarding that?
NC: Yes, and inevitably I’ll have to be brief but I think that the two trials which recruited irrespective of HRR mutation status are very similar and MAGNITUDE, actually, is quite different because it has a much harder population to deal with because of the pre-selection process. So the rPFS endpoint for PROpel and for TALAPRO-2 is the intention to treat. The PROpel data is a little more mature than the TALAPRO-2 data, but what is interesting is that in PROpel we had data cut-off 2 which, broadly speaking, corresponds with the TALAPRO data that we’ve seen at this meeting. There’s a striking difference in outcome in rPFS, the hazard ratios are very similar, the overall survival is immature, as it was in PROpel. But with PROpel now we’ve got a longer period where we’ve been able to look at survival which is not yet significant, it’s 47.8% mature and it will mature, but the striking thing is the difference in survival in the two patient groups which is over 7 months which is a really big difference. Bear in mind this is not against a placebo in the true sense, it’s against an active treatment. So that’s really quite encouraging. So in bringing forward the data from PROpel one is always a little bit circumspect in making didactic statements based on a single trial but what I think we’ve seen is data from the TALAPRO study which complements the PROpel data and that’s really quite encouraging. Interestingly, when the data is cut for TALAPRO looking at the tissue for HRR non-mutant the hazard ratio is 0.66 for effect, so really that’s quite strong. That more or less matches exactly what we saw in PROpel. So I’m quite encouraged that TALAPRO, that approach of non-HRR selection, has got validity because both TALAPRO-2 and PROpel seem to be doing the same thing, PROpel is a little bit more mature. I think MAGNITUDE has to be considered separately, it’s a different thing.
DG: Fair enough. So just to summarise then, we’ve got for rPFS a really robust signal, hazard ratios in the 0.6-0.7 range for these studies which, against an active comparator – we’re looking at a control arm with a median rPFS of 16 months or so – where we’re seeing really a clinically robust improvement in that radiographic progression-free survival. Including your Study 8 now, three separate studies demonstrating this and, at least in PROpel with the most mature follow-up, a signal in overall survival that seems to be widening over time with further follow-up. So really, to some extent, more or less validating this hypothesis in terms of the mechanisms of synergy between the conditions that we’re creating with these novel hormonal agents on DNA repair susceptibility and PARP inhibition. Freddie, if I can turn to you about the side effects because all of this is really encouraging but it’s really going to have to be balanced against the tolerability, the toxicity and what our patients can tolerate in this disease setting. Walk us through what we’ve learned so far from these studies in terms of adverse events.
FS: What we learned is that we did not have a surprise in the side effects that we have seen. We saw what we thought we would see with those kinds of molecules that are already used in other cancer types like ovarian cancer or breast cancer. What we see is anaemia, that’s for sure, but you really have to look at the data because in the TALAPRO study we see that there were already a lot of patients that had already anaemia when they came in. They had grade 1 and grade 2 anaemia which is something that we see really often in those patient populations because they have bone metastasis that we’re used to that, as an oncologist or urologist who is treating those kinds of patients. So there was no surprise. We had the anaemia grade 1 and grade 2, we saw it in PROpel that we had some dose reduction but not as much as we had in TALAPRO. In TALAPRO there was more dose reduction and MAGNITUDE is still a little bit different – they had a lot more dose reduction and they had to start the drug a little bit lower because they were more afraid of the anaemia. But I think, as a medical oncologist, this is something that you can really handle. You can stop the drug, you can wait a month and then you can reintroduce the drug on a lower level and then it goes really fine. So this is nothing that should stop a clinician to prescribe that drug. We saw in PROpel some data about thromboembolic events but this was a really small population. I think this is something that we have to look at when we’re going to put our patients on that treatment, we have to be vigilant on that, but this is not something that we have to be too concerned about. In either we saw some fatigue but in general, as a medical oncologist or urologist, we’re used to side effects, we’re used to dealing with patients, we do chemotherapy, we do treatments that are much more toxic in general than PARP inhibition. But I’m sure that we will have the discussion in the months that are going to come, now we have TALAPRO-2 data, about the balance between the benefit and the toxicity because we don’t have as much OS data as we would like to have. I know that there are a lot of clinicians who really want to see the OS data to prescribe that better. The question will be is PFS really correlated afterwards to OS and that’s what we discussed already a lot, that we think that there is a correlation but we will see with a longer follow-up if this is really true.
DG: Fair enough. I think you’re absolutely right with all these it’s still evolving data. At the end of the day we’re going to really need to see just what that true impact is on OS. But encouraging to know that the side effect profile appears to be predictable – these are the side effects we would anticipate with these agents.
FS: It’s something in the beginning you have to really look closely at your patient in the beginning, the first weeks. It’s the first three months I would say that are really crucial. You cannot put your patient on the treatment and not see them for three months, you have to see him after a month, two and three and after that it’s really working really well and there is no signal that is really outstanding or really dangerous for your patient, not at all. It’s really the first weeks and then it’s really rolling along.
DG: I want to understand now, because there has been an approval, the EMA has approved this, at least now the most mature data, the PROpel data, for olaparib in combination with abiraterone in this metastatic castration-resistant disease setting. What does this mean in terms of practice, in terms of our use of this now? Is this something we’re going to do routinely in everybody, starting on abiraterone in the castration-resistant disease state or in other settings? Or is this going to be a somewhat more selective use and what would you recommend for people? Freddie, why don’t you start?
FS: In Europe we have now the green light from the EMA which is not always something that we can have in France. We have another decision afterwards so we’re not sure that we will have access to it, we will have to see that. But there is still a lot of discussion in the community if we will give it to everybody or if we should not just give it to BRCA1 and BRCA2 mutated patients. This is something we have to discuss a lot but, for now, this is the European vision of the thing, that a lot of our clinicians will keep it maybe for the moment for the BRCA2 and BRCA1 patients. We will be more hesitating to give it to the other patients.
DG: Noel, any thoughts on this from the UK perspective?
NC: Well funding is going to be an issue, as Freddie said, so that is clear. With any treatment decision in a prostate cancer patient one has to look at the patient and see just what their condition is – comorbidity, age etc. But generally I think it’s a drug combination which needs to be considered for these patients. I’m a little more confident about giving it to patients in first line…
FS: Me too.
NC: What is unresolved is the effect of novel hormone agents given in first line for metastatic because we don’t yet know just what effect that’s going to have. We know that androgen sensitivity is critical to that combined DNA damage effect and that’s for the urological oncological community to work out with real world data as we go.
DG: Absolutely. Now, we only have a few minutes left but, Eleni, I would be remiss if I didn’t bring up the really significant effects that we’ve seen in the patients that have HRR defects, particularly BRCA2. I know in MAGNITUDE you really focussed in this subgroup population or its primary endpoint was positive. We’ve seen also improved results with PROpel and TALAPRO in those patients that have altered HRR repair mechanisms. Give us an idea, if you can, what is that mechanistically? How does that compare to using these therapies in sequence? Ultimately, is that a paradigm shift for us in prostate cancer?
EE: As we all know, and those watching us, we don’t have yet data looking cleanly at sequencing versus combination. Maha Hussain et al presented during ASCO something that is promising to show that synergy, that explosive synergy in the combination versus the sequencing, we need to learn more about that, we need to see that publication. But, as you mentioned, the power of everything that we see is in reproducibility essentially. Now, even though MAGNITUDE is different as you clearly said, all three trials unanimously declare victory. It’s such a victory with hazard ratios that are outstanding, short confidence intervals, that I would be probably a little bit too strong in saying that it becomes almost unethical to not give the combination in some fashion or where approved for the patients. I have actually implemented it in my clinic for my germline BRCA2s because you know better – in the US we have generic abiraterone and we have an approval. And those were all really exposed. Now, this is a little bit more pushing the extreme but trying to make a point that this is what I expect to be the future.
DG: That’s fantastic. Noel and Freddie, anything to add in terms of now in practice? Does genetic testing go away as we think about intention to treat populations or, as Eleni said, this is a population we can’t afford to miss and we need to understand. How will genetic testing evolve in your practices?
FS: I think the message of PROpel and TALAPRO is not to not test anymore. This is not the message that we want to send. The message is that we still have to test patients because it’s a predictive marker, it has so many other implications on family history, for example. So there is still a place to test patients, it’s still a place for PROfound patients to have the testing. We have still issues with funding too – can we test all those patients? We would like to do that but we have to work on that – do we have the funds to do it? But I think we should not go from these studies to saying testing is not needed anymore. It’s more to see it from the other side that even if we have a patient that is not mutated we can still give him that drug and give him the chance of maybe having a benefit of it. I think it’s more the other way around.
NC: Well I’m a great advocate for genetic testing. I think we need to get geared up and I think we need to get skilled up. So we need to broaden the horizons for genetic testing in general practice in urology and urological oncology. As clinicians, practising clinicians, we need to understand the key genetic components. We mustn’t fall into the trap of trying to rely on geneticists exclusively because there simply aren’t enough of them. This is a common problem, we need to, as I say, get our skills up, keep thinking, keep reading and just initiate this.
DG: Fantastic. I can’t thank you all enough for this incredibly enlightening and very, very up-to-date now discussion around this exciting, evolving field of PARP inhibition and combination therapy and where we are and where we’re going in the future. So thank you all for joining me and on behalf of ecancer thank you for listening to our round table discussion today