ASCO 2023: Latest in PARP inhibitors in prostate cancer

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Published: 6 Jun 2023
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Prof Rana McKay, Dr Friederike Schlurmann, Prof Gunhild von Amsberg

Prof Rana McKay (The University of California, San Diego, USA), Prof Gunhild von Amsberg (Martini Clinic, Hamburg, Germany) and Dr Friederike Schlurmann (Centre Hospitalier Universitaire de Brest, Brest, France) discuss the latest in PARP inhibitors in prostate cancer.

The panel analyses the secondary datasets from trials such as PROPEL 2, TALAPRO 2 and MAGNITUDE and discuss how it impacts our understanding of best practice with the use of PARP inhibitors in prostate cancer.

They cover the recent FDA approval of olaparib with abiraterone and prednisone (or prednisolone) for adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC).

Dr Schlurmann and Prof McKay further talk about testing for BRCA mutations and when to test for it. The panel concludes by discussing their clinical experience in using the available combinations in their daily practice.

Summary of the MAGNITUDE 2 trial
Summary of the PROPEL 2 and TALAPRO 2 trials
Testing for BRCA mutations and the use of PARPis
Testing for BRCA mutations in Germany
Takeaways from the PROPEL 2 trial
The LuPARP trial
Olaparib monotherapy in prostate cancer
Upcoming studies in the mHSPC setting

 

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

ASCO 2023: Latest in PARP inhibitors in prostate cancer

Prof Rana McKay – The University of California, San Diego, USA

Prof Gunhild von Amsberg – Martini Clinic, Hamburg, Germany

Dr Friederike Schlurmann – Centre Hospitalier Universitaire de Brest, Brest, France

RM: Hello, welcome everyone. My name is Dr Rana McKay, I’m a GU medical oncologist at the University of California in San Diego. I’m so excited to be here with ecancer today at this year’s ASCO 2023 discussing the landscape of PARP inhibitors in prostate cancer. I’ve got my wonderful colleagues with me today that will introduce themselves.

FS: Thank you so much for having me today. I’m really thrilled to be with you two together. I’m Dr Friederike Schlurmann, I’m a medical oncologist, GU oncologist, in France.

GVA: My name is Gunhild von Amsberg, I’m a GU oncologist located in Hamburg, Germany, at the Martini Clinic and I’m, of course, very happy to be with you as well.

RM: It’s so wonderful. The landscape for PARP inhibitors in prostate cancer has really been changing. We’ve definitely demonstrated the role of monotherapy with both rucaparib and olaparib for people with advanced disease. We saw data that got presented from TRITON3 at GU ASCO. This past year really solidifying the role of PARP inhibitors in the pre-chemotherapy setting, that earlier use is probably better. Now we have a series of studies that looked at the combination of PARP inhibitors with an ARSI in unselected patients that have really begun to shift the landscape in prostate cancer. Maybe we can go through and describe those studies; really a lot has happened over the last year and a half since the studies first got presented at GU ASCO last year.

GVA: Yes, let’s look at those three trials. Different, really, in this whole setting is the MAGNITUDE trial because when we first saw the data we somehow discussed that it’s two trials within one trial because we have an HRR pre-selection in this trial and then the patients were either put in the HRR positive or in the HRR negative cohort. Actually, the combination out of niraparib and abiraterone was compared to abiraterone monotherapy in those two cohorts. Unfortunately, the HRR negative cohort was closed early due to futility of this cohort and then we had data updates on the HRR positive cohort at ASCO GU this year. So we may be discussing this later on. The two all-comer trials, actually, were PROpel and TALAPRO-2 and in both trials we did see updates at ASCO GU and ASCO this year. PROpel is examining abiraterone in combination with olaparib compared to abiraterone, while TALAPRO-2 is comparing talazoparib in combination with enzalutamide, so a different NHA, compared to enzalutamide alone. Both trials did have an all-comer population, meaning that they did not pre-select for HRR positive patients, however they both looked at HRR positive patients separately. In the TALAPRO-2 trial we had an extension cohort and that was presented at ASCO this year where a special focus was put on the HRR positive patients.

RM: Yes, thank you for giving us that great summary about those trials because they are complicated, sometimes we get them confused. It's interesting, as we think about these studies, because they’re really designed in the frontline mCRPC setting with patients not having previously been escalated in the mHSPC setting. So it’s that unique population that we hope is shrinking over time, we hope that we’re appropriately escalating in the mHSPC setting, but as we try to summarise this data and make sense of it one of the things that we can say, probably with definitiveness, is that actually in the BRCA1/2 patients that’s where we see the strongest signal. Maybe Friederike you can give us some insights there?

FS: Yes, there is no question anymore, patients who have BRCA1/BRCA2 mutations you have to intensify them. Like you said, we really hope that those patients will disappear one day, those who were not intensified in the first place. But, unfortunately, when we see data we still have between 30% and in France it’s even 50% of patients who are not intensified so they’re still there. So there is still an unmet need for those patients. When you have a BRCA1/BRCA2 mutation you have to test, that’s for sure. The biggest question is do we really need to test since we have PROpel and since we have this cohort which is not mutated and we still have that PFS which is positive? We don’t have the OS data, it’s not mature; it was presented, the final analysis, but it was not really positive. We have a positive PFS, the question is is that enough? Is that enough to give this treatment to the patients? I think that’s really a discussion with the patient about toxicity, about quality of life. If you see the data the quality of life is pretty good, in fact, with PROpel. So patients are tolerating it pretty well but I think we have to talk about testing because we have done so much work about testing, we tried to find pathways like how to test patients, when to test patients, with all the pathologists and all the communities. So I think we still have to work on that and the message is not don’t test anybody. You have to test because we have seen data again at ASCO this year that BRCA1/BRCA2 is predictive and prognostic. So patients who have the BRCA1/BRCA2 mutations will do less good than those who don’t. So we know that; it’s not the same patients. This is regardless of how you treat them in the first-line setting, if it’s taxane or NHA, they’re kind of like the losers, unfortunately. So we really have to know if they are mutated or not. So that’s really the big message – keep on screening, keep on testing for BRCA1/BRCA2. What we will have to see in our daily practice now is how we’re going to implement PROpel and MAGNITUDE and TALAPRO because we all know that we have the FDA label that just came in three days ago.

RM: Yes, very different than the European label.

FS: Exactly. For once we’re pretty open in Europe; often it’s like the other way around. 

RM: Right, usually it’s the other way around.

FS: It was really funny, we got the EMA label before all the data was presented. So we have a pretty open label and we do that in France and you do it in Germany too, we can give it to all patients, all comers, all in. So, now we have the FDA who are restricting it to BRCA1/BRCA2 mutated patients. So we have to figure out right now what are we going to do, how are we going to treat patients but overall it’s really good news. It’s good news for those who are mutated, it’s really pretty good news, because we saw in PROpel that we have an overall survival of 42 months which is something that we have never seen before in the mCRPC setting. So it’s super-good news for those patients.

RM: Absolutely, I echo that sentiment completely. These studies, initially at their onset we were thinking, ‘Oh gosh, do we never need to test?’ but these studies actually prove that, no, in fact we have to test, we have to test because everybody is… the effect size in the BRCA mutated patients is very different than in the HRR non-BRCA and then in the non-mutated patients. So teasing that out is going to be really important. Then, of course, germline testing and somatic testing.

FS: Exactly. That was done in this study. In this study we had germline and somatic testing and, like you said in PROpel, it was done with a prespecified analysis. It was just not the stratification, the other studies it was a stratification, so that’s the difference. But it was tested. Today we always have to try to test, if we can, on tumour, if we can do it on the prostatectomy, for example, that would be great. If you can do it on tumour biopsy; if you can try not to get bone that would be better for pathologists, they don’t really like that, it’s difficult. But you have to test and I think today we have to test right away, up front. Every patient mHSPC should be tested today. We don’t have the guidelines everywhere for that. I think in the US you can do that a little bit better; in Europe it’s not the guidelines for the moment, it’s more for mCRPC patients who are candidates for PARP inhibition or who have a family history. Then obviously you have to do the testing. But I think we have to do it in mHSPC, you have to do it on tumour if you can. If you don’t have tissue, if tissue is too old, because we know after five years tissue gets old, you really have a hard time getting good results, then you have to try to do biopsy if you can. If you cannot do biopsy then if you have the possibility you can do ctDNA. It’s getting easier and easier and I really hope that this is something that’s going to go further and we will develop that because it’s so easy and convenient to do ctDNA testing for those patients. So we really have to push to get the results. We saw that in the data that were presented on the predictive and prognostic factors of BRCA1/BRCA2 – it doesn’t matter how you get the test and if it’s somatic or not, it’s all the same. You just have to try to really get it.

RM: I love the messaging around testing in the mHSPC setting because you really have to be ready.

FS: Yes.

RM: Sometimes it can take time to get the results, there can be some delays and you really want to try to strategize what you’re going to do next when that patient does progress. Forward thinking.

FS: Forward thinking really is important and you have to do it in the beginning because that tissue is getting older. Do it in the beginning. 

RM: That’s true.

FS: It’s true. We have a lot of patients now that are candidates for the PROfound, a PROfound population, and they are now mCPRC for years and then you have a prostatectomy that’s ten years old and you already know that you’re not going to get anything out of it. So start early, do it early, on tumour if you can. I think that’s a really super-important message.

RM: And how are you all testing in Germany?

GVA: It’s a little bit different because right now we get only reimbursement for BRCA1 and 2 and only at the centres you will get broader testing. But with PROpel that’s a very nice aspect because you could actually for the ADT pre-treated patients you could start with the all-comer label and then start the testing at the same time. That’s what I actually do in practice. I, of course, explain to the patients the situation, we talk about the PFS and the OS and the aspects on quality of life and then I can start treatment without knowing if it’s an HRR positive or negative patient. In the meanwhile, because if you do the big panel with 500 tumour genes that takes up to 8 weeks and we know from MAGNITUDE that you shouldn’t have a run-in period that is too long with abiraterone because we don’t have the benefit of the BRCAness effect anymore. So what we do right now is we start the testing and the treatment at the same time and we can always think about de-escalation if we have side effects or loss of quality of life in those patients. I think that’s a very practical way to do that if you have the broad label and this time we’re really on the lucky side because we did have the restriction to BRCA1 and 2 before and there are so many sensitive mutations, like PALB2, where we just look jealously at the States and can’t do anything.

FS: That’s right. That’s one of the positive messages from PROpel when you discuss about do I really want to give that to the patient, that’s not mutated, I don’t have any OS gain. But that’s one of the positive messages is it’s a chance, the chance for patients where you don’t have the possibility to get the result, the mutation result, you can do it. You rather have to see it like this, it’s just the chance to do it. You do it, I think that’s really great. 

RM: Shared decision making, I think every patient that walks in the door, they all have different values. Some people want to be more aggressive, some people want to be less aggressive, and a broader label allows you to have that choice, to make that decision with the patient, then decide, okay, this is what we’re going to do and we’re going to adjust. That’s really nice. 

FS: Good news.

RM: It’s very good news, yes. That’s awesome. Also at this year’s meeting we saw some really interesting data about looking at PARP inhibitors in combination. We saw the data from the LuPARP study, which was very provocative, looking at intermittent PARP dosing for sensitisation to lutetium-PSMA. A very novel study looking at different doses and then different periods of doing the intermittent dosing, whether it’s post lutetium or a couple of days prior to the lutetium and then extending for two weeks. I think it’s going to be really interesting to see some of the efficacy data as that pans out. I think it’s really hard, it’s still too early for right now. But thinking about how to potentially sensitise, that’s going to be really interesting.

FS: It’s a super-interesting approach. I think it’s a really complex study because lutetium-PSMA is really complex in itself and then you add another treatment. But the good news is that apparently there is no toxicity added, so probably that’s okay, which is really great. Because we could have thought that maybe we will see more anaemia, for example. That’s not the case so that’s really good news too for the patients to move on with other combinations than with NHA.

RM: Yes, I know it’s interesting. We have a couple of studies in the US of radium-223 paired with olaparib. There’s a study called COMRADE with radium olaparib, it’s in phase II, the phase I was completed. There’s a study as well with niraparib paired with radium. So there’s excitement about using PARP inhibitors as radiosensitisers.

FS: We have so many new things coming, like ten years ago the NHAs, there were so many new things and we were really excited and then we had a gap, nothing new happening. It was boring, nothing. And now we’re in the new situation where we have so many studies with so many different results and so many combinations possible. We have new combinations coming too. So it’s really exciting that we have the chance to discuss all that because we have so many things. I think it’s really exciting.

RM: It’s exciting.

FS: The new combinations I’m so keen to see what they’re going to do.

RM: Yes, and then even now all of these drugs are moving earlier and earlier and earlier. We even saw a study of olaparib monotherapy for patients with biochemically recurrent disease without ADT, as an ADT-sparing approach, with some pretty provocative early data. It’s hard to interpret sometimes in the context of a single-arm phase II study, unselected too, olaparib in an unselected population. So we’ll have to see how that pans out.

FS: So many things going on. 

GVA: But again with a very strong signal for the BRCA positive. And knowing that those patients do have the worst prognosis, I think that’s really a chance for those patients. 

FS: It’s really good news, it’s really good news for them.

RM: Yes, and even for PARP inhibitors too, studies that are looking at giving PARP inhibitors neoadjuvant to surgery for BRCA1/2 mutated where potentially the hope is to try to cure more patients earlier on.

FS: Exactly, curative intent. That’s exciting.

RM: It’s exciting because we’re always a little bit behind the breast cancer. 

FS: We’re following them, we’re always following.

RM: They have approval for adjuvant olaparib in the perioperative setting so that’s exciting. There are a lot of studies that are coming out too in the mHSPC setting. Which ones are you all excited about there?

FS: I think they are all exciting because, like we said, we do the testing, we don’t have that many patients who have BRCA1/BRCA2 mutations. In these studies you have 8% of BRCA2 and 2% of BRCA1, that’s like what we have. I don’t have that in my clinical practice, I think I have a little bit less unfortunately. So we’re testing a lot. I don’t know how you do that but it’s a lot of testing. So we still have a lot of patients who don’t have access to those targeted therapies. So we have studies like CYCLONE-3, abemaciclib, which has almost completed already. We include right now 100 patients every three weeks which is amazing. So the study is going to be full in the next weeks, it’s done. And we have CAPItello, capivasertib, which is really exciting too, we are doing. And then we have all the other screening studies like AMPLITUDE, we have TALAPRO-3, obviously, for the mutation ones. But really those patients who don’t have any mutation or PTEN loss, there is still something…

RM: Yes, they need something.

FS: They need something. So I’m really excited about CYCLONE-3 because this is really the unmet need. We see it because they accrued so fast. So there’s really something to do. I don’t know what you think about that?

GVA: Well, there is the PSMA, additional PSMA testing.

RM: So super-exciting.

GVA: Yes, so let’s see what the next years will bring.

RM: Let’s see what happens. Next year’s ASCO we’re going to be talking hopefully about new data. But thank you all for joining us today, it’s been a real pleasure going through PARP inhibitors in prostate cancer. Thank you to our viewing audience for joining us today with ecancer at ASCO 2023.