mCRPC in focus
Transcript: PARPi in focus BRCAWAY and TALAPRO-2
Dr Neeraj Agarwal, Professor Karim Fizazi, Dr Bárbara Vieira Lima Aguiar Melão, and Professor Axel Merseburger
All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
So, we'll move on to the PARP inhibitor abstracts, and before I do that, I'd like to share some of the background information before we delve into discussion of these trials. So, last year, actually last year and early this year, we saw several abstracts or publications happening in the first-line mCRPC setting, combining PARP inhibitor with ARPIs. One trial was PROpel trial, which randomised hundreds of patients to abiraterone plus minus olaparib, and we saw another trial, TALAPRO-2 trial, where patients were randomised to enzalutamide plus minus talazoparib. There was another trial with abiraterone plus minus niraparib, and all were in first-line mCRPC setting, and we saw data from the PROpel and TALAPRO-2 trial, which both included patients who were selected for homologous recombination repair mutations and who were not selected for homologous recombination repair mutations to varying degree in these trials. I won't go into the nuances of these trials for our discussion today, but overall, the message was that combination of ARPI and PARP inhibitor had striking benefit in patients with BRCA1 and BRCA2 mutations in the mCRPC setting. Also, the efficacy was present with a hazard ratio about 0.5 in patients who had homologous recombination repair mutations, and there was some efficacy, although with a lesser magnitude, in patients who were not selected or who did not harbour these DNA-repair gene mutations.
And then there was BRCAWAY trial presented by Dr Maha Hussain in the GU ASCO 2024 meeting. It was a smaller investigator-initiated clinical trial which asked a question not asked by any of these phase 3 trial, which was in the first line MCRP setting what happens with the combo of ARPI plus PARP inhibitor when it compares, when you compare the combination with single agent PARP inhibitor. So this phase 2 IIT study randomised patients to abiratone plus olaparib versus abiraterone versus olaparib. So these are the three or four trials of PARP inhibitor plus ARPI combinations.
So I would start with the BRCAWAY trial first and then we'll go back to the correlative analysis from the TALAPRO-2 trial from Barbara if you are okay with that. So Axel, if you can please tell us about BRCAWAY study which was presented by Dr Maha Hussain raised a lot of discussions, lot of very interesting points about sequencing of therapy. So please tell us about the results and when then we can talk about what you feel, what you think about those results.
Well, Neeraj, thanks a lot and it's a little tough to summarise this now after the second PI of BRCAAway has basically summarised this trial. Thanks for helping me there, and it's really like exciting times right now, and there was a very nice editorial in European urology last year, "PARP Inhibitors for Prostate Cancer: Tangled up in PROFOUND PROpel and TALAPRO Blues." So it's really a lot of questions as we already see also in the chat. To come back to BRCAWAY, it is a biomarker preselected phase 3 trial.
As you said, Neeraj, not a large one, 160 men were randomised. And it was quite exciting because all those large phase 3 trials that looked at those combination of ARPI and PARP never looked at if it's better to start just with the ARPI or do the combination, or use the PARP alone in mutated men. And they were all ATM BRCA1 or BRCA2 positive. And the pretty exciting result is that in the arm one which received abiraterone, PFS was 8.4 months. For olaparib, as said, it's mutated men, it was 14 months and the combination, 39 months, about 20 patients in each arm 60 together. So it was small, but I think it is very supportive data on the large phase 3 trials. You gentlemen are heavily involved to support the combination of an androgen receptor inhibitor and a PARP, especially for those men mutated. And I think this is the big take home message from the BRCAway trial. We've seen the beginning of this year at ASCO GU, but I'm happy to hear your comments as I know you are a core primary investigator.
Yeah, so I think this is great. Thank you for summarising the data so nicely. I think one other striking part was the patients on the abiraterone arm were allowed to cross over to the olaparib arm and patients on olaparib arm were allowed to cross over to the abiraterone arm. So the first thing was, and we are still dissecting into the data why all patients did not crossover. About half of the patients were able to cross over. And so, if you look at the combined PFS from the day one of abiraterone and the last day of olaparib in that arm B where patients were given abiratone first followed by olaparib or you take the combined PFS of olaparib first followed by abiratone, that is 16 months, very similar in both arms. And abiratone plus olaparib, as you said, Axel, it was 39 months. So again, with all the caveats of this being a small trial, 20 patients in each arm, when Dr Hussain presented the data, still the signal was quite striking to me. We are all clinicians. We can never have absolute level-one evidence for every situation in the clinic. I thought it was quite compelling and reinforces my view of using intensification in metastatic prostate cancer whenever we get a chance.
Fully agree. If I can comment, we had a lot of discussions here with colleagues in mCRPC, why not just start with abiraterone or enzalutamide and I said no, especially in the mutated men, please combine and we see the results here really tripling the PFS for those men in this mCRPC disease. Thank you.
Karim, would you like to share your views on this combination versus sequencing?
Sure. I would actually agree with you. I think now, you know, we have quite compelling data supporting combination for patients with BRCA alterations. Obviously, the AR is important, an oncongenic driver in prostate cancer and this is true for DNA repair. So, combining number one makes a lot of sense. But again, this is now supported by clinical data. BRCA is one, but also, the phase 3 trials you mentioned rightly, Neeraj. So that's, I mean, that's quite crystal clear for me for patients with BRCA alterations. For patients without BRCA alterations are much more on the fence, I think. And also, for patients who have already exhausted an AR pathway inhibitor, which is more and more of a reality. When they develop mCRPC, they've seen already an AR pathway inhibitor.
So whether it's where it is worth it combining a second ER pathway inhibitor with a PARP inhibitor, if they have BRCA alterations, I don't know, but we don't have the data. But for patients without BRCA alterations, again, I think that the jury is out for patients with CDK 12 alterations, for those with PARPi2 alterations, I think there's a clear signal supporting PARP inhibitor and combination. But for others, I'm really not sure the signal is strong enough as compared to the toxicity related to those combos to support clinical use. At least I would not do it outside the trial right now. But again, understanding that we may have other opinions regarding this question.
Of course. So again, the BRCAway trial was conducted in patients with BRCA1 BRCA2 ATM mutations in these patients. So obviously, data as you said, Axel and Karim, the data applied to those patients. But I thought the difference in the PFS was so striking that I would like to use combination therapy, rather than sequencing whenever I'm using, when I'm contemplating PARP inhibitor in a patient, I'll use ARPI plus PARP inhibitor. So now, coming back to you Barbara, there were two abstracts on the TALAPRO-2 trial and again for our recollection we are getting close to the time limit, but I'll still like to have your views on what do you think about these two interesting correlative study-based abstracts? One was the utility of CtDNA as a prognostic biomarker in the TALAPRO-2 trial, which was a phase 3 study of talazoparib plus enzalutamide versus enzalutamide. And this combination is approved now in the US for HRR mutation positive patients and in other areas it is also available. And then there was a match adjusted indirect comparison of talazoparib plus enzalutamide versus olaparib plus abiraterone which was approved also based on the results of the PROpel trial in first line mCRPC setting. So would you like to, it would be awesome if you could share your views on these two abstracts.
Well, sure, I will briefly comment since a matter of time, and I had a great background of you three, so I'll go straight to the results of the abstract. The first one is the matching adjusted indirect comparison, the [indistinct] of TALAPRO and PROpel. So there are, although there are different approved combinations of PARP inhibitors and ARPIs, we don't have head-to-head studies. So this study use the data from TALAPRO and PROpel on OS and RPFS and adjusted baseline characteristics and also some prognostic factors, such as PSE levels, prior chemotherapy, bone metastasis only, metastasis. The authors disclosed that "One of the limitations of this study is that was not possible to adjust all of the prognostic factors, but the result of RPFS and OS favour the combination of TALAPRO-2 which is talazoparib and enzalutamide, and RPFS and OS," as I said. "But it was now no statistically significant, but it favours TALAPRO-2." And I will go jump onto the data on CtDNA burden, the utility of this as a prognostic for efficacy, a biomarker for efficacy in TALAPRO-2, in patients of TALAPRO-2. So they demonstrated, actually, that CtDNA has a potential to be evaluated as a biomarker, and they perform a retrospective analysis of CtDNA burden baseline in week nine. And they categorise the CtDNA burden as high when it was quantifiable and low, when it was unknown. And what they found, it was very interesting that high CtDNA was prognostic to inferior RPFS. And the conversion from high to low CtDNA, it was prognostic to improve RPFS and the best scenario when we had CtDNA low from the beginning. So very interesting data, I think, that's what all of us want biomarkers to better select therapy, to better tailor treatment for our patients to observe treatment response. So we have two co-authors of these abstracts here, so I'm really, really looking forward to you to comment.
Thank you, Barbara. So it looks like CtDNA burden may emerge as a prognostic biomarker for our patients with metastatic CRPC being treated with combination ARPI plus PARP inhibitors. And I think this may apply to pretty much all drugs in various settings of metastatic prostate cancer. Thank you very much.
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