mCRPC in focus
Transcript: Full mCRPC roundtable discussion
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.
All right, so let's get started with the updates in metastatic castration-resistant prostate cancer and we'll be focusing on 2024 ASCO and ASCO GU meetings. There are many abstracts, which were not necessarily oral presentations or plenary representations, but we will like to highlight them as well. So let's start with the first abstract, which is the quality of life data from the PSMAfore trial. But before I move forward, let me have the honour of introducing the speakers and the discussants here on the panel. My name is Neeraj Agarwal, I'm a Professor of Medicine and if we can please go back to the faculty slide. Thank you. I'm a Professor of Medicine and Director of Genitourinary Oncology Programme at the Huntsman Cancer Institute, University of Utah in Salt Lake City, U.S.A. Next is Professor Axel Merseburger. He is a Professor of Urology and chair of Department of Urology at the University Hospital. And Axel, you'll have to help me with this, make sure I don't mispronounce the name. Would you like to mention your institution yourself?
You're on mute-
It's Schleswig-Holstein in Lubeck.
Okay.
Thank you.
Maybe we can have faculty introduce themselves, Dr Fizazi.
Sure, thank you, Neeraj, and happy to be with all you guys today. I'm Karim Fizazi, Medical Oncologist from Gustave Roussy in Villeneuve, France. And Villeneuve is just two kilometres far from Paris.
And last but not the least, Dr Melao. Dr Melao, if you could please introduce yourself.
Hello all, well, I'm Barbara Melao and I'm the Director of Oncology of Hospital Adventista de Manaus in Brazil.
Fantastic, so let's get started. Let's discuss, we'll be focusing on androgen-deprivation therapy for metastatic CRPC. We'll be talking about some, as I said, abstracts, and most recent data presented in the ASCO and the GU ASCO 2024 meetings. So now let's go to the first one, and this will be on "Health-related Quality of Life and Pain in phase 3 Study of Lutetium-PSMA-617 in Taxane-Naive Patients with Metastatic CRPC," which was the PSMAfore trial presented by Dr Fazazi just recently. And let's hear from him what he thinks about the data.
Thanks, Neeraj. Yes, I think PSMAfore is an important, phase 3 data also, I recognise I'm biassed here, so basically, that's the second phase 3 trial, looking at the role of lutetium-PSMA in men with metastatic castration-resistant disease. We learned already from VISION three years ago that for patients who have exhausted basically every treatments of a prostate cancer, including castration, but also taxane and an AR pathway inhibitor, lutetium-PSMA prolongs life, improves radiographic progression for survival and also, prolongs the time to deterioration of quality of life. And this is becoming more and more I think a standard of care for men with very advanced disease. I think I'm happy to speak about that with you guys, but I think we are using a real lutetium-PSMA, one of the label, obviously, in all of our respective countries in this indication. So this is what we knew. When PSMAfore or really address the question as to whether we should use lutetium-PSMA earlier in the course of the disease, i.e. in patients with metastatic castration-resistant disease, but who have not received chemotherapy and who are just progressing while on an AR pathway inhibitor. So typically, a population of men where either you go for chemotherapy if they have aggressive disease, rapidly rising PSA, clinical deterioration or symptoms or visceral metastasis for example. Or you are in a situation where there's no fantastic standard to be honest when they have more indolent disease. And typically, you speak about chemo, but you don't use it immediately at least. And actually, this is quite a lot of men who are in this situation and who are demanding something but chemo. So really PSMAfore address the question of lutetium-PSMA for this population of men with more indolent mCRPC. And what we did was we randomised these patients to receive either lutetium-PSMA immediately or a second AR pathway inhibitor, understanding that in case of a progression, patients would be the label for crossover to lutetium-PSMA. So I guess for the patient it was a nice deal of lutetium-PSMA today versus lutetium-PSMA tomorrow, tomorrow meaning in six months time, which is basically, the time it took for them to progress in the control arm. So the trial is positive, but the graphic progression-free survival was significantly improved with approximately a 60% reduction in the risk. And this was already presented last year at ESMO. What we showed ASCO was whether there is also, a true direct benefit to the patient besides this radiographic progression for survival benefit. So in other words, do patient benefit clinically in terms of quality of life, in terms of time to pain deterioration and on top of safety as well? And what was, we could show using the FACT-B questionnaire and the EQ-5D questionnaire for quality of life was that with that indeed time to deterioration in quality of life is improved or is delayed, if you will, with lutetium-PSMA with a reduction in the risk of 40% for these men when they receive lutetium-PSMA. Interestingly, also, different domains of quality of life are improved including physical well-being, which I guess was expected because this is kind of direct, a measure of the delay in symptoms patients may experience with this treatment when it's active, but also functional well-being and emotional well-being is also improved. In parallel to that, patients receiving lutetium-PSMA experienced a 30% reduction in the, or improvement if you will, in the time to deterioration in pain, which also, is clinically super important. When we focused also on typical side effects that may impair negatively quality of life such as fatigue or anaemia. Actually, we, or grade three anaemia, we didn't see any difference between the two arms. So I think we have a clearer package, if you will, for all the patients now regarding lutetium-PSMA in this indication. We're clearly postponing imaging-based progression, which is important from a registrational standpoint. Obviously, we are also postponing time to PSA progression, which is psychologically important to patients. They hate to see their PSA rising, but most importantly, we're postponing time to deterioration in quality of life and in pain deterioration, which is directly for the first time probably, measuring clinical benefit, which I mean, to me as a doctor is so important to decide whether I should go or not for a given treatment in my practise. So this is where we are, and I'm happy to to hear your opinions about those data, obviously.
Thank you so much for such a comprehensive outline and summary of the results and it was a great presentation by the way, in the recent meetings we have had a chance to hear you. So it looks like great option for patients and especially many patients as you said, Karim, do not want chemotherapy. Your real-world use of chemotherapy with docetaxel remains around 30% in the U.S. So at least hoping that we will have another option for those patients who are very reluctant to pursue chemotherapy with docetaxel, they will have a chance or opportunity to have lutetium therapy before having to undergo chemotherapy. Thank you so much. So we'll keep moving. I'll talk about CYCLONE 2 study and this was a trial which did not meet the primary endpoint. So we will like to keep it short as we know that it was a phase 3 trial with the abiraterone plus minus abemaciclib in first-line mCRPC setting. And just for our recollection, we know AR signalling activates CDK 4/6 to sustain proliferation of prostate cancer and up-regulation of cyclin D1 as a potential mechanism of resistance to AR signalling therapy. So there was a lot of preclinical rationale. So this phase 3 trial, it was actually adaptive phase 2, phase 3 trial, which was designed to look for the efficacy of abemaciclib when added to abiraterone. Unfortunately, trial did not meet the primary endpoint of progression-free survival being improved by abemaciclib. So it was not, a trial did not meet the primary endpoint although we saw signal in patients or higher efficacy, signal of higher efficacy in patients with more aggressive disease such as high Gleason score, patients who had de novo disease at the presentation high PSL levels. So at this time it is suffice, it would be sufficient to say that we don't have, we don't foresee abemaciclib being an option in our patients with metastatic prostate cancer at this current time. And we don't know if CDK 4/6 inhibition will maybe utilise as a strategy in a more biomarker selected patients down the line. So with that, I'd like to move on to the third abstract, which I thought was quite exciting. And this was the phase 1 study of actinium-225 labelled antibody targeting human kallikrein 2 is a new target on metastatic prostate cancer or prostate cancer. So we have talked about PSMA being a target from Dr Fazazi. Now, we are talking about a new target, human kallikrein 2, on metastatic CRPC. So Barbara, would you like to discuss, tell us about the results of this phase 1 study presented by Dr Mike Morris?
Absolutely, thank you, Neeraj. Well, since we have some treatment options in mCRPC that move it early on, we need more options, and I'm happy to present the novel agents at the new target, the human kallikrein 2. Well, so far in prostate cancer, we just have one cell surface target, which is PSMA and lutetium-PSMA as presented is approved in mCRPC after ARB and taxane for now. And while JNJ-6420 is a radioligand that delivers alpha radiation targeting human kallikrein 2. And human kallikrein 2 is cell surface antigen, highly expressed in prostate tissues and prostate cancer cells and also little or non-expressed in non-prostate tissue. So it's also very specific and its expression is driven by AR signally and higher expression is correlated with cell, increased cell proliferation in mCRPC. So probably a very good target. So this phase 1 trial presented by Michael Morris from Memorial, patients enrolled had at least one prior ARPI, chemotherapy was allowed, but no prior radioligands were allowed. Primary endpoint was recommended phase 2 dose and safety. Well, they started scheduling with dose escalation and there were important therapy-related adverse events. Thrombocyto, persistent thrombocytopenia to grade 5 events due to interstitial lung disease. So they moved to establish a dose cap of 500 microcuries and the antitumour activity was maintained, however, still important treatment related events that were not totally mitigated. So they moved to a scheduling an adaptive dose, dosing of 250 microcuries. A wait for a biochemical relapse and a recovery of platelets and then redose with 150, respecting the dose cap of 500 microcuries. So it was adjusted for patient's individual response and tolerance. And then the dose cap and the scheduling, the adaptive scheduling, they could mitigate to persistent thrombocytopenia and also, interstitial lung disease which was, which were dose-related and interstitial lung disease only occurred with doses of 600 microcuries. So the population was heavily treated. Patients with mCRPC, half of them had two prior ARPIs, two thirds had prior chemotherapy and one third had two prior, received two prior chemotherapies. So they also looked at response, anti-tumour activity, and it was very promising, 44% of the patients had PSA 50 response, 9% of them, PSA 90 response. And for patients with measurable disease 18 had overall response rates. And about the duration, almost one third have a response greater than six months. And Morris showed some patients that are on the trial and with durable response up to 27 months. So in conclusion, it's a very promising radioligand, the new radioligand, with a very good target and I'm looking forward to hear your thoughts and especially Fazazi, which is very involved in radioligands.
Sure, you know, happy to, thank you, Barbara. Happy to comment on that. Well, you know, first I think regardless of how we target it radioligand or something else, I think it's the first time we have a clear demonstration, clinical demonstration that targeting kallikrein 2 can make a difference and can be active and efficacious in this disease. It's obviously, not a new target. We know HK2 for two or three DKs at least. And when, you know, when you think about it, it's actually bizarre that we never designed or that the pharma industry never designed drugs targeting HK2 because, you know, speaking about kallikrein, you know, the most famous kallikrein is actually PSA, which is HK3. The bad thing with PSA is that it's a secreted protein. So if you're inventing a drug that targets PSA, it'll go to your blood, but not to cancer cells. But HK2 in contrast to PSA is actually, partially, a transmembrane protein and partially secreted as well. And it's highly, as you rightly said, it's highly expressed at the surface of cancer cells. So that's, a quite important target potentially. So, again, it's the first time it is being targeted with an agent, really active. We need to better figure out whether the expression of a protein makes a difference, yes or not. And when you think about it, in just less than a year, we saw two new targets being validated. Steap1, which was shown to be targetable at ESMO last year with clearly activity as well and now HK2. The question in the long term to me is whether we will target HK2 using actinium, which was done in this particular trial or whether the antibody can be linked with, to something else. It can be an ADC, it can be also a bispecific strategy. And I know that all that is currently ongoing. So, but again, I think it's super important for us to see that for the first time, the new target is validated. Perhaps in just, I don't know, three or five years from now, we will use a combo of PSMA targeting HK2 targeting and Steap1 targeting together and maybe AR targeting, who knows, but I think it's a very important signal for the future because it means that very, very likely these targets are here to stay and we will probably use one weapon or another in our practise.
Such exciting times for our patients and for us who are practise medicine in prostate cancer. I agree with you, thank you very much for such fantastic summary and the analysis, your viewpoints of, on this trial. So let's move on to the next promising target, which is PROTACs, androgen-receptor degraders. So Barbara, maybe you can tell us briefly about the initial results of a phase 1/2 study which used AR V-7 66, a new AR degrader.
Of course.
Thank you.
Thank you, Neeraj. Well, you know, since studies is in before is that prostate cancer is an androgen-dependent malignancy and then we target the AR signalling pathway. So doing so and especially now that we are intensifying this target AR signalling pathway inhibition and hormone sensitive castration, some tumours can develop resistance and for many mechanisms, one of them is the mutations in the AR, which is found in 20 to 25% of our patients in mCRPC. So PROTAC androgen receptor degrader uses the body natural mechanisms to degrade, pertain and target clinical relevant mutations in the AR, lagging biting domain, which is specifically associated to poor prognosis in these patients. So this is a phase 1/2 trial. In part one, the phase 1 though, it was the phase 1 dose escalation and actually, patients enrolled had prior to systemic therapies and the dose escalation and the endpoint was the safe and tolerability of RP2D and the second part, the phase 2 expansion, cohort expansion, patients enrol again heavily-treated patients with metastatic, mCRPC, and the pharmacogenetics of ARV-766 was dose-dependent. They didn't reach maximum tolerate dose and there were no dose limiting toxicities, different from the prior phase 1 trial that phase, that I presented. And actually, this phase 2 they did, the dose was randomising 100 and 300 milligramme orally QD. And the other points was the anti-tumour activity of ARV-766. So there were more than 120 patients and all of them have received prior ARPI, half of them received prior chemotherapy. One quarter of them had visceral metastasis and as I said, there were no dose limiting toxicities. But one third of the patients had grade 3 or 4 therapy-related adverse events. Most common were fatigue, nausea, diarrhoea, 7% of the patients have needed dose reductions. 8% of them needed discontinuations and the results are very promising. 43% of the patients had 50% PSA decline, half of them had 30% PSA decline and patients with soft tissue lesions, and this data is waiting for confirmation but 30% had objective response rates in soft tissue lesions. So in conclusion, it's very well-tolerated targeting these clinically relevant mutations in AR ligand binding domain with promising clinical activities.
Fantastic, thank you so much, Barbara. So promising drug targeting a well-known target. We have always known AR in prostate cancer and we are really hoping that these results will pan out in larger trials and we'll have another treatment option for our patients in the near future. So with that we'll go back to Dr Fazazi. So Karim, this is a trial, it's a phase 2 study of induction docetaxel and carboplatin in patients with mCRPC with homologous recombination and DNA repair deficiency, followed by maintenance therapy with rucaparib. So I thought that trial design was interesting. Please, would you like to share your views on this abstract?
Sure, unfortunately, this is a rather small trial, not the investigators [indistinct] obviously, it's simply that Clovis that develop rucaparib actually bankrupt. And so during the course of a trial so that we could not treat more patients. But really the concept indeed is an interesting one. This is based on what we're doing in ovarian cancer where typically, we are treating patients with cisplatin or carboplatin-based chemotherapy and then we're using PARP inhibitors as a maintenance strategy, especially in patients with DNA repair defects. And basically, we're using response to chemotherapy as a biomarker to indicate that PARP inhibitors is likely to work and help these women. So for a while there is, you know, the idea that we should do the same in prostate cancer. I know there are efforts an ongoing trial probably at MD Anderson for example doing that. But I think this was really the first trial retesting the hypothesis. Again, unfortunately, the number of patient is too small to tell. What we share with that, number one, is doable as expected. But number two also, it appears that the PARP inhibitor is not able to circumvent resistant to taxane plus platin combo, suggesting that the mechanism of resistance between the two or three maybe, are similar. And actually, this is supported by my own experience the other way around. I've been treating some patients who had with DD alterations mostly BRCA patients who had exhausted a PARP inhibitor with a platin, mostly carboplatin progression. And it's, in my experience, it's been rarely successful with I think just one or two patients benefiting out of probably 20 or 25 patients we've been treating so far. So again, makes sense of resistance may be really common to the two families of agents, unfortunately. But I have to applaud the investigators for doing this trial. Again, not sure we can do much with this, but again, not their fault really. We'll need probably more data and more trial to figure out whether instead of testing for mutations for BRCA for example or something else, we should actually treat all patients with a platin and then select platin sensitive patients to get a PARP inhibitor, again, as we do in ovarian cancer. This still needs to be addressed in prostate cancer, we don't know at this point.
That's great, so drawing analogy, learning from ovarian cancer treatment paradigm and applying to metastatic prostate cancer. That's great. So we'll move on to the PARP inhibitor abstracts and before I do that I'd like to give, share some of the background information before we delve into discussion of these trials. So last year in, 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 the 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 the, 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 who are or who were, who did not harbour these DNA repair gene mutations. And then there was BRCAAway 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 mCRPC setting, what happens with the combo of ARPI plus PARP inhibitor when it compares with, when you compare that combination with single agent PARP inhibitor. So this phase 2 IIT study randomised patients to abiraterone 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 BRCAAway 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 BRCAAway 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 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, "PPARP Inhibitors for Prostate Cancer: Tangled up in PROfound, PROpel and TALAPRO-2 Blues." So it's really a lot of questions as we already see also in the chat. To come back to BRCAAway, 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 RP and PARP never looked at if it's better to start just with the RP 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 were heavily involved to support the combination of an androgen-receptor inhibitor and a PARP especially for men mutated. And I think this is the big take home message from the BRCAAway 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 with 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 cross over about half of the patients were about, were allowed, were able to crossover. 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 abiraterone first, followed by olaparib or you take the combined PFS of olaparib first followed by abiraterone, that is 16 months, very similar in both arms. And abiraterone plus olaparib, as you said, Axel, it was 39 months. So again, with all the caveats of this being a small trial, 20 patients each 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. So-
Fully agree, if I can comment, we had a lot of discussions here with colleagues in mCRPC, why not just start with abiraterone and 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 have, 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 as a 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 a reality when they develop mCRPC, they've seen already an AR pathway inhibitor. So whoever it is worth it combining a second AR pathway inhibitor with a PARP inhibitor, if they have BRCA alterations, I don't know, we don't have the data. But for patients without BRCA alterations, again, I think that the jury is out the, for patients with CDK12 alterations, for those with PALB2 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 all our opinions regarding this question.
Of course. So again, the BRCAAway trial was conducted in patients with BRCA1, BRCA2, ATM mutations in these patients. So obviously, data as you said, Axel and Karim, the data apply 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 to, 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 U.S. for HRR mutation positive patients and in other areas, it is also available. And then there was a match adjusted in direct 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, what do, it would be awesome if you could share your views on these two abstracts.
Well, sure, I will briefly comment since it's 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 in direct comparison the mics of TALAPRO and PROpel. So there are, although there are different approved combinations of PARP inhibitors and ARPIs, we don't have had had to have 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 PSA levels, prior chemotherapy, bone metastasis only, future 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 but and rPFS and OS as I said. But it was now no statistically significant but it favours TALAPRO-2 and I will go jump to the data on ctDNA burden the utility of this as a prognostic for efficacy, 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 and weak line 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 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. There was an abstract from a community-based practise, AI Concert oncology 144 patient data on from real-world patients. And these are the patients who had mCRPC and they had homologous recombination of mutations. And the reason we included this abstract is to basically talk about the real-world results with PARP inhibitors and how they compare with the registration trials. So just for our listeners recollection, PROfound was the first phase 3 trial, which was biomarker, where patients were biomarker selected based on a biomarker and it was positive. And then in this trial, olaparib, a PARP inhibitor was compared with an alternate ARPI in patients who had disease progression on a prior ARPI. And they could have been, they could have received docetaxel chemotherapy and many patients did. And in this trial, in patients with BRCA1, BRCA2, and ATM mutations, treatment with olaparib, significantly improved radiographic progression-free survival, about 60% reduction in risk of progression and improved overall survival with about 30% reduction in risk of death despite 80% crossover in this trial where patients receive olaparib. So treatment with olaparib improved PFS, radiographic PFS, and OS compared to alternate ARPI. And if you look at the overall survival, it was 19 months in these patients after they started olaparib and it was about 14 months in the control arm. Now if you look at the real-world community-based database, and obviously, this is not a randomised trial, so I will keep it simple and quick, we saw very similar overall survival and radiographic progression-free survival or I would say time to next therapy, which is the surrogate because these are community-based databases. We don't do scans every three months and don't do a blinded independent review of these scans. So time to next therapies usually used as a surrogate for PFS and what we saw was quite, the results were quite similar, obviously, more benefit in patients with BRCA1 and BRCA2 mutations, but overall survival and time to next therapy were quite similar to what we saw in the PROfound trial. And the message here is that these trials, registration trials, which are leading to approval of these newer therapies, we can expect to see similar magnitude of benefit, maybe little bit lesser because real-world patients are not as robust as clinical trial patients. But I think the benefit remains, the benefit is there. So I think challenge will be to make sure how to incorporate those data into the real-world practise and how to improve implementation of those data because we have seen challenges about how ARPIs is not, are not even being used in mCRPC setting and many of these therapies backed by level-one evidence are not being actually utilised by the prostate cancer community. Now before we conclude, Axel, I'd like to have your overview on the CONTACT-02 trial, which was the combination of cabozantinib plus atezolizumab compared to an alternate ARP and patients with mCRPC with prior progression on ARPI. And let's keep it brief because we don't have the results available, we don't have the combination available in the clinic and with that, after that we'll move on to question answer session.
Perfect, Neeraj, and thank you for leadership in the CONTACT-02 trial, which you perfectly and briefly introduced into the clinical trials seen here. And I think it is important because in this situation, as you mentioned, mCRPC men with a lot with visceral metastasis, 25% had liver metastasis, they all had an RP before, 20% had docetaxel in mHSPC before. So this is really a very difficult to treat patient population. So here we have an unmet need, what to do with those patients after we have done a lot with radioligand therapy and so on. So really here we have the situation, what's next? And I think it was a good idea to look at cabo again, which we know from RCC renal cancer. And now we had some data from the COSMIC trials years ago showing some activity and now with a combination of cabozantinib and atezolizumab, this was a new idea randomised against the second RP abiraterone or enzalutamide. 567 patients were randomised one to one and it was a positive trial. PFS was longer, 6.3 months compared to 4.3 months. We can argue and we can discuss if this couple months makes a difference, but we're looking at some subgroups, it was very difficult to treat men with liver metastasis. So signal was stronger and I'm looking forward to see the press release in a while on the overall survival benefit, which we can expect and to see the data in one of the upcoming conferences. So in summary, this is the only phase 3 trial, often immune checkpoint inhibitor-based regimen that showed the benefit in advanced mCRPC. So congratulation, Neeraj, on that and I think this may close an unmet need here in the last line treatment of mCRPC. Happy to hear your comments to keep it short, thank you.
Yeah, thank you very much. Let's look forward to the final results, which hopefully we'll see in a near in a meeting in the near future. With that, thank you very much to all the faculty here for their fantastic overviews of these abstracts. And now move on to the questions here from the audience. So thank you very much for putting in your questions here. One of the first question is how do you translate clinical findings into updated prac up, in the clinical practise? I want to assure the latest work inform my patient's treatment. I think this is pretty broad question, so I will like to probably ask Karim, translation of these findings. So we are seeing these major phase 3 trials being presented level-one evidence and is it really being translated into community across the world? So this is a pretty big topic, so like to hear your viewpoints.
Sure. Now this is why it's probably so important to get data in clinical trials about what's clearly related to patient's life, including quality of life, pain, scattered way events in prostate cancer because really, metastatic prostate cancer is a burn disease in most cases. This is really telling us whether we are helping patients yes or no. PFS, you know, is something, but again, you may as Axel rightly said it, you may argue whether a significant PFS benefit actually translate in a true benefit in older patients, especially when you use the same treatment in other routine practise in weaker patients and with more comorbidities. So this is why I think we should put all efforts in clinical trials capturing information regarding data which are not related to PFS overall survival. Of course, we're all happy whenever our survival is improved, but it's hard. I mean, the bar is very high and if we want to have other treatment on the market, we just need to demonstrate that we're directly helping patients besides overall survival when the bar is just too high. So this would really be my answer. Now, generally speaking, I'm not a big fan of what we call real-world studies, which is just a collection of given treatment in all the patients. I think there is one exception and the exception is that these trials or these studies may actually be able to detect rare toxicities. So in other words, if you did your trial in say 500 men or women and you show that X is better than Y and if a rare toxicity occurs in just one out of 1,000 patients, but it's a bad one, you wanna know it. And actually, those real-world studies will tell you if they are able to accrue say 1,000, 2,000, 3,000 patients. So that's really where they have values. But otherwise, usually, they're not very important scientifically and clinically to me at least. I know that the agencies and the health system wants to see them and wants to see I guess re-answering data in their environment so in their countries with more patients. But you know, usually as Axel just said it, it typically, you know, shows the same data that, that we saw in the trials with just a weaker efficacy because the selection of patients is a weaker one but usually, they're not super interesting. But I may be biassed obviously.
Yeah, and I like to, thank you, Karim, and I like to share another aspect about translation of these level-one evidence into clinical practise in the community, at the community level. And studies have shown that despite level-one evidence out there, being out there for many years, many of our colleagues may not be utilising them in our patients. And the results are multifold. It's not one factor, it's not, it is possible that real-world patients are frail or sicker and they may not be eligible to receive these treatments, but we also know that many of our busy colleagues in the community don't have time to join us in these big conferences which are happening in different parts of the world or even regional conferences. And that brings up the idea of disseminating the information, the clinical data through the digital media like we are doing right now. So getting to the real-world practitioners, how can we get to them? How can we bring the data to those busy practitioners across the world rather than expecting them to come to these large meetings. So I think kudos to Medthority and many other educational forums, which are already doing it. So I think this is very important what we are doing here right now. I will go to the next question. What is the best time to look for BRCA1 and BRCA2 mutation in a patient with metastatic prostate cancer? Do we test for them in mHSPC setting? Do we wait for mCRPC setting? So Axel, I'll come to you, what do you think? When should we test for these mutations?
Ideally, even earlier in all metastatic patients, but it depends really on the approval and the reimbursement status in each country. So I cannot just answer very broadly here because it's depending on, for example, for olaparib monotherapy in mCRPC, the testing for Europe and Germany is approved and reimbursed, but it can be very different throughout the countries. And then we have combinations like enzalutamide and talazoparib where you don't need to test, at least in Europe. So you just start and then test. So I think to come back to your question, I think from the point of mHSPC towards mCRPC, that's the best point. We really want to know what the biomarker status with regards to HRR status is. That's my opinion, happy to hear yours.
Barbara, when should we test?
As soon as possible. But as Axel said, there is a reimbursement issue that we have to analyse and I'm looking forward for the results for the studies from PARP inhibitor bringing that has been brought early on. So probably, I truly believe the target therapy, I truly believe BRCA mutated patients are HRR, some of them of these mutations have greater benefits so I really think they have to receive PARP inhibitors early on. But of course, we have to wait for these results, but as soon as possible. Once the patient progress to mCRPC, sometimes we had, we need another biopsy. We are urologist, Axel, so perhaps radical prostatectomy is the only and it's, I don't know, 10 years has passed and we cannot use this material and we need new biopsies and sometimes the metastatic sites are just not good enough for new biopsies. So as soon as possible in advanced prostate cancer and looking forward for new results for PARP inhibitors in early settings.
And this may be a mute point once if we have, hope we have positive results on the ongoing metastatic hormone sensory prostate cancer trials with, which are using PARP inhibitors, AKT inhibitors. And if those trials are positive, they are being tested in biomarker positive patients. So we may be testing them upfront. I'll come to a very nice quality of life question, Karim, I'll bring to your attention and this is what is the success rate in terms of improvement of quality of life in the current treatment of metastatic prostate cancer? And I'll make it a little bit broad based. We use different questionnaires, different methods to assess quality of life in different trials. So you mentioned quality of life as being very important. So what is your take on the value of assessing quality of life in prostate cancer clinical trials?
Sure, I think we have quite robust questionnaires for patients who are sick, symptomatic, bone pain, you know, all those things in advanced stages. And actually, when we have a good treatment, we are actually able to show a meaningful benefit in quality of life. You know, I mentioned VISION for example. There was clear benefit in quality of life with lutetium-PSMA in VISION, again, in very sick patients. Another obvious example that comes to my mind is LATITUDE. When we selected high risk metastatic castration-resistant disease using abiraterone is associated with a clear improvement in quality of life or a clear improvement in terms of time to deterioration in quality of life versus ADT alone. So again, when you're selecting a subgroup of men with really bad disease for a questionnaires are pretty good to show meaningful differences in quality of life. On the other hand, if you're selecting health, quite healthy men, actually it's, and when, you know, quality of life becomes much more subtile, it's not really a big symptoms which is arming your daily quality of life. I think all of questionnaires are very unperfect and we should actually try to improve that. Perhaps asking more upfront at the individual level what is important to vast specific gentlemen, or women, of course, for his or her quality of life, which is could be actually different to someone else. I'm sure that if you are asking us, Neeraj, Axel, Barbara, and I what's important in our respective quality of life, we may provide you different answers. So that might be actually helpful to design new quality of life assessments for people who are say more healthy. But I think this is a very important field if we want to better capture how to best help all our patients.
Very interesting that most of the questionnaires currently are really applicable to those patients who have a lot of symptoms, they are sick, but healthy patients and hopefully, we'll see more and more healthier or robust patients going on clinical trial because when they have newly diagnosed prostate cancer, they really don't have as many symptoms. So we may have to develop quality of life questionnaires or better way to assess their quality flag. Such an important point. I think we'll have time for one more question. We have quite a few questions in hormone sensitive metastatic prostate cancer setting and we do respect because we are focusing on mCRPC setting today, I'll like to exclude that, but we are always available to answer those questions offline. If you can contact us through, you know, through the organiser of this conference, we'll be happy to take them later. And the last question I'll bring up is, maybe Axel, I can ask you a more like a concluding question, overarching question. How do you see the field of metastatic prostate cancer? Or rather, let me rephrase. How do you see the field of localised high-risk prostate cancer or metastatic prostate cancer or mCRPC as far as therapeutics are concerned? How do you see this field evolving in the middle?
Thanks, Neeraj, a difficult question for the end, but I think we've come further since the last two decades from just ADT to like a very large armamentarium how we treat those patients. So that is great. And now the perspective all went to treatment intensification and I think we should work on treatment optimisation. So they are trials to de-intensify treatment in mHSPC, for example, leaving away the ADT as you said, men don't like chemotherapy and men don't like to get castrated. And I think this in combination what Barbara, you and Karim mentioned for new developments phase 1 trials catches my excitement here in the next upcoming conferences. So I hope treatment optimisation and not intensification and just really use what we have with best quality of life. And sometimes it means that like for example, Barbara and myself will probably have to work with you guys in oncology very closely together to do this perioperative treatment in high risk prostate cancer, still get in with radiation therapy and maybe even with our scalpel and our robot. So I think it's a very good multidisciplinary collaboration and I'm looking forward to see what's happening in the field of prostate cancer. Still very exciting. Thank you for letting me join this wonderful discussion.
Thank you, Axel. Karim, any concluding remarks on the field of how we are moving in the field of metastatic prostate cancer?
I feel, well, I mostly support what was said. I think that for metastatic disease, we still need to demonstrate that we can cure some patients and until we do so, I think treatment intensification or strategies to improve the efficacy will remain the key question. You know, for example, regarding the question of deescalation, I think we should be very cautious and really select very, very, very good candidate for deescalation when it comes to metastatic disease. You know, the last time we did collectively was at the time of a SWOG trial, which randomised intermittent versus continuous ADT. And even if the conclusion is that it's inconclusive, patients who receive continuous treatment actually lived one year more than those who were in the intermittent arm. So we need to be careful and I again, patients with metastatic disease still die. So I think we need really to optimise but optimise meaning improve the efficacy of all treatments slash reduce toxicity if we can, but not necessarily deescalate in most patients with metastatic disease. Now for patients without metastatic disease, clearly with Axel, I think we should actually think about deescalating, at least in some patients, that we can select. This is true for example, duration of systemic treatments. Probably we will use more and more AR pathway inhibitor in earlier stages, but perhaps not forever, not, you know, not continuously or for three years or for five years or something like that. We can actually think about shorter treatments. It may also apply to local treatments. I think we're still using too many local treatments which are too toxic in too many patients who have really non-lethal disease. So we should think about optimising that and hopefully, biomarker will help us.
So I'm not quite sure, I think we might have lost Dr Agarwal, at least his camera. So maybe Barbara, on your final comments.
Oh, I agree with all your comments. We need biomarkers. We need biomarkers to better select treatment. We need biomarkers to assess a treatment response. So we need good biomarkers thinking about the intensification, we need biomarkers to make sure patients are going well and perhaps these biomarkers following treatment response will allow us to do that or intensify or de-intensify or even change treatment before the biochemical radiographic progressions, perhaps in the future we will be able to do it. So I'm enthusiastic of target therapies. I think it's a way to deliver a better treatment with a less toxicity. So we have to think about quality of life in these patients. We have to deliver more quality of life because of patients, of course, survival benefits, it's all important, but also we have to met a patient's goals, not only ours.
Yeah, I was having some problem with my camera, so apologise. I think we can conclude our session. This has been a wonderful discussion. We actually were able to review a lot of abstracts from ASCO and GU ASCO in 2024. And again, thank you, audience, for sharing your questions and hope it was enriching experience for all of you. So thank you to the faculty again for sharing their wonderful insights. It is always a learning experience for me to hear all of you. And with that, I'd like to conclude the session. Thank you very much.
Thank you.
Thank you, bye.
Thank you, see you. Bye-bye.
Yeah.
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