Prof Eleni Efstathiou – Houston Methodist Cancer Center, Houston, USA
Prof Gerhardt Attard - Cancer Institute, University College London, UK
Dr Elena Castro – 12 de Octubre University Hospital, Madrid, Spain
Dr Brigida Maiorano – IRCCS Ospedale San Raffaele, Milan, Italy
EE: Hello, I’m Eleni Efstathiou and I’m joined by esteemed medical oncologists who are all from Europe and I will start with introducing Dr Castro from Spain.
EC: Hi Eleni.
EE: Hi, good to see you again here in Chicago. Dr Maiorano, very nice to meet you.
BM: Hi, nice to meet you.
EE: And Dr Attard, good to see you again.
GA: Good to be here.
EE: And we are all very excited about being here and discussing, what else, prostate cancer developments. We’ve had some great news during this meeting and we wanted to chat with the experts to get their thoughts on how they will move forward our practices at home. So I’ll just delve right into it, I’ll start with you, Elena. I wanted you to give us your thoughts, you presented some wonderful data with regard to prognosis of germline or somatic events that are found in our patients earlier on in the disease development. Currently, just to set the stage, in most countries the guidelines dictate that we check for such events in the castrate resistant space but you’ve brought forth some light that would probably push that envelope a little earlier – talk to us about it.
EC: What we have presented at ASCO this year is an analysis of the impact of BRCA and other HRR alterations in mHSPC. We already knew that these events have a negative impact on patients with mCRPC but I think we didn’t have…
EE: We already knew because you had done a lot of that work already, just to be clear.
EC: We didn’t know how was the impact in the mHSPC space. What we see is that these patients have shorter survival, progress faster to any therapy. But perhaps one of the most important observations is that in these patients disease volume doesn’t really seem to differentiate the outcomes that much. So BRCA patients have really poor outcomes regardless of disease volume. We see that the radiographic and PSA progression in these patients occur almost at the same time whilst in patients without these defects PSA rise usually occurs about six months before radiographic progression. So this could have implications for follow-up and, most importantly, for treatment. Because what we see is that these patients do very poorly either on ARPIs and taxanes, so we need something else.
EE: That is great. So would you, as an expert, recommend that moving forward, and before we get to what else we heard this year, this presentation, would you recommend, moving forward, checking earlier?
EC: Absolutely.
EE: Upon diagnosis? Where would you put it?
EC: Absolutely and in these patients with metastatic disease it’s something that could be easily done at the time of diagnosis when the sample is with the pathologist already. So it would be very nice to get the report of the Gleason score and all the histology parameters plus the genomics of the disease. I think it’s time to integrate biology also in treatment decision making, not just disease volume or when did the metastasis appear.
EE: I think that you’re providing excellent context, Elena, in giving us all of this data that can help us understand better the prognosis of these men. But you kind of stole a little bit of her thunder because you just presented the AMPLITUDE trial which actually brings forth the use of a drug in the context of DDR events in tumours in hormone sensitive. So talk to us about it.
GA: I think Elena’s study made my thunder louder.
EE: I understand that but you did… You stole hers. Let’s go to it.
GA: The CAPTURE study… you know what I mean. But it really emphasised what a poor prognosis group mCSPC with HRR or BRCA mutations is. The AMPLITUDE trial, yes, which I had the honour to present, asked the question about combining PARP inhibitors with ARPI for mCSPC. I guess by way of background we know that PARP inhibitors are effective for mCRPC as monotherapy when used after an ARPI and when combined with ARPI for line one mCRPC. There are two challenges in their use in mCRPC, the first is as monotherapy resistance develops relatively rapidly the median rPFS is less than 12 months. And when combining with ARPI for mCRPC, reusing ARPI generally for mCSPC.
So AMPLITUDE randomised just short of 700 patients to either niraparib with abiraterone and prednisone or placebo abiraterone with prednisone. We, at this ASCO, presented the primary and final analysis of the primary endpoint, rPFS, so time to radiographic progression or death, and interim analyses for the two key secondary endpoints – time to symptomatic progression and time to overall survival. It’s exciting because the trial met its primary endpoint with really statistically and clinically significant improvements in rPFS. We use a graphical design where we tested those three endpoints in sequence and by molecular subtype. So the first group to be tested was BRCA for strong biological reasons. In the BRCA population niraparib reduced the risk of progression or death by 48%, the hazard ratio is 0.52. So we’re nearly halving the risk of progression in BRCA patients. In the HRR population, so that’s BRCA plus seven other genes, BRCA2 or 1 plus seven other genes, the hazard ratio is 0.63, met the primary endpoint for that group. For secondary endpoints there was, again, statistically significant improvement in time to symptomatic progression by 50% in the BRCA population, 44% or so in the whole HRR. For OS the data is immature – this is the first interim analysis, we have half the number of deaths that will be required for the final analysis. But, in my opinion, the direction is already favouring niraparib. The hazard ratio in the BRCA population is 0.75, in the HRR 0.79. So to speak in some rough terms the curves are starting to split and I think it’s looking promising.
About 33% of patients in the placebo arm received PARP inhibition later and this is going to be debated because clearly patients are going to receive niraparib for longer if started for mCSPC – are we going to improve their survival? I’m confident we will although we don’t have mandated or built-in crossover as part of the trial because it’s a placebo-controlled trial. In fact, there’s never been a placebo-controlled trial with crossover. So there’s a number of reasons why you can’t do that but 36%, I’m encouraged by that because I felt that was important to us. In fact, in the trial we unblinded patients when they met the primary endpoint which I think has pushed that rate up. So, yes, at this point certainty that niraparib delays time to radiographic progression and symptomatic progression, some uncertainty over survival but the initial data is looking very promising. The last thing I’ll say is there is toxicity and we’ve been using…
EE: I was going to say, there’s a big elephant back there in the room waiting for you to address it.
GA: Yes, and we’ve used PARP inhibitors for many years and there’s no new class of adverse event – haematological toxicity, hypertension – but over 70% of patients with niraparib versus about 50% in the placebo arm have grade 3 or 4 toxicity and anaemia is by far the most common with the majority requiring a transfusion. So this comes at a cost but, again, I’m encouraged because fewer than 5% of patients who were randomised to niraparib discontinued because of a treatment-related adverse event versus placebo. So about 15% discontinued treatment due to toxicity with niraparib versus 10% with placebo. That does reflect my experience where we do see toxicity but with supportive measures we’re able to control that. Now, that’s a big ask of patients and I think a discussion needs to be had for every patient. For BRCA it’s a much easier discussion because the benefit is so great, their prognosis is poor. For other HRR genes we’ll have to be much more nuanced in our conversations with patients and I think with time we’ll see data from other trials for those other gene groups.
EE: So that brings me to a question to you and then I’ll turn to Elena about her thoughts. Am I mistaken to remember that we did not include ATM in the AMPLITUDE?
GA: Correct.
EE: There was no ATM. Do you think we’re done with ATM?
GA: Never say never. The panel was designed based on the MAGNITUDE trial in mCRPC and in that trial there was no evidence of efficacy with ATM mutants. Again, that was borne out through a number of other trials, including TRITON3, for example, specifically asked that question in mCRPC. I think biologically ATM mutant, ATM loss, may induce sensitivity but our tests are not picking up biallelic deletion effectively. That may be one reason why we’re recruiting patients with a single allele loss which is not translating into benefit.
EE: Do you agree with that, do you have anything else to add?
EC: No, no, I agree. Most of the data we currently have is that patients with ATM may not benefit much in general. There may be some individuals from PARP inhibitors and there may be other therapies that are more appropriate and should be prioritised for these patients.
EE: Yes and I think it’s a bigger discussion to decide eventually how further we can develop our assays to be more precise so that we don’t miss out on what we now consider wildtype and may benefit. But Brigida, back to you. You’re going back home, and let’s assume you’re going to Houston, like I’m going, where I can prescribe tomorrow if I want a PARP inhibitor for my BRCA2. So you’ve got, in the trial we did, BRCA2, BRIP1, CDK12, CHEK2, PALB2 and a couple more. If a patient showed up with one of those would you feel comfortable starting up front ADT abiraterone, niraparib – I mean, I’m just using this because it was tested – are you ready?
BM: So thank you, thank you for the question. With these two master colleagues and this data, I think we are facing a further evolution in the metastatic prostate cancer field in the hormone sensitive setting. In my opinion the captured data were very important, also because they precisely defined the real prevalence of BRCA and HRR alterations in this population after the data in the mCRPC setting. We were asking ourselves which was the real prevalence of BRCA and other HRR alterations. Also the trial confirmed what we were facing in the mCRPC setting, that patients with a BRCA mutation are different than patients with HRR alterations compared to those without alterations. But also that not the BRCA or the HRR alterations are created equally; the AMPLITUDE trial confirmed this evidence. So if I had access to this treatment tomorrow in my country – I think that in my country it would be very long, the approval process in Italy – but I would like to use this combination, especially looking at some characteristics of the AMPLITUDE data. For example, four out of five patients had high-volume disease and around 87%, if I remember, of patients were metastatic hormone sensitive de novo patients, so this is a challenging population. I remember that also 16% of patients received also docetaxel. So this is a huge intensification strategy. So I am growing up in the era of intensification strategies in the prostate cancer field so moving from single ADT to ADT plus ARPI or ADT plus docetaxel and now there are triplets. But this is a huge intensification in a specific population that in my opinion is different from the others. So these are specific patients requiring a specific treatment.
EE: Correct because I think we all agree that we’re changing their livelihood. These patients, especially the ones with BRCA mutations, do not have the timeline that other patients with lower volume, potentially not so many events, have. So this idea, you call it intensification, some of us call it ‘Throw the kitchen sink at people,’ it’s appropriate. And especially since a lot of these patients are going to be younger and you’ve reassured us that it can be tolerated. This was, for us, one of the most important, these two presentations, during this ASCO. We got some data, and I want to turn to you again, Brigida, regarding other prognosticators for hormone sensitive disease. We’ve always been challenged by this idea that it’s a good thing when the PSA becomes undetectable. Tell us about the IRONMAN database, that was a nice example of that.
BM: I’m a bit enthusiastic about this idea because, as we know, in this disease the PSA is important. It is also a field where we have no real prognostic or predictive factors. In this registry they included more than 1,200 patients that were analysed for PSA response at two timepoints, 6 and 12 months. They analysed three cut-offs of patients, so the not responders with a deep PSA response, patients not reaching the levels of PSA below 0.2, the good deep PSA responders, so from 0.02 to 0.2, and the ultra-deep PSA responders, so patients with levels of PSA below 0.02. Showing a prognostic value for those not achieving a deep PSA response there was a seven- to eightfold risk of progression or death compared to those who achieved a deep PSA response. So in my opinion this is very important because we are talking a lot about the deep PSA response. This large registry confirms the hypothesis that a deep PSA response, we already know from the clinical trial of ARPI and also of docetaxel and also of triplets, that deep PSA response has a prognostic role. But there are some questions about this deep PSA response, so how to define really the deep PSA response – should we use the undetectable PSA, so the PSA below 0.2 or the reduction? It is not the same to achieve an undetectable PSA than achieving the PSA90, so a reduction of 90% starting from the baseline, and when we should measure the deep PSA response – at 3 months, at 6 months, at 12 months? So a lot of food for thought in my opinion.
EE: More questions generated. I think that we could go on discussing forever all the little nuances that came out of this presentation but what it pointed to is that these patients should be investigated more. I’m trying to tie it in with what you said. Maybe these patients have not been checked for DDR events, so that would be a good opportunity if you don’t see the PSA become undetectable within 6 months, for instance, it’s just a thought, or other events that are going on. With that in mind I think we had a great meeting, more data to come soon. I’m very excited about hearing about the newer PARP inhibitors that are now in the pipeline that may have less toxicity. So we might start hearing in the coming meetings. So with that in mind, thank you for your attention and stand by for more data coming soon.
