Karim Fizazi: Thank you, Neeraj.
Noel Clarke: Thank you, Neeraj.
Neeraj Agrawal: And thank you for your leadership on the CAPItello-281 trial. Dr. Fizazi, you presented the trial in the ESMO meeting, and obviously raised a lot of questions about the prognosis of PTEN-deficient prostate cancer. We have seen a lot of discussion ongoing. So I'd like to start with both of you first about, before we get into the results of the trial, what is PTEN-deficient prostate cancer and how it is different? And we are talking about metastatic hormone-sensitive prostate cancer. So what is PTEN-deficient metastatic HSPC, and what was your experience in the trial? So maybe I can start with Karim, you first, and then Noel after that.
Karim Fizazi: Sure. Thank you, Neeraj. So first, what is PTEN loss in prostate cancer? First, bad news, and I'm saying that because this is clearly associated with poor outcomes for patients. This is true for men with localized disease. It's been also shown to apply to men with castration-resistant disease. And obviously, CAPItello-281 confirms that this applies to men with metastatic hormone-sensitive disease. These patients clearly have a worse outcome as compared to patients without PTEN loss. Why is that? Probably because in these men, the AKT/PI3 kinase machinery is activated in parallel to the androgen receptor pathway. So basically, every time you're targeting the AR pathway, you're activating the PI3 kinase pathway, and vice versa. So ideally, in these men, we should try to target both pathways at the same time with an AR pathway inhibitor and an AKT inhibitor, and this is exactly what we've tried to do in the trial because this was predicted by the biology.
Neeraj Agrawal: That's great. Noel, your experience from the trial, when you started these patients on standard of care androgen deprivation therapy with abiraterone, the standard doublet, ADT plus ARPI, what was your experience in terms of progression-free survival? Obviously, overall survival data are not mature yet. So what did you see, how it was different from a garden variety patient with mHSPC?
Noel Clarke: Well, I'll take a step back, Neeraj, if I may. The rational basis for the trial was built on preclinical evidence. Karim's also already mentioned the influence of the AKT/PI3 kinase pathway, which stimulates proliferation, migration and so on. And there was a combination of studies in cell lines and animals suggesting a synergy with androgen deprivation, and particularly with the ARPI-type androgen deprivation. So that gave a rational basis, plus evidence from other clinical studies and smaller-scale studies looking at the combinations. So that led to the design of the combination, and abiraterone was the available drug at that time. It had been put in combination with other metabolic inhibitors of different sorts and DNA repair inhibitors, so it seemed like a natural choice.
Now, of course, starting a study like this means a big screening program to find out those men who would be eligible, in other words, those that had PTEN-deficient metastatic hormone-sensitive prostate cancer. And if we look at the literature, we got between 10% and 30%, even 10% and 40% of men, it turned out it was about 25% eligible in the CAPItello-281 study. And they were pretty advanced patients, really high-volume, a significant number of visceral metastases, pulmonary and liver. So we were looking at this hard actor group of patients where the event rate we were expecting was quite quick, and that turned out to be the case. And so, getting going involved quite a lot of structural and logistic support, which was provided by the company, AstraZeneca ran the trial, and we had about 6,500 patients screened to get our study population. But recruitment there was pretty good, really. It was multinational, it was international, and there was good patient compliance all along.
Neeraj Agrawal: That's remarkable. So I think this is the first time we got solid data, prospectively speaking, that 25% of these patients have PTEN-deficient prostate cancer, as defined by the 90% loss based on the IHC. Karim, you presented the results at the ESMO 2025 meeting, could you please remind us what the results were?
Karim Fizazi: Sure. So again, radiographic progression-free survival was the primary endpoint, and actually CAPItello-281 is a positive Phase III trial, our PFS was significantly improved. As Noel emphasized it already, the outcome in the control arm was not good, approximately two years as a median, and this was improved by approximately 20%, which translates into a 7.5 additional months in median for rPFS. So this is rPFS, it's good to have, because, of course, the agencies, if you will, like to see rPFS or OS. But as doctors, I guess it's fair to say, Neeraj and Noel, that you and me would probably prefer to see symptoms, overall survival, quality of life, stronger endpoints.
And actually, it's probably too early to say, as we were saying. There was a clear trend for better outcomes in terms to time to [inaudible 00:07:09] events, which, again, more directly measure a direct benefit to the patient in terms of what seriously impairs the patient journey. Overall survival, it's too early to say, the follow-up is not long enough, so we're planning to look at this again in probably, say, a year from now when we have sufficient maturity. But at the end of the day, what's probably even more important to me was when we looked at the biomarker analysis in the trial. And indeed, as you rightly said, Neeraj, cutoff for entry was PTEN deficiency in more than 90% of cells that were assessed by central immunohistochemistry. And again, the primary endpoint of rPFS was assessed in this all-comer population of all of them having greater than 90% PTEN loss.
But actually, when you fine-tune this analysis by an even more stringent definition of PTEN loss, so say more than 95%, more than 99%, or even 100% PTEN deficiency, the amplitude of benefit, the magnitude of benefit, becomes greater between the experimental arm and the control arm, and this applies to actually both radiographic progression-free survival, the primary endpoint, but also, and to me, to be honest, more importantly, also by overall survival. So it may well be that we should perhaps look at patients with even greater loss in PTEN to decide for treatment intensification using an AKT inhibitor in metastatic hormone-sensitive disease. Again, this is exploratory as we're speaking, and in the final analysis, hopefully we'll have a clearer idea. But the signal was very clear, the greater PTEN loss, the greater the benefit.
Neeraj Agrawal: Thank you, Karim, for such a nice summary of the results and how the benefit of capivasertib increased by an increasing degree of PTEN loss, 90% to 95% to 99%, and 100%. Noel, coming back to you, regarding the PSA progression, we were almost getting there, what was your observation as far as reliance on PSA progression is concerned to assess disease progression in these patients? Because as we know, in the real world, many of these patients are just followed by the PSA, and they may not get scans as often as we get them on the clinical trial. So what was your observation here?
Noel Clarke: Well, this was one of the more fascinating facets of the study and was highlighted when Karim presented the data at ESMO, and that is that, effectively, the systemic effect, the skeletal event effect, if you will, the sort of things that patients suffer from or complain from and doctors take up and take notice of, happened irrespective or independent of the change in PSA. So PSA was not a very good marker. And interestingly, what we saw in other trials, and particularly the STAMPEDE comparison of docetaxel and abiraterone, was that there was dissociation of the two with the two different treatments. Docetaxel, the PSA failure occurred earlier, but the survival was the same. So we're looking at different mechanisms here, and I think this calls into question just how we will evaluate such patients who go in ultimately to have treatment with PTEN-type drugs like this or directed drugs like this, and it, I think, behooves us to look more carefully at the biology of what's going on with different drug interactions.
Neeraj Agrawal: So Karim, based on this, it looks like a substantial number of patients met the progression criteria by radiographic progression, imaging-based progression, and they did not meet the predefined protocol-specified PSA progression criteria. Could you please elaborate on that?
Karim Fizazi: Sure. And I think we're still on our way to better understand what's ongoing, because indeed, in some of these patients with terrible disease, very aggressive disease, you may imagine that some of them will develop cancer progression without any PSA rise, so zero. It happens, of course. The question is how often this truly happens. And we're all familiar with some patients with neuroendocrine differentiation, very undifferentiated cancer, very aggressive, clearly not anymore adenocarcinoma of the prostate. Fair enough. But having said that, I suspect that a fair number of patients also experience a rise in PSA, perhaps before they develop the radiographic progression, but actually, the rising PSA was not high enough to characterize this progression by PCWG3, or even four soon to come, definition, which I just want to remind the audience, which requires a 25% rise above two nanograms per mL.
And actually, this is perhaps a too high bar, which was partly empiric when this was defined basically 20 years-plus ago and not on very solid grounds. It's actually not really the first time. I think Fred Saad reported that already in a trial, that actually, any rise in PSA in this patient has some importance. Of course, not if it's just a bump, not confirmed. But if it is confirmed, it has some importance. And actually, really would like to dig into more details to really tease out between those two scenarios. Again, one being no PSA rise at all, okay, fair enough. But the other one being a rise, but not reaching the 25% increase/greater than two nanograms per mL. I think this is very important for all of clinic and for guidance.
Neeraj Agrawal: Thank you, Karim. So Noel, coming back to you, we heard from both of you that these patients have a much shorter progression-free survival, about two years, on standard doublet of ADT plus abiraterone. We heard that PTEN deficiency may be associated with not a proportionate rise in the PSA level, so definitely implications on the monitoring of these patients and how often we should see them in the clinic. Based on these two observations, even putting the results of the trial on the side, it looks like testing for the PTEN has become more important than ever, especially when 25% of our patients with mHSPC are going to have this remarkable level of PTEN deficiency. How are you dealing with that in your clinic in UK?
Noel Clarke: Well, we're not in any way geared up to adopting this philosophy at the moment, but the evidence is that we should. The question at the minute is whether that should be with immunohistochemistry, as in the case in CAPItello-281, which is relatively straightforward to do and quite repeatable, or whether we should be more sophisticated. The recent paper from the STAMPEDE team published in Cell this year by Emily Grist, one of our researchers, showed that the RNA levels looking at PTEN do indicate differential behavior in relation to different treatments, for example, docetaxel sensitivity. And so, I think that starting at the basement, if you will, then immunohistochemistry is something that we should do, it's something which should be available in clinics around the world.
The more sophisticated stuff, I think, is for the translational science to help us understand really what the role of PTEN is in individual patients, and how we might target different treatments depending on PTEN loss and the ability to inhibit that. So I think it's a double-edged sword really. It is, on the one hand, suggesting to us that we should think about our practice and how we deal with that on a clinical day-to-day basis, but also to think about what's actually happening at a cellular level to try to understand how this mechanism is working and how we might individualize that to our patients.
Neeraj Agrawal: I agree with you, Noel. I don't think any of us are routinely doing PTEN-deficient status testing by IHC. So Karim, what is your guidance for all of us, and how should we embark on this testing for PTEN deficiency by IHC? I'm sure all of us should be gearing up for this.
Karim Fizazi: Neeraj, we started this year, 2025, as oncologists/urologists treating all the patients with metastatic hormone-sensitive pretty much the same, without any biomarker assessment. Basically, for all patients, we are using either a doublet or triplet, depending on what we think about the data, about fitness of patients for docetaxel, all these things. But in January, this year, we were not using a biomarker. I think this year is really the year when we are changing this policy. And I'm saying that not only thanks to CAPItello-281, which highlighted obviously the role of PTEN loss and potentially capivasertib to help these men, but also with the data from the niraparib Phase III trial in mostly patients with BRCA alterations, suggesting that indeed we should test to try to identify who these men are, and treat them probably upfront with a PARP inhibitor. And potentially the same will apply to patients with strong expression of PSMA. We just saw the very first data from PSMAddition, which are perhaps not completely convincing as they are.
But again, I'd love to see more data correlating the efficacy of lutetium PSMA, or more general PSMA targeting, in patients with strong expression of PSMA. So you see, for example, three different biologies, three different biomarkers, and that's just in one year, or not to say six months. So I really think we are just moving to biomarker-based medicine in metastatic hormone-sensitive disease. Now, whether this is going to be immunohistochemistry, NGS, PSMA PET or some others, of course, I don't know, and science will need to tell. But the movement is there, and that's clearly our soon future, and most importantly, all the patients' soon future. So I'm really convinced that we should test. This will need some fine-tuning, but at the end of the day, we will not treat any longer all the patients all the same, and this is good, this is exactly what we want to do.
Neeraj Agrawal: And our colleagues in other areas, in lung cancer, in breast cancer, in colon cancer, they are used to testing.
Karim Fizazi: Of course.
Neeraj Agrawal: So I think this is time for us.
Karim Fizazi: I agree.
Neeraj Agrawal: Noel, any final comments?
Noel Clarke: Well, you've hit the nail right on the head, Neeraj. We often hang onto the coattails of the breast cancer fraternity, they're way ahead of us, and breast cancer is very similar in so many ways to prostate cancer. And look at the effects that biomarker testing is having on the management of lung cancer, as Karim has just said. We really need to get on board with this and stop thinking about a disease which old men get and don't die of. They do, and they need to be treated individually according to what's going to work for them, we need to work that out.
Neeraj Agrawal: Karim, any final comments for us?
Karim Fizazi: I think all said, hopefully we will see even more data in 2026 for patients with metastatic hormone-sensitive disease. Regarding AKT targeting, the bad news is that, again, PTEN loss means aggressivity, and this means that we should have an updated analysis of CAPItello-281 in the non-very long future, because again, patients in the control arm unfortunately will develop cancer progression and some of them will pass away, meaning that the maturity of a trial will probably soon be here. And again, this emphasizes the unmet need for these men. We need to invent better treatment for patients with PTEN loss, and hopefully AKT inhibition will be one of those.
Neeraj Agrawal: Well, thank you so much to both of you for taking the time to share these insights with us.
Karim Fizazi: Thank you very much, Neeraj.