Karim Fizazi: Thank you, Neeraj. Thank you for your kind words.
Neeraj Agarwal: So Karim, first of all, congratulations for completing the phase three CAPItello trial. It takes so much time, investment and work to complete a phase three trial and presenting the trial results at the ESMO 2025 meeting. Could you tell us more about the trial and what you found and what we learned from the trial?
Karim Fizazi: Sure. Thank you again, Neeraj. So, CAPItello-281 is a very large phase three trial, and I'm saying that because we had to screen, or pre-screen should I say, more than 6,000 men to enroll more than 1,000 into the trial. So what is that? This is really a trial about metastatic hormone-sensitive disease and PTEN deficiency. We selected these men with PTEN loss, because preclinical data, but also clinical data, achieved in the mCRPC setting suggested that in these patients with PTEN loss, you have double activation of androgen receptor pathway in parallel to the PI3 kinase/AKT pathway. And actually, in these men, it appears that targeting both pathways at the same time may achieve a greater efficacy. So this was already our hypothesis.
So again, approximately 1,000 men with metastatic hormone-sensitive disease were randomized. They all had PTEN deficiency, and this was defined as greater than 90% PTEN deficiency by immunohistochemistry, so no viable malignant cells in the cytoplasm in these cancers. These patients were randomized to receive abiraterone/prednisone at the classical dose, plus or minus capivasertib, given four-days-on, three-days-off schedule. The primary endpoint was radiographic progression-free survival, and of course, we had a number of secondary endpoints, including obviously overall survival.
The trial met its primary endpoint, as you can see on the screen, I guess. We have approximately a 20% reduction in the risk of radiographic progression or death, which translated into an absolute benefit of 7.5 months in median, which are [inaudible 00:02:58] which is not surprising, because we all know that this is aggressive disease. Patients in the control arm progressed or developed cancer progression or died by approximately 26 months as a median, and this was improved to more than 33 months in the experimental arm. I think a very important finding also in this trial was that the degree of PTEN deficiency appears to predict strongly for even greater benefit from this combined treatment. And indeed, when we tested various cut-offs of PTEN deficiency, as I said before, the initial cut-off was greater than 90%, but we also tested more than 95%, 99%, 100%. We saw increased benefit with the combination arm, and this was actually true by both PFS, but also by overall survival.
Neeraj Agarwal: Karim, thank you for showing and sharing the results of the CAPItello phase three trial. Something was striking to me, which was the median radiographic progression-free survival on the control arm of ADT plus abiraterone. You showed not long ago from the LATITUDE trial, and we saw from the STAMPEDE trial results, the median progression-free survival was higher in all-comer patient population, even though they were high-risk in LATITUDE and all-comer mHSPC in the STAMPEDE, it is definitely lower in the CAPItello trial. Why is that?
Karim Fizazi: True. I was actually not surprised, to be honest. We already had, or have, many data in various situations of prostate cancer indicating that PTEN loss is really a bad prognostic factor. This was demonstrated in localized disease, this was also demonstrated in castration-resistant disease, and now this is being shown also in metastatic hormone-sensitive disease. So again, across the board, PTEN loss is just bad, it's really associated with poor outcomes. And actually, this was reflected by the baseline characteristics of this population, simply they had high-risk disease, high-volume, high [inaudible 00:05:46] score, high everything, as compared to a general metastatic hormone-sensitive population.
Neeraj Agarwal: And you presented during the ESMO another interesting finding, that you noticed a lot of these patients experiencing radiographic progression without concurrent PSA progression. Can you please tell us more about that finding?
Karim Fizazi: Yeah. That's, I think, clinically an important finding. And indeed, as you said, some patients when they have PTEN loss tend to develop a clinical detrimental event first before their PSA rises above the greater than 25% increase, which is required by the PCWG3 definition. So in other words, we should indeed pay attention to PSA, as we probably all do when we are following up these patients with metastatic disease, but we also need to pay attention to their clinical behavior and potentially repeat some imaging.
I'm actually not saying that PSA is not rising at all, and actually, most often, you see some rise in PSA, but it doesn't reach the above two nanogram per mL and above greater than 25% increase, which, again, is required by the international definition. So basically, any rise in PSA in these patients is important to consider. This, to me, is a very good reason to order new imaging, even if this was not necessarily pre-planned. Typically, I don't do repeated imagings in my patients with metastatic hormone-sensitive disease, but in these patients, even with a slow rise in PSA, I would clearly do that, because you can really find bad surprises, including liver metastases, for example, which are obviously lethal.
Neeraj Agarwal: Thank you for clarifying that, that we just cannot rely on a PSA rise to meet the PCWG3 criteria, because many of these patients may have progression, clinical or radiographic, without that PCWG3-defined PSA progression. Karim, before we conclude, any comment on the side effects and the management?
Karim Fizazi: Yeah. Basically, we saw what we expected to see based on the prostate cancer experience with this compound, capivasertib, but also based on the breast cancer experience. So basically, we saw an excess in rash, in diarrhea, in hyperglycemia and anemia. The typical side effects from abiraterone and prednisone were actually even between arms, so that is not being changed. Good news was that diarrhea was probably rarer as compared to what we've seen in women with breast cancer. Hyperglycemia was probably higher, probably reflecting the fact that the prostate cancer population is older, perhaps more obese, pre-diabetic, so this is something we should really pay attention to.
Now, the key question is really, based on the benefit and the risk with side effects, what's next? And I really hope that we will be able in the longer term, because this is pre-planned, to show overall survival benefit with this combination, at least in patients with truly PTEN loss, say more than 95%, more than 99%. It really appears that these patients, number one, need new treatments, because really, they have aggressive disease, but also, that the combination has greater efficacy in these men.
Neeraj Agarwal: Great, very helpful. So just to summarize for our audience, phase three CAPItello trial met the primary endpoint of radiographic progression-free survival when capivasertib was added to the backbone of ADT plus abiraterone in patients with metastatic hormone-sensitive prostate cancer with PTEN loss, as assessed by immunohistochemistry. One of the most important messages to me as a practicing oncologist is, while we see further results on the overall survival and more maturation of the data, something which is directly practice-impacting to me, which is I cannot rely on the PSA progression to meet the PCWG3-defined PSA progression, because many of these patients can have clinical progression or radiographic progression before that. And second, as the degree of PTEN loss is higher, goes higher, the magnitude of benefit with capivasertib increases, and the benefit with ADT plus abiraterone decreases, if you will. And hence, we really hope the trial shows even more promising survival outcome data and we can have the drug in the clinic in the near future.
Karim Fizazi: Absolutely. Thank you, Neeraj.
Neeraj Agarwal: Thank you very much for joining us today.