Daniel George: Thanks, Raj.
Neeraj Agarwal: And education.
Daniel George: Yes.
Neeraj Agarwal: So thank you, Dan, for being here.
Daniel George: My pleasure. Thanks for having me.
Neeraj Agarwal: So first of all, congratulations to you and the investigators for doing this massive trial, the phase three CAPItello trial just presented in Berlin in ESMO last week, it's not even last week. And you screened 6,000 patients to get 1,000 patients eligible to be randomized who had PTEN deficient prostate cancer. So first of all, congratulations.
Daniel George: Thanks so much, Raj. This is a study, I think have been a long time coming. We've known for a long time that PTEN is a poor prognostic indicator in prostate cancer. It regulates the PI3 kinase AKT pathway, which is a proliferative driver pathway sort of in parallel to the androgen receptor driving pathway. And we've had drugs before that block this pathway. Capivasertib is, or what I call capi, is the latest pan-AKT inhibitor. And this is really the ideal setting, metastatic hormone-sensitive prostate cancer where we can block both AR and AKT kind of simultaneously to kind of give the cancer less of an opportunity to escape. And so that was really the strategy around this study.
Neeraj Agarwal: So tell us more about the design of the trial and what was the primary endpoint and then we can go through all the learning aspects of what we got from those results.
Daniel George: Yeah, yeah. So as you know, we don't typically check for PTEN status in our prostate cancer specimens, but we did as part of this study. And as you said, it took 6,000 patients, screening about 25% had loss of PTEN at the threshold that we were looking for, greater than 90%. So it had to be a significant loss of PTEN by immunohistochemistry. And then those patients were then randomized to either receive capi, which was 400 milligrams twice a day for four days on three days off, and abiraterone, standard dosing, 1,000 milligrams and prednisone or placebo and abiraterone and prednisone. We followed patients until disease progression, death and primary endpoint was radiographic progression-free survival and overall survival was a key secondary endpoint.
Neeraj Agarwal: Tell us about the results.
Daniel George: Yeah. So the top-level results, the study was positive. It met its primary endpoint for RPFS. We saw a median improvement in the median RPFS of 7.5 months from like 25.7 months to 33.7 months. So we improved the median RPFS. It was a hazard ratio of 0.8, statistically significant and just a little bit immature on the overall survival at this point in time. It's only 18 months median follow-up, but already we have 26% events in overall survival. There is a trend in favor of the CAP ER, but it's not significant. It's early.
Neeraj Agarwal: Yeah, I'm glad you brought this up. About median PFS of 25 months on ADT plus abiraterone arm, which is so much lower than what we have seen in all comer metastatic hormone-sensitive prostate cancer trials, which spans usually from 36 to 39 months. So let's start from that point.
Daniel George: Yeah, this is really critical. Again, it's the first study we've done solely in patients with loss of PTEN. So this is a different biology. This is a more aggressive biology, and we're seeing that. We're seeing this shorter time to RPFS with abiraterone and ADT. Actually, if you look by time to castration resistance, it's 22.7 months. It's even shorter for the time to castration resistance.
Neeraj Agarwal: It is like on single agent ADT on all comer patient population, which is about 16 to 17 months.
Daniel George: Almost. And the concern is that that's also going to track into the castrate-resistant disease that this is a poor prognostic indicator in castrate-resistant disease. So this prognosis doesn't go away.
Neeraj Agarwal: So we should be checking for PTEN loss going beyond whether we are going to use capivasertib or not, I think these patients ought to know that they have PTEN loss because of multiple learning aspects of, multiple learning tools we got out of this trial. So please talk about those learning lessons from this trial.
Daniel George: Yeah, Raj, this is I think some of the most important things when you do a study, a big prospective study in a new population like this, kind of like the first time we did BRCA populations in prostate cancer. You learn some things about the natural history of this disease on our best standard of care. So on abiraterone or on ADT, what we see, which to me is really fascinating is we have this RPFS, but when we look at symptomatic skeletal events, when we look at death, and then we also factor in the PSA progression, that's where we get this time to castrate resistance. It's really a composite of all of those things. But what's fascinating, Raj, is of that composite, the amount of patients that actually had PSA progression as part of that composite was relatively small. It's less than half. So over half of our patients that are progressing to castration-resistant prostate cancer are doing so without a rise in PSA. I mean, that's not what we typically see.
Neeraj Agarwal: Absolutely.
Daniel George: And you look at some of our older studies like ARCHES and stuff, and we see it's usually about 20, 25%. This is a real enrichment for that population, which is probably telling us something. That this AKT pathway is a driver of that non-PSA progression and it's associated with more symptomatic, [inaudible 00:06:19] events, with early death, with radiographic disease progression as well. So we need to be looking for those kinds of things we need to be protecting for those kinds of things. And that's where knowing the PTEN status will really give you a jump on what you need to do for this particular patient.
Neeraj Agarwal: So to me, these are already practice influencing data in my clinic because if I see a patient with PTEN loss, there's a pretty high probability that patient will have disease progression without PSA progression. And I think the current standards across the clinics, my colleagues, real world colleagues, academic setting, we don't necessarily do CT and bone scans every three months on these patients. We rely a lot on PSA levels. So I think to me, the first learning lesson is if I see PTEN loss and I can extrapolate to NGS testing results also, although this was not from the trial, it was IHC testing, I'll be doing CT scans and bone scans more often.
Daniel George: This is exactly the point, Neeraj. I'm glad you bring it up because typically when we treat a patient with our AR pathway inhibitor and ADT and we see the PSA go way down, we're happy. The patients are happy, we're happy, these drugs are working. But when we have loss of PTEN, we need to be thinking, we need to be cognizant that there's other biology that we're not measuring by that PSA. And that's precisely why doing those kinds of scans and doing a bone density study, getting those patients on bone health agents and all those kinds of things can help.
Checking the other genetics associated with that can all really help. And then let's not forget the fact that CAPI improved that progression-free survival by itself in addition to abiraterone and ADT added to that, an extra 20%. Now you might say, "Well, that sounds kind of modest." But remember, this is against the worst actors. This is against a disease that is already pre-wired for resistance. And so being able to show that just targeting that PTEN checkpoint can already impact this natural history of disease, is hugely important and we can build on this. This is gives us an opportunity, a stepping stone to build on this population that's been typically pretty recalcitrant to treatments.
Neeraj Agarwal: And what I've found was very interesting from Dr. Karim Fizazi's presentation in ESMO that higher the degree of PTEN loss, the hazard ratios seem to favor capivasertib more. So what do you think about this?
Daniel George: It's remarkable. We saw this a little bit with ipatasertib. This is another pan-AKT inhibitor that was developed in metastatic castrate-resistant prostate cancer that, again, improve progression-free survival in that MCRPC setting for the PTEN loss patients only. And the greater the PTEN loss, the greater the benefit. We looked from 90% to 100% because remember, all of our patients had at least 90% and 95%, 99, 100% all got progressively better and better RPFS benefits and even wider and wider overall RPFS benefits at this interim analysis.
So this is still early on, it's not statistically significant, but the trend is very consistent with what we've seen before. The trend is very consistent with the biology. The more homogeneous that loss of PTEN, the more dependent that tumor is on this sort of rescue pathway, the more sensitive it's going to be to that PTEN blockage. And what we see is really interesting. The overall response to the AKT inhibitor is about the same in terms of the RPFS and the OS. What changes is the control arm, the abiraterone group, as you get greater and greater loss of PTEN has a worse and worse RPFS and OS. So we're seeing a separation-
Neeraj Agarwal: So it's become less and less efficacious with higher PTEN loss?
Daniel George: That's right. That's exactly right.
Neeraj Agarwal: So fascinating, again, really learning experience for all of us to hear these data, to see these data and real implications on our practice, I would say. Just for our listener, can you summarize the top three lessons from the CAPItello phase three trial?
Daniel George: Sure. I think first off, PTEN is prognostic and we need to be checking this on a routine basis, talking to our pathologists about adding immunohistochemistry for PTEN and really the percent of PTEN loss in those tissues on a routine basis for our patients that have high-risk localized metastatic or metastatic prostate cancer. I think number two is that when we see loss of PTEN, we need to be thinking about a different natural history, a biology that is not contingent on PSA as a marker of progression, that we can see a lot of progression outside of that and some of it's clinical with these skeletal events.
And then I think the third is that this is a driver of that biology, that AKT and this AKT inhibitor specific for that. It's got its side effects. We do see some diarrhea, we do see some rash, we do see a little bit of anemia and stuff, but they're manageable. They happen early, they're manageable. 80 plus percent of patients were able to tolerate the drug long term. So this can be given in this setting and it does impact the natural history of this disease. It does slow the course and for our patients that are going to otherwise have an accelerated course of disease, being able to change that, it's the first step in really improving the outcomes for our sickest patients.
Neeraj Agarwal: Indeed, remarkable. Thank you, Dan, for joining us today and for sharing your insights.
Daniel George: Always my pleasure. Good to see you, Raj.