Updates from Industry Clinical Trials
SESSION 4: Updates from Industry Clinical Trials
Moderator: Howard Soule (Prostate Cancer Foundation)
PSMAddition: Initial Results from the Phase III Trial of Lu-177-PSMA-617 in Metastatic Hormone Sensitive Metastatic Prostate Cancer
Oliver Sartor (Tulane University)
A Phase 3 Stude of Capivasertib + Abiraterone vs Placebo + Abiraterone in Patients with PTEN Deficient De Novo Metastatic Hormone-Sensitive Prostate Cancer: CAPItello-281
Daniel George (Duke University)
CAN-2409 with Radiotherapy for Localized Prostate Cancer: A Phase 3, Randomized, Placebo-Controlled Clinical Trial
Paul Peter Tak (Candel Therapeutics)
View the Transcript Below:
Updates from Industry Clinical Trials
Howard Soule, PhD [00:00:16] So, we’re gonna do a session on new treatments. We knew clinical trial results. There’s a lot, you know. ESMO was just a few days ago. There are a number of ESMO Encore presentations and some other interesting clinical trial results. And the first one will be on PSMA addition, presented by Oliver Sartor from Tulane University. Oliver, you were right here. Oh, there you are.
Oliver Sartor, MD [00:00:53] Howard, I’m coming to dinner, I promise. So, I’m standing on the podium right now, but there are probably three individuals who could be standing in the podium, one of whom is me, but the other of whom is Mike Morris, who is head of the steering committee, and I hope Mike is here somewhere. And we also had a rather amazing presentation at the presidential by Scott Tagawa, who did a beautiful job. So, I’m kind of the encore guy, I’m not the important guys, but it turns out this is nice data, and I’m glad that we have the chance to present it now. The declaration of interests are long, and that’s good and bad, I suppose. We keep working and trying to make people have better outcomes. That’s really the key thing. I’m gonna call it Pluvicto in the beginning, and then probably just lutetium as we go through. You know, this is PSMA-617, lutetium-177. It binds to PSMA on the cell surface, and then it will radiate cells in proportion to that binding. It turns out that we have two FDA approvals right now. One is from the VISION trial, which is in the post ADT ARPi and taxane setting, and the other is what we call the PSMAfore setting, which is post ADT and ARPi metastatic CRPC. And of course, you have to have positive PET scans for the PSMA in order to be able to see and treat the disease. So, this particular trial comes into the hormone-sensitive space. So, it’s a hormone-sensitive metastatic prostate cancer space. So many of these patients will have just started their therapy. Very different than the PSMAfore trial or the VISION trial previously presented. Now, here’s the basic design. You know, we have these eligible patients, they have metastatic hormone-sensitive prostate cancer. And the very fine print at the bottom, they should have started their hormonal therapy less than 45 days ago. And that’s a little bit tough. You know, you’re running an academic trial, people get diagnosed with metastatic prostate cancer, they get a shot of leuprolide, and before you know it, you know, they’re 60 days before they get into your clinic and get evaluated. So, a lot of these patients had already been started on the ADT. Now, we had a very simple cutoff in terms of those who are eligible. You just have to have a PSMA PET positive metastatic disease. If you look at the PSMA PET positive disease, it begins to go away when you’re giving the androgen deprivation, particularly when you’re adding an ARPi. And we don’t have a great feel for the kinetics of that. So, we just sort of tried to catch it and say, okay, you got PSMA PET positive disease, and then we’ll move ahead from there. We have some stratification factors like disease volume that’s per CHAARTED, age, prior treatment of the tumor. Most of these patients are going to be de novo and high volume. Randomization, ADT and ARPi, ARPi of choice, so that could have been an abiraterone, darolutamide, apalutamide, enzalutamide. And that was in the control group and also in the experimental group, then you would be able to get the lutetium. And it was a 7.4 GBq Q6 weeks, up to a total of six doses. rPFS is primary, and then upon meeting rPFS with a blind independent central review, you could cross over and receive the lutetium if you were in the control arm. So, we’re going to have confounded overall survival because of the inevitable crossover effects that occurs for people in the control arm who progress after the hormones alone. If we look at the endpoints in the plans, we see the primary endpoint is the rPFS, key secondary is OS. A variety of other secondary endpoints kind of move down. What will be presenting here is the second interim rPFS. If we look at the information fraction, please remember that it’s an artificial number generated from the statistical analysis plan. It turns out that about 25 percent of the patients in the control arm will have reached an rPFS endpoint. It’s a relatively immature drop. There’s also a first interim OS that I’ll be presenting here as well. Data cutoff was in January. Medium study follow up was 23.6 months. There’s obviously going to be a final rPFS and a final OS to follow. So, what you’re seeing here. It’s not a final result; it’s the first result. And I want you to keep that in mind because it turns out that if you think this is final, I’ll tell you it’s not good enough. If you think it’s the beginning, I’ll tell you we’re off to a good start. So, here’s the actual disposition. Screening 1,529 patients having a gallium PSMA PET and 1,420. 1,232 were positive on the PSMA PET. That works out to be about 87%. Interestingly, same number that we had for VISION. So, the vast majority were PSMA PET positive metastatic disease. And then they’re going to be randomized either to ADT ARPi and lutetium or the ADT ARPi alone. And then they were going to be treated, and then you can have radiographic progression. And here, if you look carefully, down in, I don’t know if my pointer is very good, but I’m not going to worry about it. The radiographic progression was 26.6% in the ADT ARPi arm and 19.6%. So, it’s a relatively immature look. Median duration of exposure was right around 20 months. Crossover was 91 patients, and of course that’s going to be growing with time. They’re fairly well balanced at the baseline, there’s one little oddity here in my own mind. If you look at the site of disease and you go to visceral, it says 39 and 41%. I cannot figure that out. I think somebody just had a free form case report form, and who knows what they were writing in there, but that cannot be correct. Nobody has a 40% visceral metastases at this sort of stage of the disease. But anyway, it’s that’s messy, so let me just get over the mess. If we looked at the higher tumor volume, it’s 68% in each arm, and de novos about 50%. So, you know, overall, we’re talking about patients who I think the vast majority would believe need to be treated. rPFS by the blinded independent central review seen here, has the ratio 0.72, p-value 0.002, unequivocally positive. There are two ways to look at this. Oh gosh, I wish the hazard ratio would have been 0.55, you know, that would have been more like my dream. Or, oh goodness, thank goodness it wasn’t in the .8 range, because now 0.72 is pretty respectable. So, this is an ADT ARPi control arm. And it’s a little bit hard to imagine something that you’ve done across 90% of the patients, 87% of the patients, where you have this result. You cannot find it. Yes, you can look at some of the PARP inhibitor studies, you can look at the capivasertib studies for the PTEN deleted, but this is a broad swath of prostate cancer. And I think overall, my conclusion is we’re off to a good start. rPFS benefit was basically consistent across the subgroups in the forest plot. I thought there was a little bit of an anomaly down on the PSA. If you go to the baseline PSA, which is second from the bottom, if you are greater than median, then the hazard ratio came in at about 0.6, which is, you know, pretty good. That’s like that 0.55 that we’re really hoping to have. But if you came in where the PSA was less than medium, then that hazard ratio is 0.85, which is not what we would have hoped to have found. So, you know, I think we just need to look at more maturation. But it could be that these patients who are responding really well to the ADT in the beginning and already have a really low PSA at baseline, then maybe those are the ones that need a little less in the way of intensification. Maybe the ones that need intensification are the ones that have a higher disease volume and a higher baseline PSA when they’re coming in. We have so much more analytics to do here. Don’t take anything too seriously, please. The interim OS, I was actually surprised at 0.84 in a favorable way. Obviously, the confidence intervals overlap one. That was okay. And if you got crossover, you’ve got this 0.84, which is a little bit different than the PSMAfore study, which is going the wrong way initially. So, I’m pretty happy with 0.84. It’s a good start. It may not be a good finish, but it’s a good start. There are going to be more patients who are going to be meeting overall survival endpoint. More patients are going to be crossing over that’ll make it confounded. We’ll just have to see. The FDA was reasonably impressed. And they said start your submission. They didn’t say finish your submission. They said start your submission. So that is pretty nice news from the FDA. Variety of other secondary endpoints, you’ve got an objective response rate and it’s high in both arms. You’ve got time to PSA progression, not reached in either arms, but the haz ratio is 0.42 for time to PSA progression. I thought that was pretty good. PSA nadir, less than 0.2 is pretty well determined prognostic marker. Thank you, Maha Hussein, wherever Maha, yes. And she did that first. And we’re seeing 87% versus 74.9. At a little bit of an odd time, though, it’s 48 weeks. We need to be able to look at some other times. But I think that’s favorable. Time to symptomatic skeletal events, very few events. I didn’t pay much attention. Time to metastatic CRPC has a ratio of 0.7. I think that’s favorable. And PFS per investigator, actually, the haz ratio is 0.64. So that looked pretty good. You know, this is trending in the right direction, no matter what you say, it’s trending in the right direction. Adverse events, you know, there are lots of ways to look at adverse events. If you look at the SAEs, they’re maybe a tiny bit higher in the lutetium arm. But if you go down to the bottom and you look at discontinuations, it’s 8% versus 5%. Dose reductions 3.9% in the lutetium arm versus 2.3%. Dose delays 12 versus 4.8. It’s a very well tolerated therapy as a whole. Yes, they’re gonna have some adverse events. We’re gonna see that here. Here’s some of the adverse events. You can see dry mouth, you’re gonna see some nausea, you can see some constipation, decreased appetite, a little bit of vomiting, diarrhea, dysgeusia. There is a real GI side effect profile to something secreted in the gut. It’s not perfect, but it’s not imperfect either. It’s a lot better than chemotherapy intensification, I promise. AEs group by safety topics of interest will be the cytopenias. We’re running grade 3-4 in about 14% versus 5% with ADT plus ARPis. Neutropenia is 3.7 versus 0.9, thrombocytopenia is 1.8 versus 0.5, that’s a grade greater than 3. So truthfully, it worked out pretty good. Renal events 1.6%, 0.9%. You know, this is so far so good. Do we need longer follow-up? Absolutely. Is the FDA going to require longer follow-up? Absolutely. Does anybody want to not see longer-term follow-up? Everybody wants to see longer-term follow-up. Time to worsening a patient reported health-related quality of life, BPI short-form pain intensity, and this is time to worsening, no difference. Maybe a little disappointed in that, so it is what it is. And then the FACT-P total score, the has ratio of 1.14, confidence intervals do overlap one, numerically kind of going the wrong way. But you know, I think I want to see a little more maturity, a little more follow-up. You know, please remember that only about 26% of the patients in the control arm have actually progressed. This could continue to change over time, particularly if you have better disease control. So, conclusions. Combining the lutetium with ADT and ARPi, led to a statistically significant improvement in rPFS with PSMA PET positive, hormone-sensitive prostate cancer as compared to ADT and an ARPi. That’s a fact. I think there’s a positive trend in OS with the 0.84 that actually exceeded my initial expectation. That’s a fact as we start out. It’s also a fact that we have a relatively immature degree of follow-up. And we are going to need to have more follow-up. And that’s not only for the rPFS, but it’s also going to be for the OS and also be for the AEs. You know, we’re treating people with radiation. It could be that the radiation could come back and bite you. We don’t know. We have to follow the patient. I’ll say that the safety findings were consistent with the known profile of the PSMA lutetium. I didn’t really have any unexpected concerns. It was going pretty well as a whole. Yes, the AEs were a little more frequent, and yes, there were no clinically significant differences in the health-related quality of life and pain. Let’s follow up a little bit more and get a better findings. I think this is potentially clinically meaningful. I want to see more follow-up. I want to see more of an impact, but I’ll simply say that we’re off to a good start. We’re not at a good finish. I wanted to thank all the patients and their families, the investigators. This study started as an Alliance and NRG trial. It started with Scott Tagawa on the Alliance side and myself on the NRG trial and trying to put things together. We had Felix Feng. We had Mike Morris all involved. We also want to thank the Peace Consortium for helping to push forth the concept of getting lutetium tested. We’ve already mentioned Felix Feng several times today, but Felix was the head of the GU committee on the NRG side. He was kind of my report to boss, and he was immensely helpful to be able to pull this off and move it forward. As it turned out, we moved it all the way through the NCI, and then NCI said, or excuse me, Novartis said, oh, we like that trial. I think we’ll take it. So, it became a Novartis-sponsored trial. But thank you very much. Thank you for the opportunity to present today. Happy to take questions. We’re not going to do questions now. We’re going to do questions now? Or whatever you want.
Howard Soule, PhD [00:14:59] Questions now.
Oliver Sartor, MD [00:14:59] Questions now. Anybody have a question? I think Michael Hofman is first to the mic.
Michael Hofman, MBBS [00:15:12] Between it being a cooperative group trial and a Novartis-sponsored trial, what elements of the trial design changed the most?
Oliver Sartor, MD [00:15:20] You know, really not much at all, Michael, because we put it together, we designed it as this sort of six treatment. What it really beefed down to was the ability to monitor it more appropriately. The cooperative group just doesn’t have the resources to do the monitoring, but the truth is Novartis did. So, the trial design really didn’t change very much. We took the face page off the cooperative group and just put it front and center on Novartis. James?
Nick James, MBBS, PhD [00:15:45] Hi, Nick James from London. Very interesting data and nice presentation. There was one thing I was really I was at ESMO when it was presented, and I’ve got the slides, so I’ve had a good chance to go through them. There was one thing I was really puzzled by, which is that the time to progression, the primary endpoint, comes out as well over three years, probably. It’s hard to know because you haven’t reached the medians. Whereas the BPI and the pain and the FACT-P both have a median times progression in under a year. Which just seems really curious. Why are they deteriorating if they haven’t relapsed? I haven’t had a chance to…
Oliver Sartor, MD [00:16:24] No, that was mysterious to me. I think we have to go back and analyze more. You know, it’s still pretty fresh, but Nick, thank you for pointing that out. It’s a fact and I don’t know why.
Nick James, MBBS, PhD [00:16:33] Okay, thanks.
Oliver Sartor, MD [00:16:35] Dan?
Daniel Spratt, MD [00:16:37] Sure. Fantastic, Oliver. So, you know, you had made two comments in there. I’m wondering if it’s more congruent than we think. So right there are huge percent of visceral mets, which is unexpected.
Oliver Sartor, MD [00:16:47] Yeah. But not really, it’s fake news, no problem.
Daniel Spratt, MD [00:16:50] So we say it’s fake.
Oliver Sartor, MD [00:16:51] It’s fake.
Daniel Spratt, MD [00:16:52] But it’s still on that slide. And so, the question is, as you know and we’ve talked about this, that you know, when you start ADT for, you know, two weeks, three weeks, four weeks, up to 45 days and you get that PET. These are different patients, because most patients that are hormone-sensitive, the PET largely resolves. Are we selecting in this population? Like, is that the reason potentially why you have such a high, if it’s real, percent visceral mets, in that these are not truly de novo PET positive. These are patients that are PET positive after up to 45 days of being on ADT or RPU, which shows there’s already potentially some sign of resistance. It’s a slightly different population.
Oliver Sartor, MD [00:17:36] It’s a great question. When we get back to Novartis, I’ll tell ’em to look it up and tell us. But it is a mysterious item. We talked about it in Ed board in Berlin extensively, and no one could understand it. And the problem was that it wasn’t clarified at an individual checkpoint. It was like an open box, you know, right in the location you’re just seeing. I don’t know if people were writing in like lymph nodes and that was visceral. It’s something really weird. Because I just can’t believe that particular result. Again, I think it’s fake. Yeah.
Alexandra Sokolova, MD [00:18:05] Alexandra, Portland, Oregon. I would love to take your take on the PR.21 data that presented at ESMO, which sequenced docetaxel Pluvicto versus Pluvicto docetaxel, and the show that docetaxel followed by Pluvicto had longer second rPFS, better outcomes. How does it fit in with PSMA addition and kind of this paradigm?
Oliver Sartor, MD [00:18:25] Yeah, great question. And you know, I’ve been scratching my head on that. There are a couple of things. This is hormone-sensitive, that was castrate-resistant. I think that those patients differed in a very meaningful way from the PSMAfore population. PSMAfore had a median population, which is the post-ADT ARPi pre-chemo setting. That PSMAfore had a 24-month median survival. Here we’re talking about 15, 16 months. These patients looked like VISION patients, post-ADT, ARPi, one taxane, maybe two taxanes. It was incongruent. Now I talked to some smart people, and good news is there’s lots of smart people out there. But these are probably a higher disease burden, probably higher ctDNA fraction, probably a significant amount of visceral disease, and there was a significant amount of visceral disease. I haven’t broken it out. I have the slides from Kim Chi, and I haven’t been able to drill down just, you know, just back from Berlin. It’s a great observation. We need to learn more.
Unknown [00:19:23] Thanks, I have a comment and a question. First comment was just around the visceral. Just thought but could it perhaps be that patients who had uptake in the prostate they just ticked visceral and that might inflate it? Anyway. But do you have any information about the baseline characteristics for PSMA PET, like SUVmax, the volume?
Oliver Sartor, MD [00:19:41] Not yet, not yet. Yeah, still very preliminary. No, obviously we’re gonna drill down, we’re gonna look at the distribution of lesions, the SUVmean, the number of lesions, distribution, you know, liver, et cetera, et cetera. So right now, the analytics are very minimal. This is raw, raw, raw.
[00:19:56] Yeah. And there’s no Max either?
Oliver Sartor, MD [00:19:58] No Max.
Unknown [00:19:59] Yep, all right.
Oliver Sartor, MD [00:20:00] No max, no mean, no location, no number. I’m gonna go out and have some coffee.
Unknown [00:20:06] Was what was the threshold for it to be positive? Was it liver based? You know, PSMA positive, was it liver based as well?
Oliver Sartor, MD [00:20:13] It had to be better than liver, at least one metastatic lesion. That was the requirement. Okay. So, it’s similar to the VISION trial. You had to have at least one with an uptake or the liver. Yeah, and I’m sorry I’m a little bit apologetic, but you know, let’s be realistic. This is a big trial and there are a lot of analysis. We’re still analyzing VISION trial, you know, SUVmean, being able to look at the ctDNA, look at the fractions, look at the disappearance of fraction here and there. There’s so much more to learn. We’re gonna learn a lot more.
[00:20:38] Thanks.
Oliver Sartor, MD [00:20:39] Thank you. And with that, I think I’m done.
Howard Soule, PhD [00:20:42] Thank you, Dr. Sartor. Our next speaker is Dan George from Duke University, who will talk about the phase three CAPItello study. Thank you, Dan.
Daniel George, MD [00:21:02] Thanks, Howard. Thanks, Andrea. And thanks for the organizers for giving us the chance to present this data, hot off the ESMO press as well, like PSMA addition. And it’s really my honor to present on behalf of Karim Fizazi, our lead author here, and our steering committee. These are my declaration of interests. I have a lot of other interests, but these are the ones I have to disclose. So PTEN deficiency in prostate cancer. This is this has been well established for 30 years now. We know that when P10 is proficient, that these tumors are profoundly dependent on androgen receptor signaling. And it’s the canonical way that we’ve treated prostate cancer for the past 80 years. But when we lose PTEN, when this when this is deficient, it creates an alternative proliferative drive for these tumors. And it’s really complementary to the AR pathway. So, in these tumors, when we block AR and Androgen signaling, this this PI3 kinase AKT pathway kind of kicks in, it’s unregulated and can lead to early disease progression. And so, the idea of targeting this is associated with a poor prognosis. This idea of targeting this with AKT inhibitors has been established as an earlier drug, capivasertib that was studied in the metastatic castration-resistance setting in all comers, and we’ll talk about that a little bit later. But this drug, capivasertib- I’m going to call it Capi. Is a potent selective inhibitor for all three AKT isoforms and was specifically developed for this setting, this what we’re now terming, and I’ll be the first to say it, androgen receptor modulation-sensitive metastatic prostate cancer. Thank you very much. Okay. So, this was the CAPItello-281 study design. This was really a Herculean effort. PTEN is not the most common defect associated with prostate cancer early on. It gains in its frequency as this disease progresses. So, to look at this, we were specifically looking by immunohistochemistry at tissues for 90 percent or greater loss of PTEN. So specifically focusing on the population we thought was most likely to be driven by this AKT pathway. And to do this, we screened over 6,000 patients, submitting tumor tissue and centrally reviewed for PTEN status. We found about 25 percent met this criteria for PTEN deficiency. Of those, about a thousand were actually enrolled in the study and randomized one to one to either Capi given 400 milligrams, BID, four days on, three days off, so built in breaks, along with abiraterone and ADT standard dosing, versus placebo plus ADT in standard dosing. And these patients were followed for disease progression. Investigator assessed rPFS was the primary endpoint. We also looked at overall survival and a number of secondary endpoints shown here. Took three and a half years to accrue this study, 6,000 patients. It started, unfortunately, right after the pandemic, July of 2020. But we got it done. This was a massive effort by all investigators around the globe. Our primary rPFS data cutoff was we had a press release about a year ago, and we have about 18 months on follow-up, and we have a final OS that’s planned after 522 deaths. So, these are the baseline characteristics, and they’re basically similar across the board. A couple of things I’ll point out here that I think are important. One, we had a lot of bone mets. We had over 90 percent of patients had bone metastasis. We had about 20 percent visceral disease, and we had a very high rate of gleason-8 or above. It was almost 80 percent of patients with Gleason eight, nine, or ten cancer. So, a pretty high-risk and high, not as much high volume, but certainly high-risk disease. This was the primary endpoint. This was the rPFS, investigator assessed, and a couple of things to point out here. First, this is a positive endpoint. We hit our benchmark, our hazard ratio of 0.81, our p-value of 0.03. Statistically significant improvement in the rPFS. You can see our median improvement in rPFS of about seven and a half months. But look at our control arm. Our control arm of abiraterone and ADT, 25.7 months. You just heard, you know, somewhere, I think they mentioned around 36 to maybe even 40 months, you know, median rPFS in some of these other studies. So, we are seeing a decidedly different and much worse prognosis associated with our standard of care, ARPi and ADT therapy in this PTEN selected population. If you look at our subgroup analysis in general, everything kind of favors the Capi arm, some more or less, but basically, we’re seeing kind of across the board a consistency across all subgroups. And we had a number of key secondary endpoints. Overall survival was our first key secondary endpoint, and that has not been reached yet. It has only been 26 percent events. Remember, we only have 18 months follow-up at this point in time, but we already have 26 percent deaths in this study. There is a slight hazard ratio you know, favoring Capi, but it’s very early. This is not statistically significant. And because of that, in the hierarchical statistical methodology here, we stopped there. But we just from an exploratory standpoint looked at a number of other kinds of key secondary points shown here. And again, they generally are in favor of the Capi arm. We’re going to highlight just a few of these on their individual Kaplan-Meyer curves. I think there’s a lesson to be learned here. This is the first one. This is the interim overall survival. And it’s, as I said, it’s immature, we need longer follow-up. There’s no doubt about it. And we’ll get that. That’s planned to do. We’ve got, you know, a number of events to get to. But already we’re seeing, you know, in our control arm 138 deaths. This is symptomatic skeletal event survival. Now this includes deaths as well as our symptomatic skeletal events, our pathologic fractures, cord compressions, surgery radiation, these are life-altering events. These are highly symptomatic life-altering events. And we’re seeing with that and with these early deaths a little bit more separation than we did with just OS alone. And so, you can see the hazard ratio here kind of drops down to 0.82. Again, exploratory early but we’re seeing a little bit greater trend. I’ll point out here in our placebo arm we have 176 events at this point in time. Now we turn to time to castration resistance. So, castration resistance includes radiographic progression-free survival, so the patients that have radiographic progression, as well as PSA progression. So now we see this curve is getting even a little bit wider and a little bit earlier. Our median time to castration resistance and our again our control arms 22 months See a seven-and-a-half-month difference, again, similar to our rPFS population. And if you look again under placebo Abi in that upper right, now we got 230 events. You know, that’s almost half the patients here that we’re seeing this this time to castrate resistance. So, this is happening much earlier than what we’re seeing in some of our other study populations. Now, this is where it really caught my eye, and that is the time to PSA progression, because it doesn’t look that bad. Here we see the time to PSA progression. Again, there’s a separation here. It’s again, it’s exploratory, but Capi’s on top. But I think the bigger point here is look at our placebo plus Abi arm. There’s 82 events. I just showed you there are 231 castration-resistant events, but only 82 of them have PSA progression. The majority of patients are developing castration resistance without PSA progression. We don’t typically see that, and it’s a real concern. This is really the first time we have looked prospectively at loss of PTEN in a large population like this, and it’s telling us something about this biology. It’s different. And it’s concerning because disease progression without PSA is maybe a precursor for developing more neuroendocrine type phenotypes, androgen-indifferent disease, disease that our drugs don’t work as well in. So, this is a population that is really an unmet need. We don’t have effective therapies. Abiraterone, ADT is not cutting it in this population. Here’s the other interesting finding. So, along the way, as the study was going along, that again, that IPATtential study, the other AKT inhibitor I mentioned, being developed in metastatic androgen receptor modulating resistant disease was being done and they looked at, they looked at all comers, patients, you know, just with metastatic disease, but they also broke it down by PTEN status. And when they did, and they saw patients that had greater than 50 percent loss of PTEN, they started to see a more statistically significant rPFS benefit to the drug. And you get down to 90 or 100 percent, you start to see even greater differences, even greater benefit associated with the drug. So, we looked at our CAPItello subgroups. And we this this is a post hoc analysis. So, again, hypothesis generating. But again, this was our original analysis right here, looking at greater than 90 percent cutoff. Now, what I’m gonna show you are the CAPItello alone, the Capi alone arms. So, this is actually four curves here. The dark one is the original all population here that was treated with Capi, that arm. But then there’s the 95 percent cutoff, the 99 percent cutoff, and the 100 percent loss of PTEN cutoff. And they’re pretty much superimposable. Those are all in light blue, and you really almost can’t distinguish them. So now back to that 90 percent cutoff here. This is the Capi arm and the placebo arm. And now I’m going to show you what happens when we look at 95 percent cutoff with the control arm. And you see it drop down a little bit. And you can see over here our hazard ratio drops down a little bit. You look at 90, 99 percent cutoff, it drops down even more. And you look at the 100 percent cutoff, and it drops down even further. So, we’re again we’re seeing a story here that the greater the complete loss of PTEN, the more dependency that tumor has on it, the earlier disease progression that we’re seeing. And it really fits with this dual pathway for disease proliferation and growth. If you look at overall survival, we see the same trend. I’m not gonna walk you through all four of them. Let me just show you. This is the 90 percent, and this is the 100 percent. And you can see in light there, there’s you can see the gradations there, but it’s pretty fine. Again, this is still immature data, right? But again, now we’re starting to see hazard ratio down there at 100 percent .77. We’re seeing you know, things shifting over, and again, it’s primarily due to the early deaths, the early progression in our control arm. So that’s this population. If you look at our other key secondary endpoints, they all kind of follow the same way. I mean, the numbers get smaller. We don’t lose much going to 95 percent. That’s 80 percent of our population. But then the numbers really drop as we go down to 99 and 100 percent. But the trends are still there. And then lastly, I just want to mention the safety data here, because I think this is a concern for folks. This drug is already FDA proved and widely used in breast cancer with hormonal therapy. But prostate cancer, you know, this is a new agent for us. It is associated with known side effect profiles. I’ll show you those in a minute. But if you look here overall at our you know our grade three toxicities, you know, placebo and abiraterone was 40 percent, this was 67 percent. So, we’re taking a jump up in our grade 3 toxicities, about 27 percent, about a quarter of patients developing some grade 3 toxicities. But if you look about halfway down here, you’ll see discontinuation of the Capi slash placebo 18.3 percent versus 4.8 percent. It’s not that huge. Most of the patients are able to tolerate this drug and tolerate it for a long period of time. If you look at dose reductions, that’s more. So, as you go down dose and eruptions, I think are 62 percent, and then dose reductions are 29 percent. So again, 70 percent of patients are able to tolerate the dose, full dose, but about 30 percent are dropping the dose. So, what’s causing that? Okay, these are our again, volcano plots here, and you can see things shifted over in favor of Capi in terms of toxicity, it’s really the top five. The top three diarrhea, hyperglycemia, and rash, these are known toxicities associated with it. They happen early. They happen within the first couple of months. And remember, this is a four-day on, three-day off. So, the diarrhea tends to get better over those three days on, and it’s off again. So, it’s not as kind of constantly chronic for patients, but we do sometimes have to hold the dose, sometimes have to stop. Rash is probably the one we stop the most for. Again, it’s not huge amounts of grade three rash here. You can see it’s about 10 percent grade 3 rash. So, it’s mostly grade 1, 2, but it is something to know about, it’s manageable in the vast majority of these patients. And then you can see the hyperglycemia in there as well. Again, can you manage hyperglycemia? Yeah, we have drugs for that. Can we manage non-PSA producing disease progression in this population? Not so easily. So, these are the trade-offs, they’re known, but I think for a lot of our patients, they are manageable. Anemia, hypokalemia, these are probably exacerbations. The anemia, something I think, again, we know how to manage, it’s mostly low grade. The hypokalemia is really kind of an exacerbation of that abiraterone, probably from the diarrhea, and again, sort of, you know, mostly low grade. And then there’s the rest of them here. So, I think in conclusions for this study, we would say that PTEN deficient, metastatic, androgen receptor modulation-sensitive disease has a poor prognosis. And I would say that not only that, but PTEN is a driver, AKT is a driver of disease progression in patients with loss of PTEN. And I think that’s an important new finding that is established with this large prospective study. The study met its primary endpoint. It’s statistically significant rPFS benefit with Capi plus abiraterone, median improvement in the rPFS from 25.7 months to 33.2 months. And the hazard ratio and confidence intervals are shown there. These events, this is really consistent across the secondary endpoints. They are exploratory, but they’re trending all in the same way, including the clinically relevant predefined subgroups. The post hoc analysis is interesting. It really shows the greater and greater dependency on loss of PTEN when we see greater levels of this. And this is something that is easily quantifiable in our pathology. Immunohistochemistry for PTEN has been well established. It’s routinely done in breast cancer now. It could be routinely done in prostate cancer. I would venture to say it should be routinely done in prostate cancer, knowing the clinical significance it carries. And I think the most common grade 3 AEs of rash, hyperglycemia, diarrhea, these are known, expected, manageable. Yes, we do have to stop drug in some patients. That is absolutely true. But I think the majority of patients they can get through with this drug. So, I think this combination, I think it represents really a potential first in class targeted treatment for patients with a defined PTEN deficient Metastatic disease. It’s really our only opportunity to use this agent if it’s approved in this setting. I think it’s an important unmet need, and even if these results are modest in your mind, they’re positive for a patient population that we ultimately really need more drugs for. I’d just like to acknowledge individually each one. No, I’m not going to go through this, but there’s a number of investigators all over the globe doing this. It really was a global study. You can see that in light blue, the number of countries represented here. Over 6,000 participants, incredible effort. Thank you, thank you, to the families, the patients, the caregivers, you know, our whole staff and everything, our steering committee that that made this happen. Lastly, this has been published now. It’s available in Annals of Oncology. There’s a QR code you can scan here for that. We have the supplementary data, plain language summary, and an animal video if you want to see it. No, it’s an animated video, sorry, associated with this that you can download with this QR code. Thank you all very much. Okay, I think you are up first. Yes.
Cornelia Ding, MD, PhD [00:38:33] Hi, I’m Cornelia Ding, UCSF pathology. Just from a pathology’s working perspective, I wonder if you could comment on, for example, like if my clinician asks me to do a PTEN for this apply for this medication, but the patient doesn’t have a metastasis biopsy, should we recommend our clinician get the metastasis focused to do the PTEN or do you think the primary prostate staining will be good enough?
Daniel George, MD [00:39:00] Yes, it’s a great question. I think we can these were vastly done off of the primary biopsy, so you can absolutely use the primary biopsy from that assessment. And I think it is relevant even in our high risk localized disease, it has prognostic significance. So, I think you can justify it in a lot of situations like that.
Cornelia Ding, MD, PhD [00:39:17] And should I comment on the percentage of a cell staining PTEN moving forward? So, if there’s some significance for treatment. Also comparing to other ways like NGS and FISH, is there any benefit, pros and cons between these methods for PTEN status?
Daniel George, MD [00:39:36] Great question. So, yes, I think it you know, any more information you can give us around the percentage of loss of PTEN, I think may be helpful. Again, these are exploratory analyzes, but we’ve now got two separate studies showing that trend. So, I think it would be particularly helpful. In terms of NGS, I think there is concordance with NGS and high loss of PTEN. So, we’re going to be looking at that in this study as well, going and sequencing. It’s just going to take some time. But I you know I think you know immunohistochemistry is really our gold standard because there are other ways of knocking out PTEN besides just genetic loss. So, I think and the scalability of this across pathology is a lot easier. So at least at this point in time, I think immunohistochemistry is probably the easiest way to adapt it.
Cornelia Ding, MD, PhD [00:40:23] Thank you.
Daniel George, MD [00:40:24] Sure.
Unknown [00:40:27] Great talk, Dan. Really nice job. I think that in the back of everyone’s mind while we’re listening to both Oliver’s presentation and yours is you know chemotherapy. That’s the unspoken control arm, really, that’s included in none of these trials. But I guess I would propose to, given the Tox profile, let’s say I’m a PTEN deficient PSMA avid patient. Which therapy would you give me recognizing that everything is preliminary, we don’t have OS.
Daniel George, MD [00:41:00] Yeah, yeah. So, you know, I think this is a great question because I think this is the limitations of these phase three studies, right? And to me, this is where, you know, this is why we have medical affairs, right? To do the studies beyond FDA approval to understand, do you combine those agents? Because we have a study of docetaxel and Capi and castrate resistant disease, combining docetaxel and Capi. It was a negative study, but the safety is there. So, you can combine those. But it, but should you? That’s an unanswered question. Should you sequence them? Should you do six cycles of chemotherapy and then add it? Should you do three doses of Pluvicto and then switch? There’s a lot of different ways to address this. And I think to me it’s both and. Yeah, how you do that I’m not sure. But at the end of the day, this is a bad disease. When I see this, I know this is an accelerated natural history. This is a patient that’s going to run into complications sooner. I don’t think I can look and say you’re going to go ten years, no problem. You know, I don’t want to congratulate him on the low PSA response, I don’t feel safe with that. So, these are the kind of patients that if they can, I’m going to want to try to intensify however you want to do that, you know, and we’ll we just need to do the studies to figure out the best way.
Unknown [00:42:21] Thanks, Dan. Congrats.
Daniel George, MD [00:42:23] Yeah. Yes.
Unknown [00:42:25] Very interesting talk. I have two questions but hopefully they’re both quick. So first of all, so in the patients that were PTEN null, or PTEN deficient in the primary tumors, does PTEN get reactivated in the mets? And also, what’s the status of AKT activation in both?
Daniel George, MD [00:42:45] Great questions. And you know, I think those are the limitations of what we have for data on. We did not include patients that had AKT mutations and activation. But one could argue that biology should apply here just as well. So, I mean I think it’s less common. PTEN is the most common way that this pathway is altered, but there are PI3 kinase alterations, AKT alterations. To me, that’s an extrapolation, but we do that in clinical medicine all the time. And I think those would be reasonable. In terms of like reactivation, you know, of the pathway in in metastasis and stuff, that’s probably a good thing in the sense that maybe those are a little less aggressive, but I wouldn’t count on it. So, to me, if I see this loss in the primary, I’m going to stick with that until proven otherwise.
Unknown [00:43:29] And then one other question is, and you’re probably gonna say no not yet, but do you have any molecular insights as to the patients who are responding and not responding?
Daniel George, MD [00:43:37] It’s a great question, ’cause we know there’s more to loss than just PTEN, right? And what other features could be there? So, I think with this, you know, next gen sequencing data that we’ll get on these samples, we’ll have a lot more insights. So, you’re absolutely right, not yet.
Unknown [00:43:54] Dan?
Daniel George, MD [00:43:55] Yes? Oh.
Cora Sternberg, MD [00:43:56] Great talk, yeah. Great, great, great talk. I participated in the ipatasertib trial where we used PTEN as a cutoff immunohistochemistry of fifty percent and it wasn’t a negative trial. One patient did die due to hyperglycemia. And then when we went back again and looked at NGS, those patients that had PTEN loss by NGS, which was more though all of those patients actually were the ones who benefited. So, I’m just wondering now that we know how serious this is, shouldn’t we be recommending that PTEN be monitored and reported either by immunohistochemistry or by NGS in all patients with metastatic hormone-sensitive prostate cancer?
Daniel George, MD [00:44:37] Absolutely. In fact, our chair of pathology, Jiaoti Huang, is here and I’m going to grab him and say, look, this we’re going to start this on Monday. Because I think we need to know this, right? It’s going to change how I counsel that patient, how often I scan them when their PSA is undetectable, what I’m looking for, and even, you know, when available, what we can intensify with. So, you’re absolutely right. I mean I think this is we’re not going to get more evidence than this. This is about as good as you can get for saying this is an important driver of disease progression.
Cora Sternberg, MD [00:45:08] Did you mention anything about high volume and low volume by the old CHAARTED criteria? Do they have more high volume or I’m not sure that…
Daniel George, MD [00:45:14] You know, it it’s interesting. So, this study, and to Mike’s point earlier, I mean, we had, you know, as this trial evolved, we had the PEACE-1 and the ARASENS data come out. So, we lost a little bit of equipoise in our high-volume patients to say we can put them on, you know, abiraterone, ADT, that’s enough. Some of those patients we preferred to do chemotherapy with. So, we probably preferentially didn’t, you know, select it out some high-volume patients. So, it was like 60/40. But I suspect, you know, that’s probably a sign of the times than the real biology.
Cora Sternberg, MD [00:45:50] Thank you.
Daniel George, MD [00:45:50] Yeah.
Howard Soule, PhD [00:45:51] Thank you, Dan. We have to move on.
Daniel George, MD [00:45:52] Okay. All right. Thanks. Sorry guys. I’m in the back if you need me.
Howard Soule, PhD [00:46:02] Our next speaker is Paul Peter Tak from Candel Therapeutics to inform us about a very interesting new local therapy for prostate cancer.
Paul Peter Tak, MD, PhD, FMedSci [00:46:14] Thank you very much. Good afternoon, ladies and gentlemen. I want to first thank Howard and Andrea for inviting me to speak today and to present the data of our phase three clinical trial of CAN-2409 in newly diagnosed localized prostate cancer. So, what is CAN-2409? This is a first in class viral immunotherapy. It’s not an oncolytic virus, but it is designed to induce highly immunogenic cell death at the site of injection while also promoting inflammation. In other words, the idea is to create the optimal conditions to vaccinate or immunize the patient against the whole variety of cancer antigens that are released in the tumor microenvironment after CAN-2409 administration. And the unusual thing is that we have huge experience over many years. More than 1,000 patients have been dosed across multiple indications. Prostate cancer is clearly the largest in terms of patients who have been dosed, but we have proof of concept in borderline resectable pancreatic cancer that we see clear separation of the overall survival curves. We have very encouraging data in therapy resistant, metastatic, progressive, non-small cell lung cancer, and I’m going to present you today the data in newly diagnosed prostate cancer. We got fast track designation for each of these indications. The clinical trial that I’m going to present is conducted under a SPA special protocol assessment agreed with the FDA. That basically means there’s alignment, agreement with the FDA about the design of the clinical trial, including the primary endpoint, which is disease-free survival. After the data readout last December, we went with the data in hand to the new FDA, as I call them, and we got the RMAT designation. That’s basically a breakthrough designation for gene therapy. I asked actually ChatGPT how many investigational medicines are there where an RMAT designation was given after the data readout of the pivotal trial, and there was only one example, which is CAN-2409. So, we were extremely happy, gives us all kinds of benefits in our interactions. So how does it work? CAN-2409 is a replication defective adenovirus that’s used to deliver the HSV thymidine kinase gene to the site of the injection. So that leads to local enzyme expression. Then we give the patient a pro drug, which is valacyclovir, which is a tablet for two weeks. It has been approved in the past for the treatment of HSV infection. It is now generic. And under the influence of locally expressed HSV thymidine kinase expression, valacyclovir will be converted into nucleotide analogs, which leads to a highly immunogenic cell death. In cells that exhibit DNA damage or that are proliferating. And then the adenovirus will promote inflammation. That’s what adenoviruses do. The serotype 5 capsid proteins will induce increased expression of cytokines, chemokines, adhesion molecules, what have you. In other words, you create the optimal conditions to recruit the whole cell infiltrate while you release the whole variety of cancer antigens and cancer neo antigens that are specific for that patient’s tumor. That leads to activation of different arms of the anti-tumor immune response, but it appears that especially the CD8 positive cytotoxic tumor infiltrating lymphocytes are critical. We basically educate these T cells how to recognize the patient’s own tumor, and they will circulate throughout the body in the context of immune surveillance and will be able to recognize and kill also the unejected distant metastases, as we’ve shown in, for example, pancreatic cancer and also in metastatic non-small cell lung cancer. So, let’s now focus on prostate cancer. This is a mouse model of prostate cancer, where we implanted the prostate cancer tumor cells in the flank, that’s the orange circle that you see here. At the same time, we injected cancer cells intravenously, leading to the formation of lung metastasis. And then we only treated the flank tumor using radiotherapy. Or CAN-2409 treatment, always including the prodrug, or the combination, or control. And as you can see on the left side, as you would expect, you see local improvement after radiotherapy. We also see local improvement after CAN-2409 treatment. And when you look at the purple line, there seems to be a synergistic effect when you combine these compared to control. So very clear improvement of local tumors. We’ve shown this in numerous models. But on the right side, there’s another very interesting observation. There was also a decrease in the size and the number of the lung metastases, although we did not directly treat the lung metastasis. So, this supports the systemic anti-tumor immune response that we see after CAN-2409. Here I show you some other key experiments across different tumor models. On the left side, you can see that if you co treat the mice with an anti CD8 depleting antibody, so you wipe out the CD8 positive T cell population, then actually you abolish the effect of CAN-2409. So, this supports the notion that this is a key effector cell for this mechanism. And on the right side of the slide, you can see an adoptive transfer experiments that if you take the CD8 positive T cells from the blood from a mouse that has been treated in a tumor model with CAN-2409, and you inject it into another mouse in the absence of CAN-2409 with the same tumor model, then when you look at the orange bar on the right, you can see that these T cells have maintained the capability to recognize and kill the tumor cells, consistent with the notion that there’s a vaccination effect here. So, how about patients? Do we see an induction of CD8 positive T cell infiltration and activation at the site of the tumor? The answer is yes, across many solid tumors. We’ve shown this on the left for illustrative purposes. You see that after CAN-2409 injection into the prostate in the patient who has newly diagnosed prostate cancer, there’s massive cell necrosis associated with a significant increase in the number of CD8 positive T cells. We’ve shown the same in pancreatic cancer. As you know, the tumor microenvironment in pancreatic cancer is sometimes called an immunological desert. Very few immune cells after CAN-2409 treatment into a solid tumor in pancreatic cancer, we’ve seen massive CD8 positive T cell infiltration as shown here in the phase 1B trial. And more recently, we’ve shown in the phase 2A clinical trial that you even see the formation of lymphocyte aggregates that may resemble tertiary lymphoid structure. So, we fundamentally change the tumor microenvironment. And we have similar findings in lung cancer, that we do not only see this in the local tumor microenvironment, but also very clear systemic activation of the immune response. So, what is the clinical problem that we try to address in newly diagnosed prostate cancer? We focus on the patients who seek radical therapy and who choose radiotherapy. These patients want to live without any clinical evidence of prostate cancer. And as you know, there’s a chance of recurrence of about 30%. So, we try to increase the proportion of patients that will achieve their goal as they are treated with curative intent, thereby hoping to avoid or delay the need to give therapies like ADT and to delay or prevent the onset of metastases over time. So, what follows is the planned indication. We focus on newly diagnosed patients who have intermediate or high-risk prostate cancer. I should mention the only involved patients with a single high-risk factor in this clinical trial. And we combine this with standard of care radiotherapy. So how is CAN-2409 administered? So, we give in total three administrations in typical vaccination regimen. This is injected into the prostate which is a simple procedure in the hands of a urologist or a radiation oncologist. As you know extremely well. The whole procedure takes 15 to 20 minutes. And each administration consists of four injections in each of the four quadrants of the prostate, so we inject .5 mil in each of these, which leads to diffuse distribution of CAN-2409 throughout the prostate, as you can see on the right side of this slide. So, this is relatively simple. The procedure takes 15 to 20 minutes in the outpatient clinic, and the patient walks out of the office again. In most cases, local anesthesia is even not required. But we also asked the patients how do they actually think about this? So, in the last part of the phase three study, we sent out surveys to the patients and asked the question how did the study procedure that we inject CAN-2409 into the prostate compared to the diagnostic biopsy that you underwent previously. And as you can see, independent of the route of administration, patients indicate in most cases that it’s the same or better tolerated. It’s a less traumatic procedure than a biopsy. We use very thin needles, 20 to 22 gauge, and it’s only three times in the patient’s life. So, this is the design of the clinical trial. We enrolled 745 patients, everybody got standard of care radiotherapy, and we left it upon the discretion of the treating physician whether the patients would get short term ADT, defined as less than six months. We ended up with about 50% of the patients getting short-term ADT, and we stratified for this in the statistical analysis. So, everybody got standard of care, and then we randomized the patients two to one to receive either three administrations of CAN-2409 into the prostate or placebo with exactly the same procedure. Everybody got valacyclovir, primary endpoint, disease free survival. Which is defined as the absence of any evidence of persistent or recurrent cancer, including in a two-year biopsy, which is of course not part of standard of care. But this was agreed with the FDA as a sensitive way to detect potential recurrence or persistence of cancer at two years, which is done quite commonly in radiation oncology clinical trials. The baseline characteristics are comparable between the two groups. I will just say we had 85% of the patients in the intermediate risk prostate cancer group. Then we look at PSA levels, that’s in the order of six point seven, comparable as well, and Gleason score, most patients had the Gleason score of seven. We know already, because we’ve published this based on other clinical trials that CAN-2409 treatment is generally well tolerated. Many patients will get flu like symptoms that are typically mild, that typically last not longer than one or two days. And otherwise, when you look at serious adverse events, as you can see on the left side of the slide, there’s no increase after CAN-2409 administration compared to placebo. Gives us a lot of flexibility to combine this also with other standard forms of standard of care. This is the primary endpoint. Here we look at the improvement that we achieved in terms of disease-free survival with the hazard ratio of .7, so 30% improvement. And I should mention this is an event driven analysis. Where death due to any cause would be an event. Of course, after a median follow up of about 50 months, there are very few prostate cancer related deaths. So, most of the patients who die, die because of cardiovascular disease or an accident or other reasons. They would count as an event. That means we actually dilute the signal and still we found this statistically significant improvement. What follows is that the key secondary endpoint is prostate cancer specific disease-free survival. And you can see it looks even better. 30% improvement in prostate cancer specific DFS, then we compare CAN-2409 to placebo. We did an exploratory descriptive analysis of the different subgroups, and you can see that we see this beneficial effect of CAN-2409 independent of the use of short-term ADT, also independent of the fact whether the patient had intermediate favorable or unfavorable disease. And these data were presented by Ted DeWeese in an oral presentation at ASCO. And more recently we presented at ASTRO presentation by Glen Gejerman, that as you see on the right side of the slide, most patients received conventional EBRT in this trial. Some patients received moderate hyper fractionated EBRT. And this seems also to be independent of the specific type of EBRT. So maybe it looks even better for the hyper fractionated EBRT, but of course this is not designed for statistical significance. These data are also supported by others secondary endpoints. We found a statistically significant increase in the proportion of patients that achieved a nadir of less than 0.2 nanogram per mil comparing CAN-2409 to placebo. As I mentioned we did not expect an improvement in prostate cancer specific mortality. We had actually two deaths due to prostate cancer both at high-risk disease. One in the CAN-2409 group, one in the placebo group, and 50 patients died due to other causes. I mentioned that we took a two-year biopsy, and so here we look at the pathological complete response at two years, and you can see we achieved that in 80.4% of the patients in the CAN-2409 group, compared to 63.6% in the placebo group. Again, highly statistically significant. So, is this relevant, the two-year biopsy? Of course, this is not part of standard of care, but it is informative because we know based on extensive literature that there’s a highly significant relationship between seeing tumor cells in the biopsies at two years and subsequent biochemical failure, subsequent development of metastases, and after extended follow-up, also prostate cancer related death. So, in conclusion, we have shown the benefit of CAN-2409 treatment, just three administrations after prolonged follow-up in terms of disease-free survival, supported by secondary endpoints. This treatment is feasible, well tolerated by patients. So, this suggests a very interesting benefit risk profile for the patients who seek curative intent after radiotherapy. Finally, I would like to thank the patients, their families, our colleagues at Candel Therapeutics. This has been a project that took more than 10 years. The site personnel, Ted DeWeese and Peter Scardino, who co designed this clinical trial. In the past and then the different committees and boards that you see on the bottom of the slide that made it possible to get to this positive result. And finally, I would like to thank you all for your attention. Thank you very much.
Unknown [01:01:46] Exciting work. Thanks for sharing it. I was curious, I guess the slides went away. I’m not sure if we can go back to the Kaplan-Meyer curves.
Paul Peter Tak, MD, PhD, FMedSci [01:01:53] Could we go back to the slides please? Probably of the primary endpoint.
[01:01:58] Yeah, that’d be great.
Paul Peter Tak, MD, PhD, FMedSci [01:01:59] Give me a second. Yes?
Howard Soule, PhD [01:02:03] So my question was about the drop-off that happens right around 24 months. So, it looks like that’s being driven, presumably by the prostate biopsies being positive at a greater rate in the control arm, right? Do we know whether those patients went on to actually experience biochemical recurrence? Is this you know something that is true? This is just an odd pattern for you know recurrence.
Paul Peter Tak, MD, PhD, FMedSci [01:02:27] Yeah. That’s a very good observation, and you’re also right with your explanation. It’s completely explained. Because if there’s a positive biopsy, there’s an event in the design of this clinical trial. And the reason was to actually get to the end point earlier, right? There’s a reason that nobody’s doing such a trial because it takes forever. And this brings it a little bit forward. So now the next question is of course the events are not limited to prostate biopsies. Not everybody got the prostate biopsy, but not everybody wanted to have it. And it was also the pandemic when it was actually very challenging to get the biopsies. So, there are also other events over time. But it’s too early to really know whether we see a change in the time to salvage ADT or other therapies, whether there’s a change in the time to metastases or in the number of metastases over time. We are following these patients, obviously. So, this was the data cut from December. We are actually very close to starting the analysis that we want to submit to probably the AUA meeting. So, we hope to have the initial answer to your question based on exploratory follow up in Q2 of next year.
Unknown [01:03:34] Okay, thanks. I think it’ll be super important to understand what the natural history is.
Paul Peter Tak, MD, PhD, FMedSci [01:03:38] I totally agree. But based on what we’ve seen, the meta-analysis that I’ve presented here, my prediction would be that we’re starting to see this separation in 2026. Please go ahead.
Daniel Spratt, MD [01:03:49] Thank you.
Paul Peter Tak, MD, PhD, FMedSci [01:03:50] And then I’ll go to the left. Yeah, go ahead.
Daniel Spratt, MD [01:03:52] This is really exciting to see something new in this space. Sort of similar to the last speaker, it’s just again, looking at the curves, there’s no separation in the beginning, right? And then it seems other than the post-treatment biopsies, they pretty much parallel each other. And I guess in most trials in intermediate-risk prostate cancer, if we were to just say let’s dose escalate or let’s add ADT, we usually see at least biochemical differences in the first two, three, four, five years. Have you guys just looked at BCR itself, which is one of the lowest bars we usually set in a trial?
Paul Peter Tak, MD, PhD, FMedSci [01:04:27] Yeah, well of course if these patients are followed in the context of standard of care, right? So, during the first two years they will get the PSA test every three months. If there was an increase, it would lead to additional work up. So biochemical recurrence as such was not an event but needed to be confirmed by biopsy and or imaging, and that would count as an event. So, you can’t see it, but there is already some separation actually early on. But then over time you will see that it’s driven in part by biopsies. That’s why you see the big hit at two years, but also by just normal clinical events. Okay.
Daniel Spratt, MD [01:05:02] Yeah, it’d be fascinating just to see, you know, Phoenix definition, BCR and intermediate-risk. But yeah, that’s yeah, really cool yeah, cool concept.
Paul Peter Tak, MD, PhD, FMedSci [01:05:10] But at least I’ve shown you the difference in the proportion of patients that achieved the nadir of less than 0.2, and we’ll expect more data in the in the very near future. Please go ahead.
Unknown [01:05:20] It was really interesting. I was wondering if you had looked at the TCR of the T cells, how many of those are responding to the viral particles themselves and what does that mean for a repeat use of this therapy, say the patient develops like disease again and could you use this therapeutic again on them?
Paul Peter Tak, MD, PhD, FMedSci [01:05:38] Yeah, I love this question very much. I’m very much into experimental medicine and to try to learn as much as possible. But we are facing a limitation here that my predecessors did not collect bio samples. So, I can’t answer the question yet for prostate cancer. We will actually start an experimental medicine clinical trial in 2026, where we’re going to do a very detailed analysis not only of biodistribution and shedding, but where we’re also going to do all this sophisticated immunology that we can. But we can borrow some of the data from other fields. We’ve just published in neuro oncology the effects of CAN-2409 in glioblastoma, where we see a very clear broadening of the anti-tumor immune response as shown by T cell receptor repertoire analysis associated with improved survival. And we’re doing similar work now in non-small cell lung cancer. So, this is still work in progress. Please go ahead.
Unknown [01:06:28] Yeah, I think that anticipated my question. So yeah, it’d be important to look at prostate tumor antigen specific responses that might be protective. So even if you get PBMCs, that would be really interesting. My question is, do you think this could apply to the metastatic setting like CRPC? Obviously, it’s harder to inject, but I’m just wondering if the immune context would be permissive for this.
Paul Peter Tak, MD, PhD, FMedSci [01:06:53] Yeah, I would predict that it may well work in metastatic prostate cancer. And so why do I say that? First, because we have data in metastatic progressive non-small cell lung cancer, patients who have failed chemotherapy, they failed immune checkpoint inhibitor treatment, and we see really extremely remarkable responses. We see doubling of the expected median overall survival. We have now patients who had a very poor prognosis of less than one year with docetaxel chemotherapy, who are actually still doing fine after four to five years. So, we believe this may work in metastatic disease. We have seen this in pancreatic cancer, where we did a small randomized clinical trial. We actually have a patient who was diagnosed five years ago with pancreatic metastatic stage four pancreatic cancer, who’s still alive actually, not cured. But we see that we can change the balance between the tumor and the anti-tumor immune response. And then we also have some old data in prostate cancer, where there were patients who had failed radiotherapy, PSA levels were going up, and in those days, this was still possible apparently, they got monotherapy with the CAN-2409, and you see that PSA levels go down again, and then it goes well, and after let’s say one year it starts to creep up again. And in some patients, it was even possible to do like a rechallenge almost, do a second administration a year later, and then again, the PSA levels go down again. So, we have seen this also in more advanced disease. Data are limited, but I would hope that after hopefully approval. Of CAN-2409 in prostate cancer. We are seeking BLA submission Q4 next year, that we would also expand into late-stage prostate cancer. I don’t think I see more questions, so I would like to thank you all for your attention. Thank you very much.