Episode 510: ADCs in Prostate Cancer

(upbeat music) - Welcome everyone to another year Migos podcast. Tom and I are pleased to be joined by Tanya Dorf, friend of the show, friend of our live meeting, which by the way is coming up November 13th, 14th, again this year in Nashville. And we're gonna talk about ADC's and prostate cancer. Tanya gave a great presentation of a novel ADC at the, I think it was the mini-oral session on Sunday. And we wanted to use it as a springboard to talk about other ADC development in prostate cancer. We've talked a lot about it of course in bladder cancer, but not as much in prostate. Tanya, we appreciate your time and expertise. We're gonna start before we get to your data by talking a little bit about what's gone on before ASCO 2026 in terms of ADC development and prostate cancer. So I'm gonna turn it over to you, can briefly introduce yourself and then let's jump in. - Great, yeah, hi, I'm Tanya Dorf. I had the geno to urinary cancer program at City of Hope. And definitely in front of the show, admire of the show. And yeah, a few years back at Ju Asco actually 2022, I was asked to be part of an educational session just talking about cell surface targeting in prostate cancer. I mean, traditionally I've been doing immunotherapy, so CAR-T as well as by specific T-cellingagers, but relevant to ADC's as well. So there have certainly been PSMA targeted ADC. Those early constructs, I think were really limited by the payload, where the MMAE type payload resulted in a lot of neuropathy as well as more traditional cytotoxic toxicities, like myelose suppression, neutropenian such. But it really limited the dose that was able to get in. And as people were thinking about other payloads, they were also really looking at other targets because of the heterogeneity of cell surface expression on prostate cancer. So that is one of the things that makes the compound that I was presenting the phase one day to four unique is that it's dual targeted targeting both steep one as well as PSMA. - So Tanya, is there a reason that MMAE ADC's would be more neurotoxic in prostate versus bladder? - Yeah, that's a great question. Obviously, some concern about dose of taxal pretreatment. But otherwise, you know, your ethereal cancer population may not look that different from prostate cancer. So maybe it has to do with not just the payload, but also the cell surface target, right? I think PSMA, - And the link. - Specific membrane antigen is just not so specific. - Yeah, and the link is gonna be important here, I think. - Sure. - Because if the drug's kind of floating around in the system because the link is no good, you're basically just giving high doses of neurotoxic drugs. So I think link technology is super important. Some of the really early work, in my opinion, when prostate cancer with the MMA, payload A, C's, targeting PSMA, but also steep one. I think some of those, I think they were quite early and they're cleavable and non-cleavable, in convolicules and I think the more advanced, people call kind of second generation non-cleavable. But they, but, it's very cleavable. But that piece around the link in molecule is super important because what was shown recently in your ethereal cancer and in other cancers too, in lung cancer, is that you can have the same drug, or what looks like the same drug. So the TROP2 Topo-1 ADC family is a good example of that, exact TMT, DDXD, and of course, SGS, that's the two of them, I'll go over T-Can. And they appear to have quite distinct activity and quite distinct toxicity. And so the payload is super important. And of course, we did a podcast a couple of weeks ago with looking at Topo-1, next in four ADCs, and we're there, we talked about actually the metabolism of the payload being really important as well. So I think sometimes we get a bit, we've tried to, I think, at times sort of categorize these drugs into the same groups, but actually just as you can have different chemotherapy agents with different activity in the same class, ADCs is a three-dimensional chest compared to that. So Tom, you think it was maybe an early ADC constructs, linker technology not developed. And so there was dose limiting toxicity. And so I saw a little bit of efficacy measure by PSA50, that you just, perhaps couldn't get enough drug in or the risk, the benefit risk ratio wasn't favorable. And that was sort of the issue, more than just prostate won't respond to ADCs. - Yeah, well, Silky invited me to give an ADC talk at her APCCC meeting recently. The last time I was invited to give a talk at a prostate meeting was about the autism ab randomized data. And we know how that story ended. So I was really surprised to get invited back, actually. - I was very surprised, right? I was very surprised. And I said that at the beginning and actually people started walking out the room during my talk, who's they realized it was going and I know I started with the premise that actually taxache chemotherapy, I don't think it's very active in prostate cancer. People started throwing stuff at me. And it got worse from there. I actually the least said about the end, the better. But I think it's fair to say the following, I think it's fair to say we've tested drugs like unfortunate Aberdeutin, Nectin IV. We've tested with MMA as a payload. We've tested also the payload, the microtural disrupting agents, payloads looking at PSMA, and their drugs like MNL274 and ARX517. And these drugs actually have all had fairly modest response rates. Somewhere between 10 and 20% some of it higher, 24 patients here, 30 patients, they're small numbers. We've looked at another target, CD46. And there's a program there, which actually looks quite promising. And again, MMA is the payload response rates in a 56 patient study of 36%. That drug is called 446. So CD46 is an exciting area. And then of course, steep one that's been disappointing with again, MMA is the payload and that drug only 14% response rates. But I think these studies are quite old and I think there will be better drugs. There is one caveat and there's one thing I would like to just highlight for a second, is we, Sassatuzumab gov T-can is one of those drugs that's been tested just about everywhere. TROP2, which is expressed on prostate cancer. By the way, some of you will say it's not expressed, but it's a little bit. And TROP2, TOPO1, activity in uothelial cancer, lung cancer, breast cancer, not necessarily a home run, but here in prostate cancer in 30 patients, 0% PSA50 response rate. So that's a problem because you'd expect that sort of ADC to come home a little bit. And so it does suggest, actually, it's quite difficult to be dose of tax on. Because that's clearly active. Clearly it's a microtubal disrupting agent as a payload. And that may be important. And then of course, there's the big elephant in the room, which is the IDXD class of drugs, B7H3. B7H3 is essentially PDL3. You know, we know a lot about PDL1. PDL2, we talk about from time to time because of the biomarker. But PDL3 isn't talked about very much, but it is quite widely expressed on prostate cancer. And there are two big randomized phase three studies based off single agent trials with B7H3 with modus data. And it's not me who said it was modus. It was other people in the room and Tanya, you know, a lot more about this than I do. Because I felt the data was actually not too bad. So IDXD is the randomized phase three. That's the ideal study. And then there's BTN324, which is the biotech study. And both of those randomized phase threes are taking on single agent dose of tax on and castrate-resistant prostate cancer. So it's an area which I think is, you know, why have people gone into prostate cancer early? It's because beating dose of tax on is a big, big win because it's so much of it's used. And it's not a great drug. And it's got modus, in my opinion, modused outcome compared to some of the other spectacular ADC results was seen in lung cancer and bladder cancer and other cancer-resistant. - Yes, but not in other cancers, but not in prostate. - Sure. - So I agree that, you know, dose of tax is not that great a competitor. And yet, you know, it's a survival prolonging drug and prostate cancer. I'm just so glad that these phase three trials are taking on dose of tax and not using ARPI switch as the comparator, because then I think we'd be left with all the same questions we've discussed all the time about some of the other drugs that have been developed who did use that kind of inadequate comparator arm. So I think even with modus efficacy, like with the IDXD compound, you know, they didn't have so many prostate patients in the phase one, they did show a signal. I think it's good that they're going against dose of tax, because that's really going to tell us, you know, what the marginal advantage is. - So it sounds like just to summarize, there's been, A lot of ADC's tried in prostate cancer. Some toxicity issues, maybe around link or maybe around other considerations. There are some big trials ongoing, but it hasn't really made the splash for those reasons or other reasons that it has obviously in bladder cancer. But Tony, you presented data at ASCO about a dual targeting ADC with, I believe, a Topo 1 payload. That, to me, seemed much more active than anything we've talked about. I'll say that if you won't. So, do you wanna tell us about what you've presented? - Yeah, thank you. I was so excited and so honored to be giving the opportunity to present this. It's a drug from ABV, ABV 969. And it's a dual targeted ADC. So it can internalize by binding to either PSMA or steep one or both. And it is a different Topo isomerase payload than the IDXD, right? Apparently it's used in some other ABV compounds in other diseases, but it is novel compared to others in the field. And so this was a phase one dose escalation, first in human, we explored doses from one to 12 and a half mix per keg. The DLTs came at that highest dose, 12.5 mix per keg. And so ongoing dose exploration will not include that dose anymore, but we did show a really exciting efficacy signal, you know, with 67% of patients who are the PSA50 confirmed. So a bit higher than what's reported with the other compounds, although admittedly a dedicated prostate study, but really what struck me most about the efficacy and what I see in my patients who I'm treating with this in clinic is the durability of the responses. You know, the PSA responses, median duration was almost 11 months. And then we can also talk about the objective responses, right? Which is really encouraging to see 45% confirmed objective response, a lot of them in patients with liver metastasis with an RPFS of 15 months, you know, so that's just to go. - Just to go back a little bit for mechanism, is the idea behind dual targeting just that some cells express one in a gym, some cells express the other. So you're hitting a broader swath of cancer cells in the patient's body. Or is there something about delivery of drug when you have two antigens, right? If you're binding to two antigens? - Yeah, I think we showed a little bit of data on mRNA expression of the two targets. So while 64% of prostate cancer patients in this group, we looked at 174 patients. While 64% had dual expression, there were 15% that only had PSMA and 21% that had only steep one. And I think even within a tumor, within a patient cell to cell, there's going to be differences. So I do think to some extent it's really that just opportunity to hit more of the cancer given the heterogeneity of cell service protein expression. - And you didn't associate with response with baseline expression of one or the other target? - We haven't shown those data yet, but of course that's something that's going to be looked at. - Ryan, so I guess where do you go next with this? Do you just launch into a randomized phase three now? So what was your PSA 50 response rate, Tonya? I didn't hear. - 67.4%. - That seems really high, doesn't it? - More than double the other, what we just talked about, right? Does that fare which were in the-- - Yeah, some got to 50, some got to about 50, but they were in our handful of patients. And it's the first time a top-by-somerose payload has worked. Really? - Which is no, I mean, surely you're going to launch a randomized phase three, aren't you? Are you allowed to tell us out on the show? - No. (laughs) - You know, okay, you know. So I've got no idea if you are, but I assume you are. I assume you are, I'm not for that response rate. How many patients was it? - So we were reporting only on 49. So that was just the dose escalation. Already there's been several doses explored with a significantly greater number of patients. So those data obviously will be important to build upon these very early data. But, you know, these days people do tend to skip over phase two, like AMG 509 that I've worked on. I was all year-rhythmic. The phase one explored so many doses and really drilled down and you treated enough patients that phase three could follow. So I think that is a new paradigm, but only if we explore multiple doses in the phase one and really make sure we don't just pick a recommended phase two, but we really kind of do the phase two as part of the phase one. - So the FDA might ask you to do an optimist program in your study. They might want you to look at multiple doses in that. And the question is whether you agree with them or not. I mean, the problem with the optimist program, speaking frankly, and I sit here on the other side of the Atlantic, the problem with the program is actually trying to find in prostate cancer differences in efficacy between different subtle differences and efficacy between different doses will take you about five or 10 years. And it'll take you hundreds of patients in each arm. And so while it may be a really good idea in some areas, in some cancers, it's very challenging. In the end, for me, and again, I'm not the FDA and I know a lot more about this than I do, the concern I have with topless always one payloads with ADCs is neutropenia. And your neutropenia rates are quite high and we've had treatment related deaths, and indeed, we've had trials fail with topo-1 payloads associated with hematological toxicity. There is debate about compulsory GCSF. And what's your take on this issue? Yeah, to be clear, we did not have that student of febron neutropenia in the data we were presenting. And there was only one patient out of 49 with febron neutropenia. It's, yeah, this neutropenia is a class effect of tubisomerase inside of toxics, but I think the whole point of the ADC isn't it is to deliver greater efficacy with lower off-tumor effects. And I do think that drugs like ABBB 969 are delivering on that promise, you know, anemia was kind of the bigger issue in this particular study. And that can be a factor of just our patient population having had, in many cases, radiologian therapy, but certainly multiple rounds of radiation to marrow areas. And you know, 20% had had prior PARP. Yeah, they had all pretty much had prior side of toxics. So in that population, anemia is very much expected. But I think neutropenia will be manageable at the doses that are likely to be considered. And GCSF can overcome that. So I don't see that as sort of a fatal flaw. I don't know if you remember when Kabazatexel was presented, we were quite scared by the neutropenia and the diarrhea and the toxic depths. And then I think in our own clinics, we found Kabazatexel to be quite manageable when we use our regular medical oncology techniques. - Good point. So there was not prophylactic growth factor use in the study, correct? - That's correct. - And did some patients end up getting it because of their side of venus? Or I don't remember if you presented that data? - We didn't present that, but I'd be surprised if no one ended up getting GCSF. It was certainly allowed, you know, once neutropenia developed. And wouldn't you rather explore your dose and allow the GCSF than have to dose reduce, right? - So the answer, I guess, or the question from my perspective, Tanya, is coming back to that neutropenic species issue. You didn't see neutropenic sepsis in your study, but you did see quite a lot of, you did see quite a lot of neutropenia. And some of the other trials with these topoisomerase inhibitors also have shown that neutropenia. And of course, in your ethereal cancer, we showed we had to give that prophylactic GCSF in the randomized trials to make them successful. And in the Sassatuzimabg over Tcan trial, with the topo-1 payload. In fact, one of the reasons tropics for fail, I think, was because we ended up with neutropenic sepsis and we ended up with some deaths in the study arm. So do you think this is a phase two, which has gone to really good tertiary referral sites, great experience, great management of, and it's gonna be difficult to roll out in a randomized phase three. Or do you feel there's something slightly, slightly unusual with your drug? - Well, I think neutropenia is certainly dose dependent, as are the all the hematologic toxicities. And I hope that the design of the phase three will look at the rate and make the right decision about the use of GCSF prophylactically, if needed. Because obviously we can't do well for our patients if we treat their cancer, but we cause them to be hospitalized or even dying right from February, neutropenia. So much more attention when we pay it as we gather the data from additional patients who have been treated. And I don't know what the phase three design will be, but I hope people will think hard about that question, Tom, because I think as you point out, there's precedent for that being a deal breaker if it's not addressed correctly. - And so just before we move on, I'm just wanted to talk about some data. data from China, which was Ding Wei's data from Shanghai, and he showed the same class B7H3. He showed that group of drugs was, and so his drug is YL201. It's the same as IDXD and the biotech drug, both in randomized phase 3. It feels a little way behind because those two other competitive drugs, you know, similar design, of course. The link of molecule may be better, it may be slightly more active, and I'm not sure what level do head-dead trials. He showed 30% grade 3 or 4 newtropenia, which feels quite, you know, it feels in that area where you'd be concerned, a third of patients getting 3 or 4 newtropenia, and his PSA50 response rate was half yours at 30%. So it does seem, is there a level where you think Tanya you need to be at from a results perspective, and from a newtropenia perspective, where you're likely to beat dose attacks, or is it 50% PSA50, is it 40%, is it 30%, is it 70%, what level of PSA50 would you be confident you could beat dose attacks? Yeah, I think 50% would already be quite comfortable because there's also that durability, right, a lot of people end up needing to dose reduce and discontinue this attack, so due to neuropathy and some of the other toxicities. So the initial PSA50 response is a good signal, but I think looking at those progression and points is also really important, engaging the viability to beat dose attacks. Tanya, I want to ask you a question about your vaccine, looking at your waterfall plot and underneath you have a graphic that shows whether a patient's got prior PSA50 radio ligand therapy or and/or prior taxane, and there's certainly responses, it almost seems like some of the deepest responses are in patients who had both, and I'm probably overinterpreting a bit, but just wondering if there's some biology behind that in terms of expression of target after this therapy, you'd almost expect the opposite, of course, for a PSA50 radio ligand therapy, but do you have any any opinion on that? Yeah, I think it's an interesting observation. I don't think it's all about target, you know, and very interestingly, the B7H3 data didn't show correlation of response with target. We haven't looked at that yet, but I think the biology of prostate cancer, we certainly know becomes different as the cancer becomes resistant, and as it's exposed to multiple lines of therapy, for a very simple thing, for instance, the proliferation rate increases, right? All of a sudden you can see it on FDGPET, where you don't see early stage sensitive prostate cancer on FDGPET, because it's just not as metabolic, the active. So maybe something like a Tobisomerase payload is working well in a population where the cancer has just begun to grow much more rapidly. One of the questions I guess, which one would ask, is in the end, beating dose a taxal by 20%, massive step in the right direction, but not the answer to all our problems in prostate cancer. In small cell lung cancer, as in prostate cancer, the T-cell engages, the bi-specific T-cell engages are making great progress. You folks with the steep target, the DL-L3 target in small cell lung cancer, I guess the combination of the T-cell engages in combination with ADC's is an obvious next step. Is that something which you're already doing, or is that something that people are thinking about, or is that still aspirational? I think it's still aspirational. We're just learning about each of these practices. We should go in prostate cancer, Brian. We should do prostate cancer. We clean up. In prostate, I think your ethereal story of Enfordamab with Pembro is so compelling that there's some kind of immune activation, some synergy that needs to be sought out. But with prostate cancer, I hope we're not just going to try to replicate that and use immune checkpoint inhibitors. I hope we will be more sophisticated as a field and use something like T-cell engageers that have shown greater efficacy in this particular disease. But really important to positioning these drugs is not only beating dose of taxable, but fitting into what the landscape will be. I think it's really important to show activity after PSMA targeted radio ligand, for instance, which may be moving earlier in the disease, at least potentially in the United States. I know there's still access issues to PSMA radio ligand in many parts of the world. But I think we have to pay attention to how the patients will look in the future. Probably the immunotherapy combination trials, there's some science and some analysis that needs to be done ahead of designing those to make sure they're designed successfully. Last question for me is sort of about the future. If it's three to five years from now, where do you see ADC's fitting into prostate cancer? Is it monotherapy kind of where we use chemotherapy and CRPC? Is it combo in that setting? If you beat dose of taxable, could it even be an upfront triplet in high volume patients? Yeah, I like the idea of an induction and maintenance kind of strategy and multimodal, multi-target, hitting the disease hard from the get-go. I do think there's need for non-hormonal based strategies. So in addition to looking at things like metastatic hormone sensitive or APMN, triplet induction, I think looking at other spaces like biochemical recurrence that's high risk, all of them metastatic and whether combinations there could start to get us to a place where we have something that's non-hormonal based would be my ideal look into the future. Now I don't know because of the biology of angioreceptor and some of these cell surface targets, whether that's realistic or whether these will continue to need the angioreceptor backbone. I think that's something I've been looking for over the last 20 years. That's always been what I hear from my patients is when are we going to get to a day where everything I prescribe doesn't have that backbone of lowering testosterone. My last question, Tanya, is around duration of therapy. So the journey, the first chapter of this is ADC till progression and guessing how many cycles in the randomized trial for dose attack. So if you could tell me, I don't know, is there any endeavor in this disease type to try and I'll answer the question about number of cycles in advanced disease or are you measuring what we've done in other cancers where you just keep going for as long as you can? I think these are a class of drugs that can be used in that traditional paradigm of use them as long as they keep working because they seem to be more tolerable. But of course, I think patients are really looking for treatment holidays and rather than indefinite treatment. So the same exercise that's happening with EV Pembro, how much EV do you need to give? I think would eventually be done if that's the only way these ADCs are developed. Like, do we really need to go to progression? I think, you know, having new biomarkers to help us gauge depth of response beyond just PSA and PET scan already, I think does a better job of that potentially, but other biomarkers to really start to design better trials where we use as an amount to get a patient into a depth of remission rather than just waiting till they start progressing. In the end, in the front line setting, I'm guessing if that's where this ends, with other therapies you can't go on for years and years and years. So it's going to have to be a limit. And my feeling on this at the moment is with both payloads, there comes a point where it's hard to continue to give the drug and you end up with patients kind of coming in having treatment every six or seven weeks because they can't get after years. And I think we probably need to be brave at some point, not now, because I agree. Let's beat those attacks or keep the therapy first. That's hard to do. But we, and I don't think doing three arm trials, one with six cycles and one with ten, so you know, that doesn't feel like the way forward. But I would, I think transitioning gears quite quickly to try and answer the second question about how much you need on the assumption that some of these drugs are going to beat those attacks. So I think we'll be really neat. I think the biomarkers are going to be tough. Everything I've read about the biomarkers in this disease. You've never managed to correlate, you know, so B7H3 doesn't seem to correlate. Yours doesn't seem to correlate. So I think the biomarkers do is going to be more complicated. It clearly has to be pursued. But I would urge you to try and actually address the number of cycles sooner or later. You don't have to respond to that, Tony. It's just a suggestion. Yeah. You wouldn't be the first person to ignore everything I say. I'm sorry. I'm in silence from Tony. It's a good policy for drug development, actually, to do the opposite what I say. And actually, you'd probably like it to be successful. Tony, this has been fabulous. Really great data. I think of some of the best prostate data at Aspen, that's saying a lot. I mean, really high response rates and refractory patients. So we'll look for more great things to come. We appreciate you joining. I mean, it does seem a very high response rate. Let's look for more data. Fagulous. Definitely. Thank you so much, guys.