Alan Bryce: Yeah, Oliver, thanks for the question. Thanks for having me. PT-112 is a novel therapeutic that I've been working with since the initial phase-one studies, the first-in-human studies. And this drug is a very interesting molecule in that it has a platinum-containing core. So on the one hand, when you first look at it, you think of it as a platinum drug, and yet it's very unique in that its mechanism of action appears more to be along the lines of immunogenic cell death rather than DNA cross-linking. And then, the other interesting aspect of this molecule from a prostate cancer perspective is that it has a pyrophosphate modality as well. So, in the initial animal studies looking at drug localization and mouse models, there's absolutely an osteotropism where you see high concentrations in bones, but there's also soft tissue presence, right?
So, the drug is in lung tissue, it's in nodal tissue, liver tissue, etc. So, it's not bone specific per se, but nevertheless, there's this osteotropic activity. And so, we did the initial phase-one studies several years ago now. And by surprise, not by design, we saw results in prostate cancer patients, along with lung cancer and thymomas and some others. And Oliver, when I went into this as a GU doctor, I was hoping we might have something I could use for germ cell tumors, for those late refractory germ cells. But then, I saw this response in prostate cancer patients with improvement in pain, reduction in soft tissue metastases. So, we advanced the drug to a phase-two prostate-specific dose-finding study. And the current poster we're going to talk about is some of the results from that study.
Oliver Sartor: Terrific. And this was presented at ESMO in Berlin, and so very up-to-date data. So, Alan, take us a little bit into the phase-two design, because I'm seeing you use multiple doses, and then there's some pretty interesting biomarker results that you had embedded within that study. So, you've got dose interaction, you've got biomarker issues. Let's hear a little more about it.
Alan Bryce: Yeah. So, with PT-112, the initial recommended phase-two dose has carried forward in some non-prostate cancer studies. But in the prostate cancer study, we were treating men who were very heavily pretreated, right? As you know, the late-phase population in prostate cancer, soft marrow, older gentlemen, they've had radiation, etc. So, we knew from experience that we needed to find a different dose for our prostate cancer patients. So, we launched a dose-finding study, really trying to follow that project optimist model. And we started with two dose levels, one at 360 per meter squared on a day 1/15 schedule, and then a second 250 per meter squared, day 1/15.
And after taking a couple dozen patients through each of those arms, about 33 each of those arms, we further refined it to an arm three where we said we start with a loading dose at 360, day 1/15, and then we get to a monthly maintenance dose of 250 once a month. And ultimately, as we talk about the results, we'll see that that was really arm three was much better tolerated and we saw more responses because we were able to continue with treatment. So, this was really the dose finding to figure out what should a phase-three dose look like for further development of this molecule.
Oliver Sartor: And Alan, just briefly, tell us a little bit about the EVEREST van toxicity profiles so we'll have an appreciation for that as well.
Alan Bryce: Yeah. So, the biggest is certainly myelosuppression, anemia, leukopenia, some of those somewhat more traditional chemotherapeutic effects. We saw inflammatory side effects, probably getting to some of this kind of immunogenic mechanism of action, inflammation of a patient with RA who had a significant flare. And then, certainly fatigue, some GI toxicity as well.
Oliver Sartor: Got it. Thank you.
Alan Bryce: So then, if we get into the results of this study, right, what we're starting to report out here is what about our biomarker effects? What do we see with PSA, LDH, Alk phos? But we also have some very cool genomic data that we got from Alex Wyatt. So, Alex did some analysis based on the ctDNA based on the absolute levels, the change in levels, and the genomic data. And then, we also have some CTC data that we've looked at. And this is all being reported out as we continue to let the primary outcomes mature further. So, it's not a complete dataset yet. We don't have all the patients analyzed, but we've got a decent number, about half. So, if we walk through this, Oliver, this is a patient population. Median lines of prior treatment is five plus.
Almost all the patients have had both docetaxel and cabazitaxel. In the later parts of the study, it starts to approach 40% of them having prior Pluvicto, right? So, really heavily pretreated, everyone having been through the ARPIs and whatnot, a number of them having been through radium or radiation as well. If you look at the univariate analysis, and I think no surprise, right, PSA ends up being a weaker predictor of outcome, and LDH and Alk phos end up being much stronger predictors of outcomes, so higher LDH, higher Alk phos leading to worse outcomes. CTCs also hold up as being consistent with worse outcome. And then, no surprise at all, the ctDNA fraction, of course, correlates with outcome, right? So higher ctDNA levels, higher disease burden, worse outcomes for patients. And then, as we go into the on-treatment response, so you see with the CTCs, there's absolutely a conversion dynamic that happens. We show that in the middle panel there.
In the first table, you see how at all dose levels, CTCs tend to convert with a high rate of conversion to zero. You see the Alk phos, and I tell you, this is one of the results that excited me even in the early phase one, and we saw it continue through the phase two, but really good Alk phos responses. I saw clinical pain responses as well on these patients, but across all arms, more patients than not have reduction in their Alk phos, and you see that that effect looks better as we progress from arm one all the way to arm three. And then you go down, you see with LDH a similar story, right? So, the vast majority of patients seeing an improvement in their LDH levels, again, starting high as a negative predictor of outcome but improving on treatment. And again, having a better effect, a more significant effect at the higher dose level, at the later arm than in the earlier arm.
Oliver Sartor: I'm just going to make an offhand remark. When I see these tough patients, and we all see them in our practice after multiple, multiple, multiple lines of therapy, I tell them that the LDH is a much more important marker than the PSA because the PSA just loses the overall significance compared to the LDH and Alk phos, which now become predominant. And it's a little bit of a wake-up call for the patients because they've been PSA, PSA focused for years, and all of a sudden you got to reset them. By the way, not all the physicians recognize that. So, I'm really glad you're talking about the alternative biomarkers of LDH and Alk phos and their importance of these heavily pretreated patients. I really like the fact you're emphasizing that.
Alan Bryce: Yeah. Yeah, I agree 100%. Thank you for highlighting that. All right then. Then if we look at the ctDNA, and of course I'm a genomics guy, so I'm very interested in these results. And we had this analysis, like I said, done in the Wyatt lab, so one of the very best prostate genomics labs anywhere, right? So, Alex did this work and you see the top-line data about the ctDNA fraction. And again, ctDNA fraction correlating to outcomes overall. But you see, as we progress from arm one through arm three that our reduction in the ctDNA fraction, the impact of treatment gets better. And what this really was, Oliver, is that at the higher dose level, patients had a hard time staying on mostly because of fatigue and cytopenias.
So, as we got to a modified dose level, especially arm three, we found a dose level that patients can maintain treatment, and by maintaining treatment longer, right, we had better outcomes. And so you look at this, the majority of patients having a reduction in their ctDNA burden, again, doing better as we increase the dose. But you get down to that genomic data, and look at this genomic data, Oliver. You and I both know. I mean, you start talking about MYC amplification and 38% of total patients, RB deletion and 40%, TP53, 52%, PTEN, 44. I mean, this is a highly aggressive genotype, right? This group of patients has highly advanced, highly aggressive disease. Reflects the fact that we're beyond fifth-line therapy in most of them. So, this is really very end-stage prostate cancer we were treating in this cohort, right? And not at all what you'd see in a first-line setting or even second- or third-line probably. So, it just speaks to the aggressiveness of the disease. If you go a little higher to panel D there, I mean, you look, there's only one SPOP-mutated patient, right?
These aren't the mild good AR responders in this cohort. It's about 25% of patients had a BRCA2 pathogenic aberration, so maybe a little bit more than expected, probably within the range of error. But like I say, the big story is this deletion of the tumor suppressors, P53, p110RB. And when you say 38% MYC, that means we're really headed towards that small-cell anaplastic population, right? So really, the story here is that in a heavily pretreated patient population with highly aggressive advanced prostate cancer, PT-112 showed very promising activity in terms of reduction in biomarkers, LDH, Alk phos. Certainly see a correlation between the biomarkers and outcomes. And I think it starts to present this drug as a plausible drug for late-line NECRPC where we're really thinking in terms of neuroendocrine features emerging and not so much focused on AR signaling, right? So, you and I, being drug-development physicians, researchers in the prostate cancer space, I'm always thinking in terms of different mechanisms of action, right?
How do we open up a new class of molecules as opposed to the seventh drug in a class, right? And I think that's one of the things that excites me about PT-112 is a possibility that maybe we've got a completely novel mechanism of action, and maybe we can figure out a way to deploy this within the armamentarium.
Oliver Sartor: Terrific. Alan, we're going to need to wrap up here in just a moment, but are the trials ongoing now? Can you accept referrals for patients who might get the 112?
Alan Bryce: So, at the moment we can't because this trial has wrapped up. And so now, the conversation is with FDA about the design of the next study, right? A definitive phase-three trial design. So, hopefully, before too long, we'll have something along those lines that we can launch. There are studies ongoing in other tumor types, but nothing for prostate cancer at the moment.
Oliver Sartor: Terrific. Thank you. Alan, I appreciate you going over the PT-112. I appreciate the opportunity to learn more about a potential new class of drugs. I really like your project optimist type approach where the alternative dosing, not just the DLT, but the alternative dosing led to something that would be a better dosing for the patients, and appreciate the biomarker discussion as well. So, thank you for being on UroToday. Really appreciate all the work that you do in the field.
Alan Bryce: Thanks so much, Oliver. Great to talk to you.