Andrea Miyahira: Hi, everyone, I'm Andrea Miyahira at the Prostate Cancer Foundation. Joining me today from ASCO 2025 is Dr. Salomon Tendler, an incoming assistant attending at MSKCC in the 2024 PCF Young Investigator. Dr. Tendler, thanks for joining us.

Salomon Tendler: Thank you so much for having me.

Andrea Miyahira: So neuroendocrine prostate cancer is a very advanced form of castration-resistant prostate cancer for which there are no standard treatment options. And DLL3 is a marker expressed by NEPC and many other neuroendocrine cancers. So tell us about what you've been working on? You've been developing theranostics targeting DLL3. And here at ASCO, you presented on your PET imaging clinical trials. So we're very excited to hear about that.

Salomon Tendler: Yes, thank you. So delta-like ligand 3 is a cell surface protein that's uniquely expressed on neuroendocrine cancers. And that makes it an attractive target for the radiotheranostic approach where we really are trying to aim at getting as good tumor-to-background ratio for the imaging component and then of course, as good and high therapeutic index as possible with the therapeutic counterpart.

And basically, in NEPC, as you mentioned, we really do not have any good standard of care treatment options. And this is a subpopulation that is only growing. And we believe that this is an important subgroup of patients to study further. So that's why we're very excited to continue our work in this space.

Andrea Miyahira: OK, thank you. And how common is DLL3 expressed on NEPC? How many patients would be eligible for something like this?

Salomon Tendler: That's a great question. And I think it very much depends on the cohort at hand because we're talking about usually a biologically transformed, meaning that the cancer has started off as the typical adenocarcinoma phenotype and then become the neuroendocrine differentiated prostate cancer.

But we believe that this number now is about 15% to 20% of the aggressive prostate cancer population that will develop NEPC. And delta-like ligand 3 is commonly expressed in a majority of these cancer cells. And therefore, it is a very attractive target to be further investigated.

Andrea Miyahira: OK, thanks. And can you describe the trial and which patients it's being investigated in?

Salomon Tendler: Sure. So this is a phase I/II first-in-human, first-in-class imaging study that looked upon patients both with lung cancer, so small cell lung cancer, as well as neuroendocrine prostate cancer. And the idea behind this study was that we injected a small amount of the full-length antibody, so about 1 to 2 mg, and then also a small amount of the radiotracer zirconium 89, which means that once the patient is injected, they go home.

And after either three to five days afterwards, we actually take the PET image. This is basically the scope of the study. And the first couple of patients with full dosimetry on which showed that the tracer was completely safe and that we showed that the half-life matched very nicely with the PET tracer.

Andrea Miyahira: OK, thanks. And tell us about some of the findings from this study. How successful was DLL3 in identifying NEPC? And there was an IHC component that you're comparing this to, so how did that match up?

Salomon Tendler: Exactly. We showed very promising results that made us all very excited at the team at Memorial. And basically, the DLL3 PET tracer was actually able to delineate tumors in most of the NEPC cohort. And furthermore, which is important to highlight, is it could also find lesions that were not showing avidity, meaning uptake on the conventional scans, such as the FDG PET, or PSMA PET, or even a regular computed tomography.

And the other thing was it correlated also very nicely with the immunohistochemistry from the biopsies obtained. So we really believe that the main findings of this study are, number 1, that we can showcase DLL3 avidity in these patients. And number 2, that we can better understand the biology and heterogeneity that we actually see in this cohort as well. And furthermore, it was completely safe. And we showed no adverse events in this study.

Andrea Miyahira: OK. Well, that's all very promising. So I'm looking forward to what's going to happen next. So yeah, tell us what are the next steps for moving this agent forward? And has the dosimetry been optimized?

Salomon Tendler: It has. And the next steps really have been to expand the cohort further to more patients. And second of all, we also have now looked upon patients that do not have neither NEPCs, or neuroendocrine prostate cancer, or small cell lung cancer, but actually other types of neuroendocrine carcinomas that also express this delta-like ligand 3 on the cellular surface.

And we are actually showing that in an abstract here at ASCO as well, that in five patients with gastrointestinal pancreatic neuroendocrine carcinomas, a majority of those also showed avidity of this tracer. So we really are starting to look at this more as a pan-cancer target and the radiotheranostic approach as an excellent pair that could help these patients.

Andrea Miyahira: That's exciting and good to hear. So your team is also developing a DLL3-targeted radioligand that could be paired with this PET imaging agent. So tell us a bit about what the status is of the radioligand?

Salomon Tendler: Right. So the radioligand really can be paired in different ways. It's the same antibody, which means you're only swapping out the linker, as well as the radionuclide, to either a beta emitter, such as lutetium 177, that we all know has shown tremendous progress with end results with PLUVICTO, and other drugs, and then also with an alpha emitter such as actinium 225. And in the laboratory, we have shown now that in multiple different mouse models that the results are very promising for both of these agents.

So we're very excited and hope to move this forward as soon as possible to a phase I clinical trial, which would really be a pair study where you're first imaging the patients, stratifying and selecting the patients that have the DLL3 target expressed. And only in those cases would you then either swap out to a beta emitter, first of all, lutetium 177, and then perhaps, in a further study, also with an alpha.

Andrea Miyahira: OK, thank you. And then do you have any final take-home messages for our viewers on the clinical potential for DLL3-targeted agents in neuroendocrine prostate cancer and beyond?

Salomon Tendler: I think it's a very exciting time for this very aggressive subset of cancers. And we really hope that the radiotheranostic approach targeting DLL3 will help many patients very soon. Also, it is very important to highlight that there are other DLL3-targeting agents out there that actually could benefit from utilizing the imaging probe also for their studies moving forward to better stratify patients that have the target.

And finally, we, at Memorial, and the team really want to thank all the supporting funding mechanisms, such as the Prostate Cancer Foundation, the Scannell Foundation, and to all patients and relatives that have been involved in the study.

Andrea Miyahira: Well, thank you so much. This is an exciting project and very promising for patients with this very aggressive type of prostate cancer and other cancers. And thanks for sharing with us today.

Salomon Tendler: Thank you for having me.