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Andrea Miyahira: Welcome, everyone. I'm Andrea Miyahira, the Senior Director of Global Research and Scientific Communications at PCF. Today I'm joined by Dr. Eugene Shenderov, an assistant professor at Johns Hopkins. Dr. Shenderov team have recently published a paper, Neoadjuvant Enoblituzumab in Localized Prostate Cancer: A Single-Arm, Phase II Trial in Nature Medicine. Eugene, thanks for joining us today.

Eugene Shenderov: It is my pleasure to be here. It's my pleasure to discuss our recent work. The paper we just published, as already introduced, was looking at a window of opportunity trial in a localized setting of intermediate to high-risk men with prostate cancer prior to treatment and we are really excited to discuss it.

The issues with immunotherapy and prostate cancers, by way of introduction, is that the current two workhorses of checkpoint blockade, the PD-1 axes and the CTLA-4 targeted therapy, so for example, nivolumab, ipilimumab, pembrolizumab, they only demonstrate modest activity in prostate cancer, really, regardless of AR-V7 status for advanced prostate cancer as well. Selection seems to be required for immunotherapy in the prostate setting. There is no prostate cancer unselected FDA approval for any checkpoint. There is the basket trial approval for utilization of, say, pembrolizumab across mismatch repair deficiency, there is benefit to HRD potentially, there are emerging biomarkers, there's yet undiscovered parameters. But really, we need better targets beyond the PD-1 and CTLA-4 axes within prostate cancer.

B7-H3, which is also known as PD-L3 or the CD276 gene, was shown in a large multi-cohort group of radical prostatectomy samples back in 2017 by Benzon and Ashley Ross and colleagues to really overexpress B7-H3 compared to the other PD-L1, PD-L2, and PD-L4 B7 co-family members. For biochemical recurrence in metastatic prostate cancer, they showed that higher B7-H3 really led to poorer outcomes compared to lower, indicating a classic potential checkpoint situation and B7-H3 is a presumptive immune checkpoint, as well as potentially showing that maybe recent PD-1 axes agents weren't working in prostate cancer as well as we would hope, compared to, say, lung or melanoma or other cancers, was maybe it was not the right expressed target at the right level.

And so, in a recent work in collaboration with Dr. Tamara Lotan and published in ACS cancer in 2022. We've also shown that upstream of the B7-H3 promoter, there are AR binding sites that really seem to be more expressed in terms of being notable within primary prostate cancer or CRPC, even compared to benign prostate tissue, which links the first presumptive immune checkpoint with the first true AR linkage, possibly explaining why it's overexpressed in prostate cancer. We showed this was a very likely a positive relationship and we do not know of AR binding sites that are equivalent, for example PD-L1 or PD-2. And so, this gives us potential new insights into the applicability of B7-H3 for prostate cancer-specific immunotherapy applications.

While the paper we've published really builds on the insights that we've discussed and used the window of opportunity setting to try to tease out biological mechanisms of activity, the safety of giving B7-H3 targeted therapy to see if this allows a new approach to treating prostate cancer in a localized setting due to the fact that enoblituzumab in prior phase I all-comer trials seemed to be relatively very safe compared to CTLA-4/PD-1 therapies, and so it potentially opened it up to being in a neoadjuvant setting in terms of trying to do a neoadjuvant trial like this.

The primary endpoints were PSA recurrence at 1 year and safety. We completed a cohort of 32 out of 32 patients and this was done with enoblituzumab, a humanized FC engineered to enhance antibody-dependent cellular cytotoxicity activity, which would utilize NK cells, macrophages to bind to any cells that are bound by the antibody, therefore inducing immunological cell death. The idea there was that 6 weeks of treatment were given prior to radical prostatectomy for men who had wanted to get and consented to radical prostatectomy and to the trial. This was six weekly doses for that 6-week period. And then they had a radical prostatectomy, they were followed up for up to 3 years. And it was a very biomarker-rich trial, with multiple correlatives described in the manuscript.

One of the key things that was very exciting was the fact that we were able to, because of the neoadjuvant window of opportunity study setting design, show that there was B7-H3 binding into tumor glands compared to benign glands. Both were bound, but at much higher levels in the tumor glands because B7-H3 is expressed at higher levels in prostate cancer compared to benign prostate, even though it's expressed in benign prostate. Then the question is, was the drug going to penetrate? And this took some of the guesswork out of it because we were able to show that it does penetrate directly into the prostate at very high-staining concentrations, in a sense.

The clinical safety was demonstrated to be quite good. There were no surgical delays, there were no surgical complications beyond what would be expected with radical prostatectomy, and there were no grade 4 events. There were four patients who, between them, had 6 grade 3 events and they were relatively well tolerated. They had an infusion-related reaction, they had an asymptomatic amylase lipase increase, they had a rash, they had hypotension associated with infusion reaction. One patient did have myocardial pericarditis or pericardial fusion that occurred 4 weeks after radical prostatectomy, 6 weeks after the last dose of enoblituzumab. And that was responsive to oral steroid therapy. Now, that was 1 patient out of about 300 who have seen monotherapy with an OZ across the different phase I trials and this trial, so it's hard to know exactly what to make of an N of 1, but we've attributed it to enoblituzumab and will keep an eye on this for future developments.

What does this mean for clinical activity? For the sake of time, I won't go through the correlatives, but the correlatives as vectors all indicated some degree of TCR selection for responding versus non-responding patients for cytokines being upregulated. And then also the Kaplan-Meier curve showed that at 1 year 66% of patients did not have a PSA recurrence, with what appears to be some sort of plateau. Longer follow up and give us more information hopefully. And then also comparing grade group Gleason from biopsy to radical prostatectomy, so pre-treatment to post-treatment, we saw what appeared to be, as a predefined secondary endpoint, decreases in Gleason grade group, which is interesting.

We didn't see any complete responses pathologically speaking, but these Gleason grade group declines additionally added there might be some sort of pathologic activity going on with a key hypothesis underlying the study that we were going to be eliminating micrometastatic disease, and surgery was going to eliminate the micrometastatic or the actual prostate itself. So, hopefully micrometastatic aspect was achieved, as shown by the Kaplan-Meier PSA recurrence-free group of men, despite the fact that the trial was selected for 31 out of 32 men were high-risk disease and about 72% were actually very high-risk localized prostate cancer. That is it for our summary. Thank you.

Andrea Miyahira: Thank you for sharing that. Eugene. What is the follow-up length? How long will you look to learn the impact of the treatment on longer-term outcomes?

Eugene Shenderov: That's a great question. We've followed them up for 3 years, as per the initial study design. We are going to get IRB approval to follow these men up for longer, going out to 5, and perhaps even longer than that, years, and we'll see how the Kaplan-Meier statistics will allow us to gain further insights into the longevity of the response.

Andrea Miyahira: Okay, good. In your pathology correlative studies, did you evaluate enoblituzumab binding in normal tissues or non-cancerous regions of the prostate?

Eugene Shenderov: We did. As shown in the presentations, we tried to compare within the patients assessed whether within the benign glands compared to the intratumoral glands. There was a difference in staining, as we saw there was staining of the enoblituzumab study agent in both compartments, but at significantly higher levels within the tumor gland tissue, indicating, as we had suspected, that given higher B7-H3 expression, we should have seen higher levels of intratumoral penetration, which, as expected, we did see.

Andrea Miyahira: Okay. Did you see any immune-related adverse effects? And if not, what would this tell us about B7-H3's possible role as an immune checkpoint?

Eugene Shenderov: That is an excellent question. As described, we did see the episode of myocarditis pericarditis, where the patient was steroid-responsive, it was 1 out of about 300 patients who have seen the monotherapy with enoblituzumab across all different phase I trials In our study. B7-H3 is thought to not really be expressed that much on the myocardium, so it's hard to know, because it was 4 weeks after surgery, if it was some sort of surgical complication, if it was a true immune-related adverse event. However, we're keeping an eye out on it for future developments.

And, of course, we saw other things like infusion reactions, rashes, which are more typically also seen with just any antibody infusion rather than potentially a monoclonal. We didn't see things like colitis or pneumonitis, which would be more commonly associated with, say, a CTLA-4 or PD-1 axis approach, which, from that perspective, does appear to be a different profile. But again, the expression profile of B7-H3 is thought to be much higher in, say, the prostate compared to the lung or the colon. And so it's possible that we are seeing a more compartment-specific related set of complications, but in this case geared towards the prostate tumor vasculature where it's known to be expressed. And since the patient was undergoing radical prostatectomy and there was no significant delays and complications to surgery, we were not too concerned and are actually heartened by the safety profile overall.

Andrea Miyahira: Okay. Yeah, I saw that was very promising. What are your next steps for testing this in the clinic?

Eugene Shenderov: That's an important question that we are actually working on right now. Obviously the current trial is non-randomized, it's limited in size with only 32 patients. And so that means that we really need a randomized trial, we need a larger trial to understand whether the activity seen is really efficacy or just some sort of bias-induced artifact, and so we are planning a larger investigator-initiated trial that would be randomized, that would also be in the neoadjuvant setting, building on the fact that given how safe the agent appears to be, relatively speaking in terms of its toxicity and the fact that it might have efficacy in terms of eliminating micrometastatic disease using the composite recurrence-free survival that we sort of looked at.

If we can combine that with a randomized trial design with a larger trial design, and also with a longer follow up time, instead of, say, having the primary endpoint being for 1 year, but for, say, 3 years, then, theoretically, we could establish that we might have a relatively safe therapy to eliminate micrometastatic disease in addition to curative intent, local radiation, or surgical resection in terms of radical prostatectomy. And even if for 5-10% of men, we therefore change their paradigm and they would not occur instead of possibly recurring with high risk localized prostate cancer, that would mean tens-of-thousands of men per year, theoretically, would not be in the pool of men with recurrence and therefore not in the pool of men who would proceed, theoretically, to lethal metastatic prostate cancer. And that would be a major advance for the field.

Andrea Miyahira: Okay. Well, thank you so much. I look forward to seeing where this goes in the future. Thanks for joining us today.

Eugene Shenderov: Thank you for having me.