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Andrea Miyahira: Hi everyone, I'm Andrea Miyahira, here at the Prostate Cancer Foundation. Joining me today is Nonna Shakhnazaryan, a clinical research supervisor at UCSF.
She will discuss her team's recent ASCO poster presentation, a phase 1b dose escalation study of FOR46, a novel antibody drug conjugate targeting a tumor specific epitope of CD46 in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer.

Thank you so much for joining us today, and I look forward to learning about this study.

Nonna Shakhnazaryan: Thank you, Andrea. I'm happy to be here to present on this study as well.

So I'll be speaking on the phase 1b dose escalation study of FOR46 in combination with enzalutamide, in patients with metastatic castration-resistant prostate cancer.
That's going to be our presentation outline.

So just a little background here. So CD46 is a membrane cofactor that is involved in the negative regulation of complement activation. And the antibody we've generated here is called YS5FL. It binds to the specific epitope of CD46, and to a high degree of specificity in prostate cancer cells, which is shown over on the figure on the left, and to some degree to placental and normal prostate epithelium.

With this in mind, we've generated a FOR46 molecule with the intention of inducing cytotoxicity. So there are three parts to this molecule, including the antibody itself, the cleavable linker, and the MME payload.

For our proposed mechanisms of action, so this is a combination study, we are first inducing patients with enzalutamide at least for 14 days if they have not had enzalutamide previously. And this allows them to further express the CD46 marker on those prostate cancer cells, allowing then for more effective targeting of FOR46.

Just a little bit about our study design, so this is a Simon plus three plus three Simon design, that's dependent on dose-limiting toxicities. We've just completed the phase 1b portion and we explored the three different dose levels.

Our patient selection really focused on making sure the patients had progressive mCRPC per prostate working group criteria three, and then at least one prior ARPI, and no prior taxane therapy in the CRPC disease setting.

For our primary endpoints, we looked at determining the maximally tolerated dose, as well as the recommended phase 2 dose. For our secondary endpoints, we looked at several factors, so PSA 50 response rate, the objective response rate, as well as the median radiographic free progression survival, and then overall survival. We've also monitored our adverse events to make sure that we're looking at the safety profile of these drugs in combination.

So onto the findings. So this is some of our baseline characteristics, where one of the more notable ones is that 71% of our patients had two or more prior lines of ARPIs. And for the baseline metastases, bone metastasis was pretty dominant at 94%, with 18% at visceral disease, which is usually a marker for higher risk disease.

And the figure over in the middle for the dose cohorts that were explored, our MTD ended up being the 2.1 milligram per kilogram with the prophylactic G-CSF, and no patients experienced any DLTs at this dose level.

And then I would like to highlight, I don't think I actually mentioned this briefly, but I would want to talk about it a little bit more, is the ImmunoPet imaging study. So we are utilizing this study, it's optional for phase 1, but it's going to be mandatory for our phase 2 study.

Essentially, this is a figure from one of our patients, a 72-year-old patient, and it clearly shows tumor-specific uptake into the CD46 prostate cancer tissue. So it has potential to be used as a predictive biomarker for our patient selection.

Looking at our safety profile. So some of our more common treatment-related adverse events were fatigue, peripheral neuropathy, and decreased appetite, all of which range from grade one to grade two. Our more notable adverse events that led to treatment discontinuation were elevated LFTs, grade two neuropathy, and hyponatremia.

As for efficacy, so for the graph with the duration of treatment, each row represents a patient. We still have three patients on the study. And the median duration of treatment was six months.
Over on the left, for radiographic progression-free survival, we measured it to be the median RPFS at 10.2 months. And for our waterfall plot, anywhere where you see an E is actually patients who had previous progression on enzalutamide upon enrolling onto this study. So 71% of patients, that's 12 out of the 17, had PSA declines. Five of the 12 were patients who previously progressed on enzalutamide, amounting to 42%.

In summary, our maximally tolerated dose was established at 2.1 with the primary G-CSF. And our common treatment-related adverse events mirrored the same safety profiles of the known FOR46 and enzalutamide. And our CD46 PET imaging probe demonstrated tumor-specific uptake, supporting its utility in being a predictive biomarker for treatment response.

And so for our preliminary data, which I mentioned briefly, is we've observed PSA declines in 12 of the 17 patients, amounting to 71% and a median RPFS at 10.2 months.

For our future directions, we have an ongoing phase 2 study. It's actually almost going to reach close to enrollment for this one, to further evaluate efficacy and safety. And we are employing the use of the CD46 PET imaging study as mandatory for patient selection, and also just to improve on our current treatment protocols.

As for acknowledgments, so I want to say a huge thank you to the patients and their families, the Prostate Cancer Foundation, our partners over at Fibrogen and Fortis Therapeutics, the Department of Defense of Prostate Cancer Research Program, and the NIH. Thank you.

Andrea Miyahira: Thank you for sharing that. So this study suggests promising PSA responses and disease control rates with FOR46 plus enzalutamide in this population. Can you estimate how much of this activity is attributable to FOR46 or the combination versus enzalutamide alone? And what is indicated by responses seen in the patients who previously progressed on enzalutamide?

Nonna Shakhnazaryan: So we can't make a direct leap, just given the nature of the study. It's a combination arm study, so it would be difficult for us to predict the individual contributions of FOR46 and enzalutamide.

I think the best predictive marker of seeing if FOR46 is actually working, or if they have this synergistic effect, is looking at that waterfall plot with the five patients who previously progressed on enzalutamide had a PSA decline. And so that gives us a pretty good sense that it's working and that the combination therapy has potential.

Andrea Miyahira: So I know that using the FOR46 PET imaging probe was not required for every patient, but do you know if responses correspond with FOR46 expression?

Nonna Shakhnazaryan: So we have utilized, or at least we're currently testing out different... two IHC assays. However, they're not epitope specific and nor do they correlate with PSA50 response and the median RPFS.

So we are going to be likely utilizing the CD46 PET imaging probe data, because something interesting to note is they actually utilize the same antibody backbone as the FOR46 ADC. So we believe it'll be a better marker for patient selection than the IHC assays.

And then just a little bit more on that, so we are hopefully going to have more sufficient data to answer the questions we're going to be exploring, in terms of objective response rate and then the PSA50 response rate once patients have completed the planned phase 2 dose of the monotherapy FOR46 study, as well as completion of this current combination therapy study. So we'll likely have more data with that.

Andrea Miyahira: Okay, thanks. And just if you could detail again, what are the next steps planned for the clinical development of FOR46?

Nonna Shakhnazaryan: So we have planned a phase 2, phase 3 study, a randomized trial of FOR46 versus standard of care therapy. And then for the phase 3 portion, we are hoping to utilize the CD46 PET imaging data to better select our patients. And then we're going to submit the IND actually for this study fairly soon, in Q3 of this year.

Andrea Miyahira: Okay. Well, thank you so much for sharing this promising study with us today.

Nonna Shakhnazaryan: Thank you. And thank you for having me.