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Leslie Ballas: Hi, I'm Leslie Ballas, a radiation oncologist at Cedars-Sinai in Los Angeles, and I am so pleased to be joined today by Angela Jia, who's an assistant professor of radiation oncology at the University Hospital Seidman Cancer Center in Cleveland, Ohio. She is here today to discuss the phase three randomized placebo control clinical trial of CAN-2409 plus prodrug, in combination with standard of care external beam radiation for newly diagnosed localized prostate cancer. This was an abstract presented at ASCO in 2025 by Dr. DeWeese on behalf of the multi-institutional group that ran this trial. And Dr. Jia was the discussant at ASCO and really had some great insight into this trial and how it fits in our current paradigm for localized prostate cancer, and so we welcome her to join us today. Thanks for joining us, Angela.

Angela Jia: Thank you so much, Dr. Ballas. Very happy to be here, thank you for having me.

Leslie Ballas: So, why don't you start off by describing to our viewers what CAN-2409 is?

Angela Jia: Yeah, so, thank you. So CAN-2409, this is an adenovirus but it's not an active virus at all. What it is, is an adenoviral vector that's injected straight into the prostate, and then the patient takes a prodrug called Valacyclovir. And so when the prodrug, it will activate the CAN-2409 if you will, inside the prostate, it gets converted into an active drug that then does cell damage and kills prostate cancer cells. So it's kind of like giving a nonspecific drug but then eliciting a very targeted response within the prostate itself.

So as you mentioned, this is a large phase three trial. It was in intermediate risk prostate cancer patients. It did also include some high risk patients, I believe up to 15% were high risk. They were only allowed one high risk feature, but patients were randomized two to one, to either receive the CAN-2409, this double blind study study, but either to receive the CAN-2409 intraprostatic injections versus the placebo, and everybody had the prodrug. Short-term ADT was allowed, it was not mandated and it was a stratification factor, and their primary endpoint was disease-free survival. Now, their disease-free survival include a two-year post-treatment prostate biopsy. So after all the treatment's done, 24 months later we take a prostate biopsy, we look for viable cells. And if there were viable cells left, that would be an event. And then of course DFS also includes regional, distant failure, or death.

Leslie Ballas: And how many injections were performed on the trial? Was it just once?

Angela Jia: Yeah, there were three injections. So the first injection happened after a few days, excuse me, I don't remember the exact duration. First injection happens, second injection happens. Shortly after the second injection, radiation starts, it's external beam radiation therapy. The radiation starts, and then the third injection occurs while the patient is already receiving external beam.

Leslie Ballas: And it's done under ultrasound guidance, I presume?

Angela Jia: Right, and it's intraprostatic, so straight into the prostate.

Leslie Ballas: One of the things that you mentioned was that about 15% of patients on the trial had high-risk disease, but patients were only allowed on trial if they had less than six months of ADT, at least per the abstract. Most people would not treat a high-risk patient with external beam in less than six months of ADT. Do you know how that skews the results or was that presented at all during ASCO?

Angela Jia: Yeah, I haven't seen that and we're awaiting final publication of this and for them to break that group out more. What they did show was, they showed, I'm going to get to that high-risk point, but they showed that in the intermediate risk group, because ADT was a stratifying factor, so about half had ADT and half didn't. But in the at least intermediate risk group, when ADT was on board, the hazard ratio was no longer statistically significant for disease-free survival. Meaning if ADT was on board having CAN-2409, this intraprostatic injection, no longer seemed to have a statistically significant difference in disease-free survival. This was broken down just for the intermediate risk group and not for the high risk.

So we are awaiting, kind of seeing what the result is in the high-risk group. Was it beneficial with or without ADT? And for that matter, six months of ADT is not our typical, we typically go long-term, 18 to 24 months. So, that is a question on this trial.

Leslie Ballas: What do you make of that result that you just highlighted about the disease-free survival not being of statistical significance when ADT was on board in these intermediate risk patients? Do you think that CAN-2409 could replace ADT in certain patient populations?

Angela Jia: Yeah, I think that is unclear right now. If you look, they showed a very nice curve of disease-free survival over time. And if you look at that curve, the two curves are on top of each other in the beginning, and then right at the 24-month mark is where they separate. And that is where they get their two-year prostate biopsy, right? Two-year post-treatment prostate biopsy, where a complete pathologic response was seen in about 80% of patients getting CAN-2409, versus only about 63% of patients on placebo. And so that large difference in pathologic complete response kind of reflects the sudden separation of the curves, and the curves kind of stay in parallel from then on. Right?

So, one thought is, is the pathologic complete response mainly driving this difference in disease-free survival? So your point is an excellent one, in that if in the presence of ADT we lose the statistical significance of CAN-2409, perhaps we should have a non inferiority trial in intermediate unfavorable risk patients who get ADT, randomizing them to ADT or CAN-2409. I think that is a question right now, because we know also from RTOG-9408, which was another large phase three that did a post-treatment prostate biopsy, on that study, having short-term ADT on board cut the rate of a positive prostate biopsy by half. I think it went from about 40% to about 20%, so it cut it by half. So to your point, can CAN-2409 replace ADT? That's a question, but I think a bigger question is we know ADT doesn't just have local effects, there's a decrease in distant metastasis with ADT. And those are figures and numbers that we're still waiting to see from this study.

Leslie Ballas: So to build off of that and discuss other mechanisms of what we believe to be disease-free survival benefit based on a local benefit, based on local control benefit, the FLAME trial looked and evaluated the idea of a microboost to the area of MRI-detected disease during the course of external beam radiation. They reported, granted with a much longer follow-up, 72 months, disease-free survival with a hazard ratio of 0.45. In this study, shorter follow-up, but the hazard ratio was 0.62. When you're evaluating as a clinician two different things that seem to give a local benefit, how do you evaluate those two against one another, in concert with one another? How are you thinking about this CAN-2409 in that setting?

Angela Jia: Yeah, I think that's a really good point. And we have to remember, CAN-2409 was started earlier, before we routinely used MRI, certainly before FLAME. And so, one of the questions we do have is, how does CAN-2409 fit into modern methods of dose intensification? Especially FLAME, unlike ASCENDE-RT, which was a brachy boost and that had real grade three increased toxicities. FLAME was isotoxic in its approach, where OARs took priority and we would try to boost the lesion as much as we could without violating OAR constraints. And by doing so, you can see there's, as you mentioned, that improvement in local control.

I think it's very hard to compare the two, they're two very different methods and ultimately in CAN-2409 a question we have is, does it have any systemic effects, right? Because it up-regulates T-cells, what are those systemic effects? And I'm curious, so far OS is not different, not that we expect it to be different with a shorter follow up. And prostate cancer specific mortality is no different, I think there was one death on each arm. But what I'm curious to see are things like MFS or DM rate to try to understand if there is more of a systemic effect from CAN-2409. That, I'm not sure, but we've seen in FLAME. Now, we also have to think about CAN-2409 is a little bit more involved, in that it has these invasive procedures or intraprostatic injections, and there are three of them. And these days, as we hypofractionate more and even ultra hypofractionate more, how does that fit into how we currently treat? That's another question. So, I think at the end of the day we do have these two methods to reduce local failure, but it's very hard to directly compare them.

Then the last thing we should just always keep in mind, reducing local failure is important because salvage therapies are toxic, but local failure is really not a surrogate endpoint in localized prostate cancer, it's really MFS, metastasis free survival. We think about why that is, it's that in local recurrence it includes non-lethal, grade group one, grade group two recurrences, and also just the variable natural history of localized prostate cancer where most patients die of non-cancer related causes. And so, we just need to keep in mind that the endpoint use here would not be like a surrogate for survival in localized prostate cancer.

Leslie Ballas: Agreed, although it's obviously extremely exciting to see an oncolytic virus show benefit and be a new type of treatment for intermediate, possibly high risk prostate cancer. Do you think that CAN-2409, once it gets FDA approval, is ready for prime time? Would you use it in your patients once it's approved?

Angela Jia: Yeah, that's a great question. I think it depends. There's specific patient factors, right? I've talked about the logistics of it, it's three intraprostatic injections. Some patients these days when we do ultra hypofractionation and we use a spacer gel and fiducials, even that procedure some patients don't want to do. And you can imagine having to then convince them to do three separate intraprostatic injections. That's a logistic piece that I think needs to be discussed and worked out and see if we can just optimize, especially in the setting of, can we do this with five treatments in ultra hypofractionation, right? That's one question.

Two, given that lack of hazard ratio statistical significance in the setting of ADT, and given the fact that standard of care of intermediate unfavorable risk is ADT, short-term ADT with radiation, until CAN-2409 is shown to be equivalent to that, I think most people may just favor standard of care, especially if it's less of an invasive procedure.

But I think where it would be really interesting is if we can select for the patients who would most benefit from this, right? Maybe who have tumor biologies that would most benefit from this. So the PORTOS gene signature that was presented at ASCO-GU earlier this year, PORTOS stands for Prostate Cancer Radiation Therapy Outcome Scores, and it's a gene expression signature and was validated in two randomized control trials to predict which patients would respond to higher doses of radiation, this dose intensification in both localized setting and post-op setting, actually. But, higher PORTO scores were associated with hypoxia and immune responses, so maybe patients with higher PORTO scores are the population who would derive more benefit from CAN-2409. So, I think an interesting study would be high-risk patients who with high PORTO scores, and in them randomization between a FLAME-like boost versus CAN-2409 and seeing what the outcomes of that are.

Leslie Ballas: Even though all those patients would get 18 to 24 months of ADT.

Angela Jia: Yeah, and then that could be a discussion then, right? But you're right, yes. The standard of care is still 18 to 24 months of ADT. But yeah, trying to see if this is... Because in essence, this is another method of intensifying local treatment with a questionable potential systemic benefit that we're waiting for final publication to see if there was a difference in METS.

Leslie Ballas: Well, thank you for breaking this down for us and helping us understand this abstract. It certainly is very interesting and quite novel and is sort of a really, I would think a physician-scientist kind of dream scenario where you get a true bench-to-bedside drug or oncolytic virus that can affect patient outcomes.

Angela Jia: Absolutely, I agree. It is very, very exciting and it's another tool in our belt, and just have to figure out who's the right patient population to use this in.

Leslie Ballas: Thank you Dr. Jia,

Angela Jia: Thank you so much for having me.