Glen Gejerman: Thank you.
Phillip Koo: So it's wonderful to see these phase three trials be positive and then reported out in these prestigious journals. Just let's go right into it and talk to us about the unique mechanism of action and the rationale for this study.
Glen Gejerman: Sure. We've made significant strides in managing very-low-risk and very-high-risk prostate cancer patients. So improvements in imaging, new genomic classifiers, digital pathology, AI review, really help identify patients best managed by active surveillance. The other end of the spectrum where the high risk patients, so the addition of androgen receptor pathway inhibitors to ADT, inpatient treated either with surgery or radiotherapy, as well as a better understanding of when patients need systemic either doublet or triple therapy have improved outcomes for the patients at highest risk. But there hasn't really been any major significant improvements for those in the intermediate-risk category, and that's really probably the bulk of the patients that we see. And we know that about 30% of these patients treated with radiotherapy will have a local recurrence. So that really led to the importance and the rationale for this trial.
Phillip Koo: I think that's such an important area that you're right, where we really haven't had those types of advancements. And whenever I see that statistic of 30 to 40% of men having biochemical recurrence, it's always a little shocking. So I think it's wonderful that we have some potential new therapies here. So talk us about the study design for this.
Glen Gejerman: Sure. So this is really based on other studies. We had phase one and two studies that have shown that the addition of CAN-2409, which is a replication-defective adenoviral vector, and that carries the herpes-simplex thymidine kinase gene. And when you add that to radiotherapy, there's synergy by inducing tumor cell necrosis and CDAT cells. So our study was a phase three multicenter randomized double-blind placebo-controlled trial in patients with intermediate and some high-risk localized prostate cancer patients. Patients are randomized in a two-to-one fashion to receive injections of CAN-2409 followed by two weeks of acyclovir versus placebo valacyclovir in combination with standard of care radiotherapy with or without ADT.
Phillip Koo: This design, I think it's the randomized double-blinded that we want to see. What's interesting is you also had path correlation later on after the treatment. Can you talk us a little bit about the thought process there?
Glen Gejerman: Sure. So let's talk about the primary findings. The study was conducted under a special protocol assessment with the FDA. The primary endpoint was disease-free survival, which was unique in that it was defined as time from randomization to any event, either local or regional failure, and that included a post-treatment positive biopsy. And what we found is that patients who received CAN-2409 had a longer disease-free survival than those patients that were treated with placebo in radiotherapy. The secondary endpoints included achieving a PSA nadir less than 0.2. And so we found that 67% in patients of CAN-2409 achieved that versus 59% of patients treated with placebo and pathologic complete response. We did post-treatment biopsies at two years and we found that 80% in the CAN-2409 group versus 63% in the placebo group achieved a negative post-treatment biopsy.
Phillip Koo: I think this is very provocative in the sense that oftentimes we always want to see overall survival, but we know we can't wait to se an overall survival signal, especially for these treatments that are upfront where there clearly is an unmet need. So I don't know, we're going to take a little detour here, but talk to us about this concept of these novel endpoints that you're using that clearly show a benefit to those who received the drug versus those who did not.
Glen Gejerman: Yeah, you're right. When we designed trials, as you pointed out, you'll need to wait 10 to 15 years. That's just the natural history of localized prostate cancer. So we worked with the FDA trying to come up with surrogate endpoints. And we felt that those two endpoints would be very important looking at a PSA nadir less than 0.2 because there's lots of data published on that. And then also uniquely the pathologic complete response. Not every trial does that because it could be difficult to convince patients to go ahead and follow through with that after treatment. But the FDA felt that if we could show that, there would be better outcomes in terms of pathologic response at the two-year endpoint, that we can use that as a surrogate. And then, of course, you want to see that translate into 10, 15-year disease-free survival. But if you want to try to make a major impact early on, we felt that was a good marker. That was a good place to put in.
Phillip Koo: That's great. So whenever you see these types of treatments, there's always a question of, all right, so what's the price? What's the cost? What are the adverse events? And talk to us about safety and tolerability.
Glen Gejerman: Yeah, I have to say CAN-2409 was really very well tolerated. I had the same concerns when I started enrolling my patients. I think let's just give it the most common and then were the most significant toxicity. So the most common treatment-related toxicity was really fever and chills that lasted about 24 hours after each injection. And that's really more of an immune response, very easily managed 24 hours. It didn't last longer than that. Sometimes patients use anti-inflammatories, not everybody did, but it really was self-limited, and after 24 hours, it went away. The most common Grade 3/4 toxicity was acute kidney injury. And interestingly, that occurred about 1% of both patients, patients that got CAN-2409 or placebo. And that was easily managed just by adjusting the dose of valacyclovir and it really was not a problem.
Phillip Koo: This is a type of immunotherapy, so it's nice to see this type of efficacy ends, this type of tolerability. What's the clinical significance of all this? What does this mean for patient care from your perspective, particularly as a radiation oncologist?
Glen Gejerman: Yeah, look, when I talk to my colleagues, I talk to patients, I try to put perspective to this. So this is a phase three clinical trial and it shows statistically significant and I think clinically meaningful improvement in disease-free survival with addition of CAN-2409. This is a patient with intermediate-risk prostate cancer, so we're trying to improve their outcomes when they get radiotherapy. The patients that received the investigational drug had a better chance of achieving a PSA nadir less than 0.2 and an improvement in the rate of complete pathologic response at the two-year post-treatment biopsy. I find that very significant.
Phillip Koo: Yeah, I would agree as well. And I think this is going to breathe a lot more excitement back into an area that hasn't been addressed and hopefully there continues to be more investigations into that intermediate space and potentially the high-risk space down the road as well. So congratulations, Glen, to you, the investigators, and most importantly, all the patients on this important manuscript that was published in Lancet Oncology. So can you sum up some take-home points for the audience?
Glen Gejerman: Yeah, high level, just three points. The addition of CAN-2409 to standard of care radiotherapy significantly improved disease-free survival in patients with intermediate-risk prostate cancer without significant toxicity. And these findings really suggest a potential paradigm shift in the way we manage these patients, and there's really potential to reduce many things, cancer-related anxiety, avoiding recurrences with salvage therapies after radiotherapy. And I think overall we can improve long-term oncologic outcomes.
Phillip Koo: That's such an optimistic message, decrease in anxiety and also decrease in recurrence. And we know less men will have to go through ADT and other drugs and whatnot. So I think that really brings a lot more hope to this space. So really appreciate the hard work that you and all the investigators and all the patients put into allowing this trial to come to completion. So congratulations and thank you.
Glen Gejerman: Thank you.