And so, what is aglatimagene besadenovec, or CAN-2409 for ease? It's a replication-defective adenoviral vector that delivers herpes simplex virus thymidine kinase to tumor cells specifically, which minimizes toxicity. And it's important to note that it's administered with an oral prodrug to allow for local activation. And then this HSV-TK component in the vector converts the prodrug, which we'll see as valacyclovir into a cytotoxic metabolite that gets incorporated into the tumor cell DNAs that's undergoing proliferation or repair.
And then this radiation synergizes with the aglatimagene by inducing DNA damage and activates the tumor microenvironment. This leads to tumor cell death, which releases antigens. And then the viral particles are going to promote activation and local recruitment of immune cells, which essentially leads to a sustained and intense local immune response that can help with fighting the tumor.
This agent has been studied in a few trials. I'll highlight a trial that was published in 2015, so nearly 11 years ago, that looked in a Phase IIa trial. This drug with the prodrug in localized either low to high-risk prostate cancer across the spectrum undergoing radiotherapy. And this demonstrated very impressive results. So the freedom-from-failure rates were 91 to 94%. For reference, historical context, it's 33 to 88%. And the two-year pathologic complete response at the biopsy was 94%, which is also much higher than what we classically see at 37% to 73%. So this really proved to be a great proof of evidence, or proof-of-concept, that this combination of CAN-2409 plus valacyclovir, the prodrug, when compared to placebo could reduce prostate cancer recurrence rate in localized prostate cancer patients undergoing curative intent radiotherapy, plus or minus short-term ADT, without adding any significant toxicity given the local effects.
So this study was a Phase III multicenter, double-blind trial across 51 centers in the US and Puerto Rico conducted over nine years between 2012 and 2021. The study sponsor was Candel Therapeutics, and they also did secure additional grant support from the NIH. Study eligibility, it was NCCN intermediate or high-risk prostate cancer patients. Important to note that they could not have had more than one high-risk criterion. These patients were planned for prostate-only external beam radiotherapy, either in standard or later in moderate hypofractionation. Whole pelvis radiotherapy was not allowed and short-term ADT less than or equal six months was permitted. Since this drug does depend on an intense local immune response, naturally HIV-positive patients were not allowed, and those who are on immunosuppressants were also not allowed to be on the trial. And these patients were required to have negative findings on conventional imaging for staging purposes.
We see here in the study design that was recently presented, nearly 750 patients, as we said, newly diagnosed intermediate or high risk patients with localized prostate cancer. They were randomized 2:1 to either the intervention arm, which was the aglatimagene with the prodrug valacyclovir. I want to note here that the dosing schedule was as follows. Patients received these three injections at least two weeks apart. The first one was two to eight weeks before the radiotherapy. The second was typically within zero to three days prior to the radiotherapy. And then the third course was given two to three weeks thereafter.
Now, when it comes to the valacyclovir, the prodrug, it's typically given two grams, three times daily. And importantly, it started the day after each injection. So you give the aglatimagene and then the next day they get the valacyclovir. The primary endpoint was disease-free survival, and this was defined as we see in the schematic below, as a composite endpoint of local failure where you have a mandated biopsy two years or either regional failure distant metastasis or death as defined by conventional imaging. When we look at key secondary endpoints, these included PSA-free survival, prostate cancer-specific survival, and overall survival as well.
From a practical standpoint, how do we give this agent? So as our urologists and many other providers will know as well, it's a very familiar setup. So similar to patients undergoing a prostate biopsy, be it transrectal or transperineal. Patients are usually placed in the knee-chest lateral, or more often lithotomy position. They approach it either, as I mentioned, transrectal or transperineal. Can be done in the office under some sedation and local anesthesia or can be done in ambulatory center. You prep the agent, which is typically two mls total, and we'll see it's four injections of 0.5. Typically, you want to use a 20 to 22 gauge five inch spinal needle. And then this drug is injected in four different quadrants. It's about 0.5 mls per quadrants, so total of two, when we consider the four quadrants.
It's usually given in two passes. If we think about it in the quadrants, on the left side, you have the left basal and left apical quadrants. And then on the right side, you have the right basal and right apical quadrants. So 0.5 mls in each. And then as I mentioned before, you give the valacyclovir the day after the injection each time. And I'll turn it over to Zach, who'll go over the results and discuss the significant findings from this trial.
Zachary Klaassen: Rashid, great intro as always, especially breaking down how easy this procedure is to do. Let's look at the baseline characteristics. As expected for intermediate high-risk population median age of around 69 years. We look at the demographics. Actually, impressively here, 19% in the aglatimagene arm, and 11% in the placebo arm were Black or African American. Majority were white, around 80%. When we look at the baseline NCCN risk categories, about 15% were high-risk, 85% were intermediate-risk. Median PSA, roughly 6.5 to 6.8. Majority of the Gleason groups were grade group two or three, around 85 to 87%. Majority, about three quarters, were T1c with several T2a tumors. Planned ADT use was about 50% in each group. And as expected, ECOG performance was excellent for these patients.
This is the primary outcome, disease-free survival, median follow-up of 50.2 months. We see the aglatimagene plus valacyclovir arm in blue, placebo plus valacyclovir arm in red. And at about 24 months, we see a consistent splitting of the DFS curves. Hazard ratio, 0.70, 95% confidence interval, 0.52 to 0.94, favoring the aglatimagene arm. So this was a positive trial. Looking at the subgroups, we see here some consistent results and benefit for aglatimagene for patients less than 65 years, those with intermediate NCCN risk, those that received ADT, and those that did not receive ADT, as well as breaking down the favorable here intermediate-risk having a benefit on the subgroup analyses.
Important other outcome was time to prostate cancer recurrence or prostate cancer death. Looks very similar to the DFS curve. Again, splitting around 24 months, favoring the aglatimagene arm, hazard ratio of 0.62, 95% confidence interval, 0.44 to 0.87. The reason they made this outcome was because there was only two mortalities from prostate cancer, so they combined this as PCa recurrence or PCa death. Similar subgroup analyses to DFS. And again, the similar benefit. The younger patients, those that were favorable, intermediate, and the ADT receipt was typically benefiting those that did not receive ADT. Again, that intermediate, younger patient population seeming to have the benefit on the subgroup analyses.
Treatment emergent adverse events. So how is this treatment affecting the patients? As we see here, treatment emergent adverse events Grade 3 or higher were only around 8% in both groups. Serious adverse events, 6% in the treatment, 7% in the placebo. When we drop down to the organ-based system of adverse events, most of these were GU, just over 50%, GI about 40%. What's interesting, when we look to the right side of the screen, looking at the aglatimagene plus valacyclovir arm, majority of these events were Grade 1 to 2 and self-limiting. So the ones of interest to this injection, these three courses of treatment, chills, 33% Grade 1 to 2, influenza-like illness, 30%. Pyrexia, 25%. And usually these went away within a couple of days. So this is a well-tolerated treatment based on these emergent adverse events.
So this is a Phase III trial that showed a statistical, significant and clinically-meaningful improvement in DFS for aglatimagene plus radiotherapy versus radiotherapy alone with a favorable risk-benefit profile to patients with localized prostate cancer who elect for radiotherapy with curative intent. We know that prevention of tumor recurrence reduces cancer-related anxiety due to the recurrence, but also avoids need for salvage therapies, including ADT at the time of recurrence. The key limitation from this trial, even with a very long accrual from 2012 to 2021, a 50-month follow-up makes it impossible to really show the impact of aglatimagene, a metastasis-free survival and overall survival in this study. This would require approximately median follow-up of about 10 years.
I think the main take-home is that this injection is simple in the hands of urologists or radiation oncologists. Takes about 20 minutes in an outpatient setting. You can put local anesthesia in, you don't have to necessarily. Generally well-tolerated by the patients. Again, roughly a couple of days of maybe flu-like symptoms and then full recovery, majority of these Grade 1 to 2 adverse events. So for take-home messages, aglatimagene plus valacyclovir led to a longer disease-free survival versus placebo plus valacyclovir when added to radiotherapy for localized prostate cancer without clinically increasing toxicity. This is the first multicenter randomized Phase III trial that achieved its primary and secondary endpoints and localized prostate cancer in more than 20 years. And it offers a potential framework shift in the treatment of intermediate to high-risk prostate cancer patients who seek a cure, particularly those receiving radiotherapy.
If approved, aglatimagene immunotherapy could represent the first new therapy for men with localized prostate cancer that we've seen in many decades. We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion.