Aglatimagene plus radiotherapy improves prostate cancer-specific DFS

Extended follow-up data from the randomized phase 3 PrTK03 trial (NCT01436968) evaluating aglatimagene besadenovec demonstrate a statistically significant 39% improvement in prostate cancer-specific disease-free survival (DFS) compared with placebo, with a favorable tolerability profile, according to results presented by Mark Garzotto, MD, professor of urology and radiation medicine at Oregon Health & Science University, at the 2026 American Urological Association Annual Meeting in Washington, DC.¹

Mechanism of action and administration

Aglatimagene is a replication-defective adenoviral vector engineered to deliver the herpes simplex virus thymidine kinase (HSV-TK) gene to tumor cells. Once inside the tumor, HSV-TK converts the oral prodrug valacyclovir into cytotoxic nucleotide metabolites that are incorporated into the DNA of proliferating or repairing tumor cells, halting DNA synthesis and triggering apoptosis. Radiation enhances the effect by inducing additional DNA damage and modulating the tumor microenvironment. As viral capsid proteins are released during tumor cell death, local and recruited immune cells are activated, generating tumor-specific T cells that may establish durable immunosurveillance.

The injection procedure is performed transrectally or transperineally—analogous to a standard transrectal ultrasound-guided biopsy—and can be completed in an office setting or ambulatory surgical center with local block or intravenous sedation. A total of 2 mL of aglatimagene is drawn and delivered via a 20-22G 5-inch spinal needle across 4 prostatic quadrants (0.5 mL per site). Each injection course is followed by 14 days of oral valacyclovir 2 g 3 times daily (adjusted for renal function). Three injection cycles are administered: 14 days before radiotherapy, at the start of radiotherapy, and 14 days into the radiotherapy course.

Trial design and patient population

The phase 3 trial, conducted under a Special Protocol Assessment agreed upon with the FDA, enrolled 745 men with newly diagnosed intermediate- to high-risk localized prostate cancer. Patients were randomly assigned 2:1 to aglatimagene plus valacyclovir (n=496) or placebo plus valacyclovir (n=249), each administered with radiotherapy with or without short-course androgen deprivation therapy (ADT). Randomization was stratified by National Comprehensive Cancer Network risk group and planned ADT use.

The 2 arms were well balanced at baseline. Median age was 69 years overall. Approximately 85% of patients in both arms were classified as intermediate-risk, with 15% as high-risk. The median PSA was 6.7 ng/mL (range, 0.8-63.3 ng/mL), and 85% of patients had a Gleason score of 7. Approximately half of all patients had planned ADT. Black/African American men comprised 16.2% of the total enrolled population, providing meaningful racial representation in the trial.

The primary end point—overall DFS, defined as time from randomization to prostate cancer recurrence (biopsy, clinical, or radiographic evidence), metastasis, or death from any cause—was previously reported and is currently in press in Lancet Oncology.² The current presentation focused on the key secondary end point of prostate cancer-specific DFS, defined as time from randomization to prostate cancer recurrence, metastasis, or prostate cancer-specific death, with a data cutoff of March 15, 2026, at a median follow-up of 58.0 months (95% CI, 56.6-60.2).

Efficacy outcomes at extended follow-up

In the intent-to-treat population, aglatimagene plus standard-of-care (SoC) radiotherapy produced a 39% improvement in prostate cancer-specific DFS compared with placebo plus SoC (HR, 0.61; 95% CI, 0.44-0.85; P = .0031). Only 2 prostate cancer-specific deaths were recorded over the follow-up period—one in each arm—reflecting the early-stage, curative-intent nature of the study population.

"These data are mature but trending in the right direction," Garzotto said. "We see a longer time to salvage anti-cancer therapy as well as biochemical failure in the patients treated, and these hazard ratios are about 0.72. This separation occurs at about what you'd expect based on what would be predicted with the disease-free survival end point."

Consistent with the primary DFS benefit, both time to new anticancer therapy (HR, 0.72; 95% CI, 0.39-1.31) and time to biochemical failure by the nadir+2 definition (HR, 0.72; 95% CI, 0.40-1.31) favored the aglatimagene arm. Garzotto noted that separation between the curves on these secondary endpoints emerged at approximately 6 years, a timeline he described as expected given the biology of the disease and the nature of the primary end point.

Rates of distant metastasis were lower in the aglatimagene cohort, occurring in 8 of 496 patients (1.6%) vs 7 of 249 patients (2.8%) in the placebo group (HR, 0.58; 95% CI, 0.21-1.59). Garzotto characterized the metastasis data in the intermediate-risk subgroup as particularly noteworthy.

Intermediate-risk subgroup results

Among the 635 intermediate-risk patients, aglatimagene plus SoC was associated with a 41% improvement in prostate cancer-specific DFS (HR, 0.59; 95% CI not fully legible, p reported as highly statistically significant). Time to new anticancer therapy (HR, 0.51; 95% CI, 0.24-1.1) and time to biochemical failure (HR, 0.48; 95% CI, 0.22-1.03) both favored the aglatimagene arm in this subgroup.

"In the intermediate groups, this is the subgroup of 635 patients, we also observed a 41% improvement in prostate cancer-specific disease-free survival," Garzotto said. "And once again, we're observing improvements in salvage anti-cancer therapy as well as biochemical failure in this group with a hazard ratio that's down to 0.51. And this is very close—you can see the upper bound of the confidence interval is very close to one in both of these studies."

The metastasis data in the intermediate-risk group were also notable.

"This was positive with the hazard ratio of 0.1 or 90% reduction in the rate of metastasis," Garzotto reported.

Safety and tolerability

The combination regimen was generally well tolerated. No grade 4 or higher treatment-related adverse events (TRAEs) were reported in either arm. Serious adverse event (SAE) incidence was 5.8% in the aglatimagene plus SoC arm vs 7.3% in the placebo plus SoC arm. Discontinuation due to adverse events occurred in 5.4% vs 6.0% of patients, respectively. Treatment-related SAEs were low, at 1.7% in the aglatimagene arm vs 2.2% in the placebo arm.

The most common TRAEs—occurring in greater than 5% of patients in either arm—were chills (33.4% vs 8.6%), influenza-like illness (30.5% vs 13.8%), fever (25.1% vs 3.9%), and fatigue (18.2% vs 15.1%). More than 90% of fever, flu-like symptoms, chills, and fatigue resolved within 24-72 hours. Grade 3 TRAEs occurred in fewer than 5% of patients.

Conclusion and clinical implications

Garzotto summarized the accumulating evidence as supporting a durable clinical benefit for aglatimagene when added to EBRT. Extended follow-up data corroborate the previously reported primary DFS end point through the observation of delayed biochemical failure, reduced metastatic disease, and delayed initiation of salvage anticancer therapy.

"If approved, [aglatimagene] could offer a new treatment option that may extend the time men live free from prostate cancer recurrence," Garzotto said.

References

1. Garzotto M, Sylvester J, Wheeler T, et al. Extended follow-up shows accumulating benefit for patients treated with aglatimagene besadenovec (CAN-2409) +prodrug in combination with standard of care external beam radiation (EBRT) in men with localized prostate cancer: Update from a randomized placebo-controlled phase 3 clinical trial. Presented at: 2026 American Urological Association Annual Meeting. May 15-18, 2026. Washington, DC. https://www.auajournals.org/doi/10.1097/01.JU.0001192572.07890.f8.01

2. DeWeese TL, et al. Phase 3 clinical trial of aglatimagene besadenovec in patients with newly diagnosed, intermediate- to high-risk, localized prostate cancer. Lancet Oncol. In press.

3. Singh S, et al. 2-year pathological complete response in the ASCO prostate cancer trial following a single dose of ADXS31-142 in combination with pembrolizumab in patients with prostate cancer. Prostate Cancer Prostatic Dis. 2021;24:612-622.