Curative-intent radiotherapy is a standard treatment option for patients with localized prostate cancer, often combined with androgen deprivation therapy when clinically indicated. However, disease recurrence remains an important challenge, particularly for patients with intermediate-risk or selected high-risk disease, and salvage treatments can add substantial toxicity and affect quality of life.
A phase 3 trial evaluated whether adding intraprostatic aglatimagene besadenovec, also known as CAN-2409, plus valacyclovir to standard external beam radiotherapy could improve outcomes in patients with localized prostate cancer treated with curative intent.
The original article, titled “Aglatimagene besadenovec (CAN-2409) with radiotherapy for patients with localised prostate cancer: a phase 3, multicentre, randomised, double-blind, placebo-controlled trial,” was published in The Lancet Oncology in June 2026.
Authors: Theodore L. DeWeese, Andrea Manzanera, John Sylvester, Thomas Wheeler, Thomas Schroeder, Glen Gejerman, Gregory Chesnut, Thomas M. Facelle, Mark G. Garzotto, Christopher Pieczonka, Nilay M. Gandhi, Steven Sukin, Michael A. Liss, Ronald Tutrone, Bryan Mehlhaff, Stephen J. Savage, Megan Goody, Jenessa Vogt, Shangbang Rao, Maria Lucia Silva Polanco, Francesca Barone, W. Garrett Nichols, and Paul P. Tak, on behalf of the PrTK03 study team.
Why This Study Matters
For patients with localized prostate cancer, the goal of definitive treatment is long-term disease control while minimizing treatment-related side effects. Radiotherapy can be curative, but recurrence still occurs in a proportion of patients and may lead to additional treatments such as androgen deprivation therapy, prostatectomy, further radiation, or systemic therapy.
Aglatimagene besadenovec is a replication-defective adenoviral vector carrying the herpes simplex virus thymidine kinase gene. It is injected directly into the prostate and given with the prodrug valacyclovir. This approach is designed to induce tumor cell death and stimulate an antitumor immune response, potentially enhancing the effect of radiotherapy.
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Study Design
This was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial conducted at 51 centers across the United States and Puerto Rico. The study enrolled men aged 18 years or older with newly diagnosed, histologically confirmed localized prostate adenocarcinoma. Eligible patients had intermediate-risk localized prostate cancer or localized disease with one high-risk criterion and were planning to receive prostate-only external beam radiotherapy. Patients with low-risk disease, more than one high-risk criterion, nodal involvement, distant metastases, previous prostate cancer treatment, or planned whole-pelvic irradiation were excluded.
Patients were randomly assigned in a 2:1 ratio to receive either:
- Aglatimagene besadenovec plus valacyclovir with standard-of-care radiotherapy
- Placebo plus valacyclovir with standard-of-care radiotherapy.
Randomization was stratified by risk category and planned androgen deprivation therapy use. Patients received three intraprostatic injections of aglatimagene or placebo. Valacyclovir was given orally after each injection. Radiotherapy consisted of standard-fractionated external beam radiotherapy or moderate hypofractionated radiotherapy, with short-course androgen deprivation therapy allowed at the treating physician’s discretion. The primary endpoint was disease-free survival in the intent-to-treat population.
Patient Population
Between February 2012 and September 2021, 745 men were randomized: 496 to aglatimagene plus valacyclovir and 249 to placebo plus valacyclovir. The median age was 69 years. Most patients had intermediate-risk disease, representing 85% of the study population, while 15% had high-risk disease. Among patients with intermediate-risk disease, 38% had favorable intermediate-risk disease and 62% had unfavorable intermediate-risk disease.
Short-course androgen deprivation therapy was planned in 49% of patients. Overall, 90% of patients in the aglatimagene group and 86% in the placebo group completed treatment.
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Disease-Free Survival
After a median follow-up of 50.3 months, aglatimagene plus valacyclovir was associated with significantly longer disease-free survival compared with placebo plus valacyclovir. Disease-free survival events occurred in 113 patients, or 23%, in the aglatimagene group and 76 patients, or 31%, in the placebo group. Median disease-free survival was not reached in the aglatimagene group, compared with 86.1 months in the placebo group. The hazard ratio was 0.70, with a 95% confidence interval of 0.52 to 0.94, and the result was statistically significant.
Prostate Cancer-Specific Outcomes
Aglatimagene also improved prostate cancer-specific disease-free survival. Events occurred in 17% of patients in the aglatimagene group and 25% of patients in the placebo group. The hazard ratio for prostate cancer-specific disease-free survival was 0.62, with a 95% confidence interval of 0.44 to 0.87.
The proportion of patients achieving a PSA nadir of 0.2 ng/mL or lower was also higher with aglatimagene: 67% versus 59% with placebo. Overall survival was comparable between groups at the time of analysis. Median overall survival was not reached in either group, and only two prostate cancer-related deaths were reported, one in each treatment arm.
Pathologic Complete Response
A post-hoc blinded review of evaluable 2-year post-radiotherapy biopsies showed higher negative biopsy rates with aglatimagene. Among patients with evaluable biopsies at the 22–26-month timepoint, negative biopsies were reported in 80% of patients in the aglatimagene group compared with 63% in the placebo group. This finding supported the disease-free survival result, although the analysis was exploratory and based on patients with available biopsies.
Safety
Aglatimagene plus valacyclovir was generally well tolerated. Grade 3 or worse treatment-emergent adverse events occurred in 8% of patients in the aglatimagene group and 7% in the placebo group. The most common grade 3 or worse event was acute kidney injury, reported in 2% of patients in each group.
Serious adverse events occurred in 6% of patients receiving aglatimagene and 7% receiving placebo. Treatment-related serious adverse events occurred in 2% of patients in each group. No treatment-related deaths were reported.
The most common treatment-related adverse events included chills, influenza-like symptoms, pyrexia, increased urinary frequency, and nausea. These events were mostly low grade. Patient-reported quality of life outcomes were similar between treatment groups over 2 years.
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Limitations
The study had several limitations. Median follow-up was 50.3 months, which is not long enough to determine the impact of treatment on metastasis-free survival or overall survival in localized prostate cancer, where longer follow-up is often required.
The trial was not powered to independently test multiple subgroups. In addition, the trial included patients with only one high-risk criterion and excluded those with more than one high-risk criterion. Many patients with high-risk disease did not receive long-term androgen deprivation therapy, which is currently recommended for some high-risk patients receiving definitive radiotherapy.
The study also did not measure neutralizing antibodies against adenovirus, leaving uncertainty about whether baseline or induced humoral immunity may have influenced treatment activity.
Takeaway
In this phase 3 randomized trial, aglatimagene besadenovec plus valacyclovir added to standard radiotherapy significantly improved disease-free survival in men with localized intermediate-risk or selected high-risk prostate cancer. The treatment did not appear to increase clinically significant toxicity, and quality of life outcomes were similar between groups.
These results support aglatimagene besadenovec as a potential new treatment approach for patients with localized prostate cancer receiving curative-intent radiotherapy, while longer follow-up will be important to clarify its impact on metastasis-free and overall survival.
The full article was published in The Lancet Oncology.