Approximately 30% of men with intermediate- to high-risk localized prostate cancer experience disease recurrence after definitive radiotherapy, often requiring salvage therapies associated with substantial morbidity.[1]
A phase 3, multicenter, randomized, double-blind, placebo-controlled trial, funded by Candel Therapeutics and the US National Institutes of Health (CA124032), was designed to evaluate whether the addition of the investigational immunotherapy aglatimagene besadenovec (CAN-2409), an investigational, off-the-shelf viral immunotherapy designed to trigger the body’s immune system to attack solid tumors, plus the prodrug valacyclovir (Valtrex®; GSK) to standard external beam radiation therapy (EBRT) could improve disease-free survival (DFS) in this population. The study demonstrated a statistically significant and clinically meaningful improvement in DFS without increased toxicity, offering a potential paradigm shift in the management of localized prostate cancer.
Prostate cancer remains the most commonly diagnosed malignancy among men in the United States and a major global health burden, with 1.4 million new cases worldwide in 2020 (WHO, 2025).[1] For patients with intermediate- or high-risk localized disease, curative-intent therapy typically consists of radical prostatectomy or EBRT, with or without androgen deprivation therapy (ADT) (AUA/ASTRO Guideline, 2022).[2] Despite optimal local treatment, up to 30% of patients develop recurrence, leading to anxiety, additional interventions, and significant impacts on quality of life. There is an urgent unmet need for innovative strategies that can improve long-term disease control while minimizing adverse effects.[2]
Aglatimagene besadenovec (CAN-2409) is a replication-defective adenoviral vector encoding the herpes simplex virus thymidine kinase (HSV-tk) gene. When delivered intraprostatically and paired with a prodrug such as valacyclovir, HSV-tk phosphorylates the prodrug into a cytotoxic nucleotide, selectively targeting proliferating tumor cells and enhancing immune-mediated tumor cell death. Preclinical and early-phase clinical studies demonstrated both radiosensitization and immune activation with this approach, providing the rationale for definitive evaluation in a phase 3 setting.
Study design
This phase 3, double-blind, placebo-controlled trial was conducted at 51 centers across the US and Puerto Rico. Eligible men (age ≥18) had newly diagnosed, histologically confirmed intermediate- or high-risk localized prostate adenocarcinoma and were planning curative-intent EBRT. Patients were randomized 2:1 to receive either three ultrasound-guided intraprostatic injections of aglatimagene (5 × 10¹¹ viral particles per dose) plus oral valacyclovir, or matched placebo injections plus valacyclovir, alongside standard-of-care EBRT (either conventional or hypofractionated). ADT use was permitted per standard guidelines and physician discretion.
The primary endpoint was disease-free survival, defined as time from randomization to local, regional, or distant recurrence, or all-cause mortality. Secondary endpoints included prostate cancer-specific DFS, PSA nadir ≤0.2 ng/mL, biopsy-confirmed absence of tumor at 2 years, overall survival, and patient-reported quality of life. Safety was assessed in all patients receiving at least one study injection. The trial was conducted under a Special Protocol Assessment with the US Food and Drug Administration (FDA) and remains in long-term follow-up (NCT01436968).
Study outcomes
Between February 2012 and September 2021, 745 men were randomized: 496 to aglatimagene plus valacyclovir and 249 to placebo plus valacyclovir. Median age was 69 years, with 85% intermediate-risk and 15% high-risk disease. Median follow-up was 50.3 months.
Efficacy
Aglatimagene significantly improved DFS compared with placebo (hazard ratio [HR] 0.70; 95% CI 0.52–0.94; p=0.016). At analysis, median DFS was not reached in the aglatimagene group versus 86.1 months in the placebo group. DFS events (recurrence or death) occurred in 23% of aglatimagene-treated patients versus 31% with placebo.
Prostate cancer-specific DFS was also superior with aglatimagene (HR 0.62; 95% CI 0.44–0.87; p=0.0046). Prostate cancer-specific events occurred in 17% of the aglatimagene group and 25% of the placebo group.
A higher proportion of patients in the aglatimagene group achieved a PSA nadir ≤0.2 ng/mL (67% vs 59%, p=0.016). Among evaluable 2-year post-radiation biopsies, 80% in the aglatimagene group had negative biopsies versus 63% with placebo (p=0.0018).
Safety
Treatment-emergent adverse events (TEAEs) were common but mostly mild to moderate. Grade ≥3 TEAEs occurred in 8% of aglatimagene patients and 7% of placebo patients. The most frequent grade ≥3 event was acute kidney injury (2% in each group), with no treatment-related deaths observed. Serious adverse events occurred at similar rates in both groups (6% vs 7%). Patient-reported health-related quality-of-life (hrQoL) outcomes were comparable between arms at 2 years.
Discussion
This pivotal phase 3 trial demonstrates that adding aglatimagene besadenovec plus valacyclovir to standard EBRT significantly improves disease-free survival in men with intermediate- or high-risk localized prostate cancer, without an increase in clinically significant toxicity. The improvement in DFS, prostate cancer-specific DFS, PSA outcomes, and pathological complete response rates suggests enhanced local and systemic tumor control. Notably, the administration of aglatimagene was well tolerated, with adverse events consistent with established safety profiles for gene therapy and standard radiotherapy. The logistical simplicity of the intraprostatic injection, the short course of therapy, and the favorable toxicity profile support feasibility and patient acceptability.
The main study limitations are the relatively short median follow-up for overall survival and metastasis-free survival, endpoints that typically require extended observation in localized prostate cancer. However, the strong association between early negative biopsy, low PSA nadir, and long-term outcomes is well established. The trial’s robust design, large and diverse patient population, and rigorous oversight reinforce the validity of the findings.
If approved, aglatimagene immunotherapy would represent the first new therapeutic advance for localized prostate cancer in over two decades, with the potential to reduce recurrence, minimize the need for salvage therapies, and improve patient quality of life. Ongoing follow-up will determine whether these benefits translate into improved long-term survival.
Conclusion
The addition of aglatimagene besadenovec (CAN-2409) immunotherapy to standard radiotherapy offers a clinically meaningful improvement in disease-free survival for patients with intermediate- or high-risk localized prostate cancer, without added significant toxicity. These results support consideration of aglatimagene as a new standard-of-care (SOC) adjunct in this patient population, pending regulatory approval and further long-term data.
__
Clinical Trials
Phase 3 Study of ProstAtak® Immunotherapy With Standard Radiation Therapy for Localized Prostate Cancer (PrTK03) – ClinicalTrials.gov ID NCT01436968
Highlights of prescribing information
Valacyclovir (Valtrex®; GSK)[Prescribing Information]
References
[1] World Health Organization. Cancer Fact Sheet. 2025. Online. Last accessed on May 27, 2026.
[2] American Urological Association. Clinically Localized Prostate Cancer: AUA/ASTRO Guideline. 2022. Online. Last accessed on May 27, 2025.
[3] DeWeese TL, Manzanera A, Sylvester J, Wheeler T, Schroeder T, Gejerman G, Chesnut G, Facelle TM, Garzotto MG, Pieczonka C, Gandhi NM, Sukin S, Liss MA, Tutrone R, Mehlhaff B, Savage SJ, Goody M, Vogt J, Rao S, Polanco MLS, Barone F, Nichols WG, Tak PP; PrTK03 study team. Aglatimagene besadenovec (CAN-2409) with radiotherapy for patients with localised prostate cancer: a phase 3, multicentre, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2026 Jun;27(6):673-685. doi: 10.1016/S1470-2045(26)00071-9. PMID: 42225101.
Featured image © 2017 – 2026 Fotolia/Adobe. Used with permission.
DOI
, was designed to evaluate whether the addition of the investigational immunotherapy aglatimagene besadenovec (CAN-2409), an investigational, off-the-shelf viral immunotherapy designed to trigger the body's immune system to attack solid tumors, plus the prodrug valacyclovir (Valtrex®; GSK) to standard external beam radiation therapy (EBRT) could improve disease-free survival (DFS) in this population. The study demonstrated a statistically significant and clinically meaningful improvement in DFS without increased toxicity, offering a potential paradigm shift in the management of localized prostate cancer. ){kind=link}