A First in Twenty Years for Localized Prostate Cancer: Gene Therapy CAN-2409 Significantly Extends Disease-Free Survival When Added to Radiotherapy

KEY FINDINGS

• Trial: A randomized, double-blind, placebo-controlled phase 3 trial (PrTK03, NCT01436968) in 745 patients at 51 centres (United States and Puerto Rico) in men with intermediate-to-high risk localized prostate cancer.
• DFS gain: CAN-2409 plus valaciclovir added to standard external beam radiotherapy (EBRT) produced a 30% risk reduction in disease-free survival (DFS) compared with placebo (HR 0.70; 95% CI 0.52-0.94; p=0.016).
• Follow-up: At a median follow-up of 50.3 months, median DFS was not reached in the treatment arm; median DFS in the placebo arm was 86.1 months.
• Pathological response: The pathological complete response rate on 2-year biopsies was 80.4% in the treatment group versus 63.6% in the placebo group (p=0.0015).
• Safety: Serious adverse event rates were similar in the two arms; no treatment-related deaths were reported.

Background and Study Design

Approximately 30% of men with localized prostate cancer treated with curative-intent radiotherapy experience disease recurrence, carrying a risk both of symptomatic progression and of serious toxicity from salvage treatments. No new systemic treatment that could be added to radiotherapy had been approved for this patient group in the past two decades.

CAN-2409 (aglatimagene besadenovec) is an "off-the-shelf" gene therapy that delivers the herpes simplex virus thymidine kinase (HSV-tk) gene to tumour tissue via a replication-deficient adenoviral vector. Administration of oral valaciclovir after injection aims to convert the drug into a metabolite toxic to tumour cells through the HSV-tk enzyme, producing immunogenic cell death and an associated systemic antitumour immune response.

Study Design: PrTK03

The PrTK03 trial (NCT01436968) was conducted at 51 centres (26 community, 25 academic/military) in the United States and Puerto Rico between February 2012 and September 2021. A total of 745 patients aged at least 18 with an ECOG performance score of 0-2 and intermediate or high risk disease planned for EBRT were randomized 2:1. Randomization was stratified by risk category and use of androgen deprivation therapy (ADT). Patients received standard fractionated (78 Gy/2 Gy) or hypofractionated (60 Gy/3 Gy or 70 Gy/2.5 Gy) EBRT, with optional short-course ADT. The primary endpoint was disease-free survival (DFS), defined as time from randomization to recurrence or death.

Key Results

Overall survival (OS) was similar in both arms; during the trial only 2 patients died of prostate cancer (one in each arm). In terms of safety profile, the most frequent grade ≥3 adverse event in both arms was acute kidney injury (2% in the treatment arm, 2% in the placebo arm), and no treatment-related deaths were reported. The most frequently observed treatment-related side effects were chills, fever and flu-like symptoms, generally mild to moderate and self-limiting.

"CAN-2409, assessed together with its very favourable toxicity profile, may represent a potential paradigm shift in how we approach the treatment of men with intermediate-to-high risk prostate cancer." - Theodore L. DeWeese, MD, Johns Hopkins School of Medicine, principal investigator of the trial

Implications for Clinical Practice

1. The potential to be the first new treatment option in twenty years

These findings could open the way to a new treatment option that can be added to radiotherapy in intermediate-to-high risk localized prostate cancer. If CAN-2409 is approved, it has the potential to be the first new treatment approach developed for this patient group in the past 20 years.

2. Benefit independent of ADT use

A notable finding is that the DFS benefit was observed independently of short-course ADT use; the HR was 0.56 (95% CI 0.38-0.83) in patients not receiving ADT, while the effect appeared relatively more limited in patients receiving ADT (HR 0.92) - though it should be noted that subgroup analyses must be interpreted cautiously given the limited sample sizes.

3. The advantage of low-toxicity local administration

The fact that the gene therapy can be delivered by local injection with lower toxicity than systemic immunotherapies carries practical value, particularly in terms of the potential to reduce the need for salvage treatment. How such combination strategies will be integrated into treatment algorithms in future is a development to watch closely in intermediate-to-high risk patients planned for adjuvant/salvage radiotherapy after robotic radical prostatectomy or choosing radiotherapy as primary treatment.

Conclusion

The PrTK03 trial provides strong evidence that a gene therapy added to radiotherapy can meaningfully and clinically importantly extend disease-free survival in localized prostate cancer, and can do so without an increase in toxicity.

Long-term follow-up data and overall survival analyses are ongoing, and how these results feed into regulatory processes and clinical guidelines will be followed closely in the period ahead.

References

• DeWeese TL, Manzanera A, Sylvester J, et al. Aglatimagene besadenovec (CAN-2409) with radiotherapy for patients with localised prostate cancer: a phase 3, multicentre, randomised, double-blind, placebo-controlled trial. The Lancet Oncology. 2026;27(6):673-685. - pubmed.ncbi.nlm.nih.gov
• Clarke H. Adding CAN-2409 to radiation significantly extends DFS in localized prostate cancer. 17 July 2026. - urologytimes.com
• DeWeese T, Wheeler T, Sylvester J, et al. Phase 3, randomized, placebo-controlled clinical trial of CAN-2409+prodrug in combination with standard of care external beam radiation (EBRT) for newly diagnosed localized prostate cancer. J Clin Oncol. 2025;43(suppl 17):5000.
• ClinicalTrials.gov. PrTK03 Study (NCT01436968). - clinicaltrials.gov