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.

5000 Background: Standard of care (SoC) for intermediate to high-risk localized prostate cancer (PrCa) includes surgery or external beam radiation (EBRT) +/- androgen deprivation therapy (ADT). Nearly 30% of men undergoing EBRT will experience recurrence requiring ADT and salvage therapies that negatively impact quality of life. CAN-2409 is a replication-defective adenovirus encoding the HSV-tk gene that, when combined with valacyclovir (prodrug), results in immunogenic cell death. This results in immunization against tumor antigens and long-term tumor control. Methods: We conducted a phase 3, multicenter, double-blinded, randomized, placebo (PBO)-controlled clinical trial in PrCa patients (pts) planning to receive EBRT+/- short course ADT (<6 mos); NCT01436968. 745 pts were randomized 2:1 (496 in CAN-2409+prodrug and 249 in PBO+prodrug) and stratified by NCCN risk group and ADT use. Three intraprostatic injections of CAN-2409 (5x10 11 v/2mL) or PBO were administered, each followed by 14 days of prodrug. Follow-up included a prostate biopsy 2 years after EBRT. Primary endpoint was disease-free survival (DFS), defined as time from randomization to PrCa recurrence (local/regional failure or distant metastasis) or death in the intent-to-treat population. Median follow up time was 50.3 mos. The study was conducted under a special protocol assessment (SPA) granted by the FDA. Results: Treatment with CAN-2409 reduced the risk of PrCa recurrence or death by 30% (median DFS not reached vs 86.1 mos, p=0.0155, HR 0.7, 95% CI 0.52 to 0.94). PrCa-specific DFS (exclusion of non PrCa- related deaths) demonstrated an even greater effect with a 38% decreased risk in the CAN-2409 arm vs. PBO (p=0.0046; HR 0.62, 95% CI 0.44 to 0.87). Statistically significant secondary endpoints included increased percentage of patients achieving prostate-specific antigen nadir (67.1% vs 58.6%, p=0.0164) and an increase in pathological complete responses in the 2-year biopsies in the CAN-2409 arm vs. PBO (80.4% vs. 63.6%, p=0.0015). Most common treatment-related adverse events included chills (33.4% vs. 8.6%), flu-like symptoms (30.5% vs. 13.8%), and fever (25.1% vs. 3.9%), mostly Gr 1-2 and self-limited. Serious adverse events (SAEs, 5.8% vs. 7.3%) and treatment-related SAEs (1.7% vs. 2.2%) were uncommon across treatment groups. Conclusions: In this randomized, double-blind, Phase 3 trial, CAN-2409 significantly reduced the risk of PrCa recurrence or death when added to SoC EBRT+/- ADT. The addition of CAN-2409 was not associated with significant added toxicity. These data represent the first potentially new therapy for patients with intermediate and high risk PrCa in over 20 years. Clinical trial information: NCT01436968 .