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 11v/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.