Evaluating synergistic versus additive effects of the triplet regimen in metastatic castration-sensitive prostate cancer: a modeling analysis.

The ARASENS trial demonstrated a significant overall survival (OS) benefit for a triplet regimen in metastatic castration-sensitive prostate cancer (mCSPC). We aimed to determine whether this benefit is synergistic or additive. Using a mathematical model of independent drug action and published data from the ARASENS and ARANOTE, we compared the observed OS of the triplet regimen to a predicted OS curve. Reconstructed individual patient data were compared using a Cox model. The observed OS was statistically superior to the predicted OS (hazard ratio [HR] 0.82, 95% CI 0.68-0.99; P = .047), indicating a clinical benefit ~18% greater than the expected additive effect. To address confounding by subsequent therapies, we analyzed time to initial subsequent anticancer therapy, which showed an even more pronounced greater-than-additive benefit (HR 0.57, 95% CI 0.44-0.74; P < .001). These findings suggest the triplet regimen provides an early therapeutic advantage that exceeds additive expectations, supporting an upfront combination strategy in mCSPC.