Target trial emulation of early docetaxel and enzalutamide for metastatic hormone-sensitive prostate cancer.

Abstract

To apply a trial emulation method using the 'ENZAlutamide in first line androgen deprivation therapy for METastatic prostate cancer' (ENZAMET) trial data to assess the effects of adding early docetaxel to enzalutamide on overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC), as the benefits of adding early docetaxel to novel androgen-receptor pathway inhibitors (ARPIs) are unclear. The ENZAMET trial randomised 1125 patients with mHSPC to testosterone suppression plus enzalutamide or standard non-steroidal antiandrogen therapy. Investigators indicated at pre-randomisation if they planned to use early docetaxel. We emulated randomised comparisons of four treatments: (i) docetaxel plus enzalutamide, (ii) no docetaxel plus enzalutamide, (iii) docetaxel plus no enzalutamide, and (iv) no docetaxel plus no enzalutamide. Propensity score matching was applied to mitigate selection bias. OS was evaluated using Cox proportional hazards regression. Among 987 matched participants (87.7%), baseline characteristics were balanced. OS was similar with or without planned use of early docetaxel (hazard ratio [HR] 1.02, 95% confidence interval [CI] 0.92-1.12; P = 0.72), with effect modification by enzalutamide use (interaction P = 0.02). Among those assigned enzalutamide, OS was similar according to the planned use of early docetaxel or not (HR 1.18, 95% CI 0.94-1.49), regardless of disease volume (interaction P = 0.37). Among those assigned no enzalutamide, OS was longer with the planned use of early docetaxel (HR 0.90, 95% CI 0.82-0.98), especially in high-volume disease (interaction P = 0.006). Early docetaxel did not appear to improve survival when added to enzalutamide, regardless of disease volume, whereas it did appear to improve survival when enzalutamide was not used, particularly in high-volume disease. While residual confounding could not be excluded, these findings do not support the routine addition of early docetaxel to enzalutamide in mHSPC.