Transcriptome profiling of prostatic tumours from ENACT trial patients with or without enzalutamide.

Abstract

To evaluate the longitudinal transcriptomic changes that occurred over time in patients from the ENACT trial (ClinicalTrials.gov identifier: NCT02799745). ENACT evaluated patients with low- or intermediate-risk prostate cancer, comparing the efficacy and safety of enzalutamide plus active surveillance (AS) to AS alone. Gene-expression profiling was conducted using the Decipher Genomic Resource for Intelligent Discovery (GRID) platform (Veracyte, Inc.) on 131 patient samples (enzalutamide plus AS: n = 57; AS alone: n = 74) collected at screening, Year 1, and Year 2. Pre-defined GRID signatures were analysed for associations with biological and clinical features, including immune activity, treatment sensitivity, metastatic risk, and molecular subtypes. Statistical analyses utilised Cox proportional hazards models and logistic/linear regression, while longitudinal changes were evaluated using linear mixed-effects models. At Year 1, patients treated with enzalutamide plus AS showed significant transcriptomic changes, such as downregulation of androgen-receptor signalling and immune-suppressor signatures, alongside upregulation of immune-activated and basal-like markers. Many of these transcriptomic alterations, including immune-related changes, were transient and reverted to baseline levels at Year 2 after enzalutamide treatment cessation. This exploratory biomarker analysis highlights transcriptomic changes in patients undergoing AS and those treated with enzalutamide, providing insights into molecular disease progression on surveillance and the effects of transient exposure to enzalutamide. The observed immune modulation during enzalutamide treatment suggests opportunities to explore immunotherapy strategies.