Transcriptomic Heterogeneity of Metastatic Disease Timing within Metastatic Castration-Sensitive Prostate Cancer

Abstract

Metastatic castration-sensitive prostate cancer (mCSPC) is commonly partitioned into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes, however less is known about any potential underlying biologic differences between these disease states. Herein we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy. We performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous vs metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease time. Median genomic scores between groups were compared with Mann-Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from time of metastasis. Survival analysis was performed with the Kaplan-Meier Method and Multivariable Cox regression. A total of 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-yr OS (39% vs 79%, p<0.01) and demonstrated lower median Androgen Receptor Activity (AR-A) (11.78 vs 12.64, p<0.01) and Hallmark Androgen Response (HAR) (3.15 vs 3.32; p<0.01). Multivariable cox-regression identified only high-volume disease (HR = 4.97, 95% CI 2.71-9.10; p<0.01) and HAR score (HR = 0.51, 95% CI 0.28-0.88; p = 0.02 significantly associated with OS. Finally, patients with synchronous (HR = 0.47, 95% CI 0.30-0.72; <0.01) but not metachronous (HR = 1.37, 95% CI 0.50-3.92; p = 0.56) disease were found to have better OS with Androgen Receptor (AR) + non-AR combination therapy as compared to monotherapy (p value for interaction = 0.05). We have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low volume disease, those with metachronous low volume disease have a more hormone dependent transcriptional profile and exhibit a better prognosis than synchronous low volume disease.