1971P Neuroendocrine (NE) expression profiling in non-castrate tumours is associated with poor therapy benefit and adverse clinical outcome in metastatic castration-resistant prostate cancer (mCRPC) patients

Abstract

NE dedifferentiation is associated to clinical aggressiveness and resistance to androgen receptor (AR) inhibition in prostate cancer. We analyzed the correlation of a NE expression signature in non-castrate tumors with the clinical outcome of mCRPC patients treated with taxanes or AR signaling inhibitors (ARSI; abiraterone or enzalutamide). Patients with mCRPC were retrospectively tested for a customized signature of 45 NE-related genes in total RNA from formalin-fixed paraffin-embedded non-castrate tumor samples by the nCounter platform (Nanostring Technologies). Patients were grouped as high and low NE profile according to the unsupervised clustering of gene expression data and correlated with treatment response and clinical outcome. Ninety-six patients were included, with a median follow-up of 20 (1.17-81.3) months. Median age was 69.2 (55.8-87.1) years. All patients received taxanes (68 docetaxel, 10 cabazitaxel and 18 both), 29 received ARSI as first line in CRPC and 53 received ARSI after taxanes. Patients classified as high NE expression profile (59 vs. 37 patients) were associated with a shorter time of CRPC development (median 12.6 vs. 30.8 mo, HR 3.3, 95%CI 2-5.5, P<0.001) and shorter OS from CRPC diagnosis (median 24.3 vs. 42.2 mo, HR 2.2, 95%CI 1.4-3.4, P=0.001). Regarding taxanes outcome, high NE profile patients correlated with lower PSA-PFS (HR 1.7, 95%CI 1.1-2.6, P=0.011), radiologic (RX)-PFS (HR 1.8, 95%CI 1.1-2.8, P=0.012) and overall survival (OS) (HR 1.7, 95%CI 1.1-2.6, P=0.009), and they were independently associated with shorter PSA-PFS (HR 1.8, 95%CI 1.1-3, P=0.023). In first-line ARSI-treated patients, high NE profile patients (15 vs. 14 patients) correlated with shorter PSA-PFS (HR 3, 95%CI 1.3-7, P=0.011), RX-PFS (HR 2.5, 95%CI 1-5.9, P=0.042) and OS (HR 5.8, 95%CI 2.3-14.9, P<0.001). NE-related gene expression in non-castrate tumor samples is associated with adverse clinical outcome and both poor taxanes and ARSI benefit in mCRPC patients. Thus, molecular characterization of primary tumors may be useful to guide treatment strategies in mCRPC.