Background: Androgen deprivation therapy (ADT) with docetaxel or new antiandrogens has demonstrated a survival benefit in metastatic hormone-sensitive prostate cancer (mHSPC). However, treatment selection for individual patients (pts) remains a challenge. We propose that TMPRSS2-ERG and cell plasticity [neuroendocrine (NE), epithelial to mesenchymal transition (EMT)], immune-related, androgen receptor (AR) and tumor suppressor genes (TSG) (RB1, PTEN and TP53) expression signatures may predict clinical outcome in mHSPC pts treated with ADT+docetaxel. Methods: This is a multicenter retrospective biomarker study performed in mHSPC pts treated with ADT+docetaxel. A customized panel of 184 genes was designed and tested in total mRNA from FFPE tumor samples by nCounter platform (Nanostring Technologies). Expression levels were correlated with castration resistance-free survival (CRPC-FS) (primary endpoint) and overall survival (OS) by Kaplan Meier and multivariate Cox modeling. A predictive modeling approach was performed with Bujar R package to develop a signature able to predict CRPC-FS. R (v.3.6.3) software was used for statistical analyses. Results: 136 pts were included, and 120 of them were eligible. Median age was 66.9 years (range 46.3-83.6). Gleason score was ≥ 8 in 80.8% of pts; 87.5% and 20.8% of pts had bone and visceral metastases, respectively. Median follow-up was 30.7 months (m) (range 5.5-70.6). 76 pts (63.3%) developed castration-resistant prostate cancer (CRPC). Median time to CRPC was 20 m (range 16.9-23.1) and median OS was not reached. High AR-signature expression independently correlated with longer CRPC-FS (HR 0.4, 95% CI 0.2-0.7, p = 0.003). Considering AR-signature individual gene expression, ARV7 was independently associated with shorter CRPC-FS (HR 1.7, 95% CI 1.2-2.4, p = 0.003). Low expression of all TSG (PTEN, RB1 and TP53) independently correlated with shorter CRPC-FS (HR 0.3, 95% CI 0.2-0.7, p = 0.003) and OS (HR 0.2, 95% CI 0.1-0.5, p < 0.001). Similarly, low expression of 2 out of the 3 TSG genes or only RB1 plus PTEN were also independently associated with shorter CRPC-FS (HR 0.5, 95% CI 0.3-0.9, p = 0.015; HR 0.4, 95% CI 0.2-0.7, p = 0.003, respectively) and OS (HR 0.4, 95% CI 0.2-0.9, p = 0.027; HR 0.2, 95% CI 0.1-0.6, p = 0.001, respectively). TMPRSS2-ERG expression, NE, EMT and immune-related signatures were not associated with clinical outcome. Bujar analysis defined a 17-gene signature (including ARV7, RB1, PTEN, BRCA2 and ATM) that was able to discriminate pts at different risk of developing early CRPC. Conclusions: High AR-signature expression correlates with a longer CRPC-FS while ARV7 expression is associated with shorter CRPC-FS. Low expression of TSG is associated with an aggressive clinical evolution in mHSPC pts treated with ADT+taxanes.