Background: Genomic alterations in PTEN are associated with an aggressive disease and treatment resistance in patients (pts) with castration-resistant prostate cancer (PC). The aim of the present study is to characterize the molecular alterations associated to tumor PTEN-low mRNA expression in different cohorts of metastatic hormone-sensitive PC (mHSPC) pts and its prognostic value. Methods: This is an ongoing multicenter ambispective study enrolling mHSPC pts receiving different treatment strategies. PTEN status was assessed in FFPE tumor samples by mRNA expression by nCounter and RNA-seq. PTEN expression was correlated with castration resistance-free survival (CRPC-FS) and overall survival (OS) by Kaplan Meier and multivariate Cox analysis. Results: 297 pts were included: 125 treated with ADT + docetaxel (ADT+D), 79 with androgen deprivation therapy (ADT) + abiraterone or enzalutamide (A/E) and 93 with ADT alone. Median follow-up of 46.3 months (m) (6.7-223). Median age was 66.4 years, 75.7% of pts presented de novo stage IV and 67.9% had high-volume disease. RNA-seq analysis was performed to assess differences in gene expression between low vs. high/medium PTEN expression tumors in 66 pts. There was a significant correlation between PTEN expression detected by nCounter and by RNASeq (p=8.7e^-11). Differential expression analysis found 13 genes differentially expressed (padj<0.05 &abs(LFC)>0.26) in PTEN-low (25.8%) vs the rest, including PTEN and 2 novel transcripts (Table). In the functional analysis PTEN-low tumors had overexpression of several pathways including cell cycle, DNA repair, metabolism and immune regulatory response, and infraexpression of the androgen-response hallmark. In the whole cohort (n=297 pts), PTEN-low (30.5%) was independently associated with low CRPC-FS (HR 1.8 (95% CI, 1.3 – 2.4), p=8.7e^-5) and OS (HR 1.7 (95% CI, 1.2 – 2.2), p=0.0038). Conclusions: Lower expression of PTEN correlates with a distinct molecular profile and a more aggressive disease in pts with mHSPC, supporting the development of new therapeutic strategies in pts.