Clinical impact and molecular profiling of <i>PTEN</i> loss and <i>TMPRSS2:ERG</i> fusion in metastatic hormone-sensitive prostate cancer.

5101 Background: PTEN loss in prostate cancer (PC) is associated with aggressive disease and resistance to conventional treatments. TMPRSS2:ERG fusion (TE+) is one of the most frequent genomic alterations in PC and frequently co-occurs with PTEN loss, yet the clinical impact of this association remains unclear. The aim of the present study is to evaluate clinical outcomes in metastatic hormone-sensitive PC (mHSPC) patients (pts) stratified by TE and PTEN status and to characterize associated gene expression signatures. Methods: We conducted a multicenter ambispective study enrolling mHSPC pts receiving different treatment strategies. The primary objective was to evaluate castration resistant PC-free survival (CRPC-FS) according to PTEN and TE. TE fusion and PTEN status were assessed in FFPE tumor samples using mRNA expression profiling by nCounter. PTEN low was defined with a previously validated cut-off (Jimenez, Eur Urol Onc 2023). RNA-seq analysis was performed to molecularly characterize PTEN low and TE associated transcriptional profiles using gene set variation analysis. Results: A total of 295 pts were included; median age was 72.9 years, 46.1% had high-volume disease and 66.8% presented de novo stage IV disease. Treatment consisted of androgen deprivation therapy (ADT) plus abiraterone (n=97), apalutamide (n=157), enzalutamide (n=41). Overall, 74 pts were PTEN low and 90 pts were TE+. There were no significant differences in baseline characteristics according to PTEN or TE. Among PTEN low pts, 33 (44.6%) were TE+. There was a positive correlation between PTEN low and TE+ ( p =0.01). With a median follow-up of 31.9 months (range 0.8 – 91.3), 32% of pts progressed to CPRC and 31.2% died. In the overall cohort, PTEN low /TE- tumors (14.1%) were associated with the poorest clinical outcomes, showing significantly inferior CRPC-free survival (HR 2.1, p =0.0027) and overall survival (HR 2.1, p =0.0058). Within the PTEN low subgroup, TE+ tumors demonstrated significantly improved CRPC-FS compared with TE- negative tumors (HR 0.45, p =0.04), with a non-significant trend toward improved overall survival (HR 0.48, p=0.07). In the 35 pts with RNA-seq analysis, PTEN low /TE- tumors were characterized by enrichment of DNA repair and neuroendocrine and EZH2 signatures ( p =0.04 and p= 0.03 respectively). PTEN low /TE+ had enrichment of PI3K signaling ( p =0.01) and epithelial differentiation ( p =0.05). Androgen-response hallmark was infraexpressed in PTEN low tumors regardless of TE status. Conclusions: PTEN low /TE- tumors exhibited the worst clinical outcomes, while TE+ in PTEN low disease partially rescued the adverse phenotype. Combined PTEN and TE stratification may therefore inform risk-adapted treatment escalation and intensification strategies.