Genomic and transcriptomic correlates of HER3 expression in prostate cancer.

3142 Background: HER3 ( ERBB3 ) is a key receptor in prostate cancer (PC) that signals via HER3 heterodimerization to promote PI3K-AKT-mediated survival and adaptive resistance in castration-sensitive (CSPC) and castration-resistant prostate cancer (CRPC). Despite its biological relevance, the clinical and genomic significance of HER3 RNA expression remains poorly defined. We therefore performed a comprehensive multi-omic analysis to evaluate the prognostic relevance of HER3 RNA in PC. Methods: DNA (592-gene or whole exome) and RNA (whole transcriptome) sequencing were performed on prostate tumor samples (n=19,238) submitted to Caris Life Sciences. HER3 expression was quantified as transcripts per million (TPM) and stratified into high (HER3-H) and low (HER3-L) groups defined by the top and bottom quartiles, respectively. CRPC was defined as ≥3 months of androgen deprivation therapy before tissue collection. Real-world overall survival (rwOS) was obtained from insurance claims data and calculated from biopsy to last contact. Tumor microenvironment (TME) cell fractions were estimated by RNA deconvolution using quanTIseq. Group comparisons were conducted using Mann–Whitney U and chi-square tests as appropriate. Survival outcomes were evaluated using Cox proportional hazards models and log-rank testing, with false discovery rate correction for multiple comparisons. Results: Across genitourinary malignancies, PC demonstrated highest median HER3 RNA expression (107.04 TPM). Within PC, HER3 expression varied by tumor site and race, with higher median levels in primary tumors compared to metastatic sites (116.5 vs 86.22 T PM, p<0.0001), and in tumors from Black patients compared with White patients (115.3 TPM v 103.3 TPM, p<0.0001). Prognostic associations differed by tumor source and castrate status: HER3-H expression was associated with improved rwOS in metastatic tumors (32.0 vs. 23.3 months, HR 0.72, p < 0.00001), and in CRPC (29.3 vs. 21.3 months; HR 0.84; p < 0.001), but not in primary tumors or CSPC. Immune profiling revealed that HER3-high tumors exhibited significantly reduced inferred infiltration of Tregs, neutrophils, macrophages, and NK cells (q < 0.05), while PD-L1 positivity and TMB-high status were not significantly associated with HER3 expression. Genomic analysis revealed enrichment of FOXA1 and SPOP alterations (q<0.05) in HER3-H tumors, whereas HER3-L tumors were enriched for TP53 , RB1 , AR , CDK12 , and APC ( q<0.05). On multivariable analysis, HER3-H status remained independently associated with improved rwOS in CRPC. Conclusions: HER3 RNA expression defines biologically and clinically distinct subsets of PC, with HER3-high tumors exhibiting luminal, androgen receptor–dependent biology, an immune-cold phenotype, and improved survival in metastatic disease and CRPC, supporting HER3 as a tumor-intrinsic therapeutic target and rationale for HER3-directed therapy.