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Abstract Background The role of the androgen receptor (AR) in breast cancer (BC) is not fully elucidated. TRIO030 was conducted to identify molecular changes in BC tissue following short-term exposure to darolutamide (DAR), a new next-generation AR antagonist. Methods TRIO030 was a multicenter, tissue-acquisition trial in women with treatment-naive early BC, T ≥ 1.0 cm, N0-1. Primary objective: identify molecular alterations in BC tissue following preoperative exposure to DAR (600mg bid for 14-35 days). Formalin-fixed paraffin-embedded (FFPE) blocks and fresh frozen tissue (FFT) were collected before DAR and at surgery (or pre neoadjuvant therapy). AR, ER, PgR, HER2, Ki67, Cytokeratin 5-6 were assessed by IHC. Gene expression microarray (GEx) and Reverse Phase Protein Analysis (RPPA) were done on FFT. Differentially expressed genes (DEGs) were found by ANOVA from an integrated gene expression analysis software (Resolver). A gene enrichment search by Gene Ontology (GO) analysis was done using Database for Annotation, Visualization and Integrated Discovery (DAVID). Results 36 patients (pt) (median age 61.5) were enrolled (20 HR+, 7 TNBC, and 9 HER2+ per central lab). Median duration of DAR was 14.5 days. 32 pts were evaluable by RPPA, 31 by GEx. Based on AR level changes in both RPPA and GEx in pre vs. post-DAR samples, cases were grouped: AR upregulated (≥1.2 fold increase, n = 14), AR downregulated (≥1.2 fold decrease, n = 11), AR unchanged (n = 6). 233 unique DEGs were detected with 84 identified as forming two GEx profiles among the 3 AR groups. GO analysis revealed that DEGs profiles were enriched in an immune (IMM) signature or cell proliferation (CP) signature which were anti-correlated (e.g., if CP is upregulated, IMM is down). No correlation between AR groups and BC subtypes was found. One pt had a grade 3-4 adverse event (non-serious ALT-AST increase). Conclusions TRIO030 suggests an association between DAR and immune regulation genes. There was no association between pre/post-DAR AR level changes and BC subtype. Future studies will likely be needed to further investigate the role for AR blockade in BC as well as the mechanism of action for DAR at molecular level. Clinical trial identification 2016-004151-79. Legal entity responsible for the study Translational Research in Oncology. Funding Bayer (provided the study drug), Translational Research in Oncology (not for profit organization, funded other aspects of the trial). Disclosure All authors have declared no conflicts of interest.