Abstract 550: Cell-free DNA alterations in the AR/enhancer locus measured before AR signaling inhibition portend poor overall survival in metastatic castration resistant prostate cancer patients

Background: We previously developed a liquid biopsy assay called Enhancer and neighboring loci of Androgen Receptor Sequencing (EnhanceAR-Seq) (Dang & Chauhan et al, JCO PO, 2020). We applied it to a heterogeneous cohort of metastatic prostate cancer patients after the start of AR-directed therapy, and showed that alterations in the AR locus were associated with worse survival. Here we asked if AR/enhancer genomic alterations detected in plasma cell-free DNA prior to the administration of first-line AR-selective inhibitors (ARSIs) can predict survival in metastatic castration resistant prostate cancer (mCRPC) patients. Methods: We applied EnhanceAR-Seq to plasma cell-free DNA isolated from 20 mCRPC patients from Tulane University collected between April 2015 and June 2017. Assay results were correlated with patient overall survival (OS) and progression-free survival (PFS) from the time of blood collection. Results: Median follow up time was 32 months. Seventeen patients had blood plasma analyzed before first-line ARSI treatment, while three patients had received prior ARSI treatment before blood collection. EnhanceAR-Seq revealed that the most frequent genomic events detected were AR/enhancer alterations (copy number gain, tandem duplication or missense mutations) in 9 patients (45%), of which 5 patients had both AR gene body and enhancer copy number gain. The other 4 patients each had a single genomic event detected by EnhanceAR-Seq: AR amplification, AR enhancer amplification, AR and AR enhancer tandem duplication, and AR W742C single nucleotide variation. Cell-free DNA-detected alterations in the full AR locus including the AR enhancer were highly significant for inferior OS (P = 0.0009; HR = 17.0) but not for PFS (P = 0.2; HR = 2.2) by Kaplan-Meier analysis across all 20 patients. Subset analysis of the 17 patients with plasma analyzed prior to first-line ARSI treatment revealed that AR/enhancer alterations again predicted significantly worse OS with a median survival of 16.1 months vs. not-reached (P = 0.0009; HR = 14.1). Conclusions: AR locus alterations detected by EnhanceAR-seq in plasma cell-free DNA collected prior to ARSI administration correlated with significantly worse overall survival in patients with mCRPC. If corroborated, our results suggest that AR/enhancer genomic alterations represent a potent pre-treatment prognostic biomarker in mCRPC patients. Citation Format: Pradeep Singh Chauhan, Steven H. Hartman, Ha X. Dang, Jace Webster, Haley Ellis, Wenjia Feng, Peter K. Harris, Elisa M. Ledet, Ellen B. Jaeger, Patrick J. Miller, Sydney A. Caputo, Russell K. Pachynski, Oliver Sartor, Christopher A. Maher, Aadel A. Chaudhuri. Cell-free DNA alterations in the AR/enhancer locus measured before AR signaling inhibition portend poor overall survival in metastatic castration resistant prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 550.