Molecular evolution of HRR gene alterations in metastatic prostate cancer: A ctDNA-based study.

• DOI: 10.1200/jco.2025.43.5_suppl.255
• Publication Date: 2025-02-18T14:43:07Z
• Authors: Chinmay Jani; Eli Tran; Nicole Zhang; Jill Tsai; Jianjie Dong; Elizabeth Pan; Justine Panian; Rana R. McKay

255 Background: Homologous recombination repair (HRR) genes, including DNA are increasingly recognized for impacting treatment resistance and prognosis of metastatic prostate cancer (mPC). Next-generation sequencing circulating tumor (ctDNA) enables non-invasive, longitudinal monitoring molecular alterations in patients (pts) undergoing systemic therapies. This study explores the dynamic changes ctDNA profiles mPC, particularly focusing on HRR alterations. Methods: We utilized GuardantINFORM, a clinical-genomics database containing de-identified test results commercial payer-claims data. Eligible pts had diagnosis mPC underwent testing pre (within 3 months before initiation) post discontinuation initiating subsequent treatment) Androgen Receptor Pathway Inhibitors (ARPi), poly ADP-ribose polymerase inhibitors (PARPi), taxane chemotherapy. Mann-Whitney assessed differences mutations. also examined association between burden overall survival (OS). Results: From 21,682 with 145 collected pre/post-ARPi, 54 pre/post PARPi 115 Pre-to-post-ARPI, individual increased from 21 to 34, most common (%pre/%post) genes be altered, ATM (5.5/7.6), BRCA2 (3/6) CDK12 (3/2). In group, prevalent altered were (28/22), (28/20) BRCA1 (4/6). Although prevalence declined, 11 new unique detected post-PARPi, along an increase (2 4) (16 21) Three 25 (12%) who serial pre- post-PARPi exhibited BRCA reversion notable included (4/3), (1/3), (1/3). Patients higher pre-treatment samples worse OS. Conclusions: reveals gene using profiling. observed ATM, BRCA1, post-treatment, mutations, indicating potential mechanisms. These findings underscore importance tailoring therapeutic approaches based mPC.