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

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