Detection of mutations in homologous recombination repair (HRR) pathway genes using liquid biopsy in metastatic, castration-resistant prostate cancer (mCRPC) patients without tumor tissue availability.

Abstract

98 Background: Accurate detection of mutations in HRR pathway genes among patients with mCRPC is essential for selecting patients who would benefit with poly (ADP-ribsose) polymerase (PARP) inhibitor therapies. Traditional tissue-based detection methods can be associated with practical challenges as acquisition of specimens can involve significant risk or high costs. For prostate cancer patients, obtaining adequate tissue samples can be even more difficult, considering the unique characteristics of the disease. This study aimed to evaluate the real-world performance of liquid biopsy using circulating tumor DNA (ctDNA) in detecting mutations in HRR genes, among mCRPC patients who did not have tissue available for genomic evaluation. Methods: Blood samples (20ml of whole blood) were collected from 760 mCRPC patients in 10 Asian countries. Samples were collected once for each patient, regardless of treatment type or cycles as long as the patients were followed up for their mCRPC. All patients included were confirmed from each participating site to have no tissue available for genomic analysis. Blood samples were analyzed using a next-generation sequencing (NGS) based ctDNA assay, covering 15 genes in the HRR pathway ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L) . Results: ctDNA NGS testing was successfully performed in all 760 mCRPC patients. Any mutations in the HRR pathway genes were detected in 63.7% of the included patients and deleterious or suspected deleterious HRR pathway gene mutations were detected in 32.5% with the assay. Deleterious/suspected deleterious BRCA1/2 mutations were detected in 68/760 (8.95%) of the cases. Other detected deleterious/suspicious deleterious mutations included mutations in CDK12 , detected in 59/760 (7.76%) patients, followed by ATM mutation in 39/760 (5.13%), and CHEK2 in 31/769 (4.08%) by frequency. Conclusions: ctDNA testing for HRR gene mutations offers a practical tool for therapy selection in mCRPC patients. This non-invasive approach enables testing for patients who were not eligible for evaluation by tissue-based methods and can expand access to adequate targeted therapies.