Genomic profiling of circulating tumour DNA (ctDNA) and tumour tissue for the evaluation of rucaparib in metastatic castration-resistant prostate cancer (mCRPC)

Abstract

Background: The phase 2 TRITON2 (NCT02952534) and phase 3 TRITON3 (NCT02975934) studies are evaluating the poly (ADP-ribose) polymerase inhibitor rucaparib in patients (pts) with mCRPC who have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or other homologous recombination repair (HRR) gene. Here we present initial results from central genomic screening of plasma ctDNA and tissue samples in TRITON2 and TRITON3. Methods: Plasma samples were profiled for genomic alterations (GAs) in 64 genes using a Foundation Medicine, Inc. (FMI), next-generation sequencing (NGS) assay. FFPE tumour tissue samples were profiled for GA in 395 genes, genome-wide loss of heterozygosity (LOH), and tumour mutational burden (TMB) using an FMI NGS assay. Results: As of 28 Feb 2018, ctDNA samples from 300 pts with mCRPC and disease progression were sequenced. Cell free DNA burden was significantly higher (P<0.0001) in pts who had progressed on prior androgen receptor (AR)-directed therapy and taxanebased chemotherapy (TRITON2) vs on AR-directed therapy alone (TRITON3). Prevalence of TP53 GAs in ctDNA was similar in TRITON2 (45.5%) and TRITON3 (46.0%). A deleterious GA was detected in BRCA1 (2.0%), BRCA2 (10.7%), or ATM (8.8%). We also sequenced 500 pts' tissue samples (Gleason score ≥ 8, 78%) from primary prostate cancer tumours (74%) or metastases (19%). A deleterious GA in BRCA1 (1.6%), BRCA2 (8.2%), or ATM (5.8%) was observed in 15.6% of samples; of these GAs, 56% were biallelic. A deleterious GA in CDK12 or 1 of 11 other HRR genes was detected in 5.6% and 6.4% of pts. Genome-wide LOH was determined for 339 BRCAwt tissue samples and was significantly higher (P<0.0001) in metastatic (median, 9.1%) compared to primary (median, 7.0%) samples, suggesting a higher degree of DNA damage in more advanced disease. Median TMB observed in 443 tumour samples was 3.5 mutations per megabase, with 81% having low, 18% intermediate, and 1% high TMB. Conclusions: Genomic profiling of both ctDNA and FFPE tumour tissue samples using NGS successfully identified pts with a GA in an HRR gene for the evaluation of rucaparib in mCRPC. Additional and updated genomic analyses will be presented.