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

2018; Elsevier BV; Volume: 29; Linguagem: Inglês

10.1093/annonc/mdy284.004

1569-8041

S. Chowdhury, Ray McDermott, Josep M. Piulats, Jeremy Shapiro, Inge Mejlholm, David Morris, Peter Ostler, Arif Hussain, Igor Dumbadze, Evan R. Goldfischer, Elias Pintus, A. Benjelloun, Mitchell E. Gross, Sheela Tejwani, Gurkamal Chatta, Albert Font, Andrea Loehr, Andrew D. Simmons, Simon P. Watkins, Wassim Abida,

Cancer Genomics and Diagnostics

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 taxane-based 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. Clinical trial identification: NCT02952534. Editorial acknowledgement: Writing and editorial support, funded by Clovis Oncology, Inc. (Boulder, CO, USA) was provided by Nathan Yardley, PhD, and Shannon Davis of Ashfield Healthcare Communications (Middletown, CT, USA). Legal entity responsible for the study: Clovis Oncology, Inc. Funding: Clovis Oncology, Inc. Disclosure: S. Chowdhury: Consulting, Advisory role, Speakers bureaus: Clovis Oncology, Sanofi, Pfizer, Astellas Pharma, Janssen; Honoraria: GlaxoSmithKline, Novartis; Research funding: Sanofi, Johnson & Johnson. J.M. Piulats: Consulting, Advisory role: Clovis Oncology, Astellas, Janssen, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Pfizer, Roche, Novartis; Research funding: Merck Serono, Bristol-Myers Squibb, Pfizer, Janssen, Astellas. D. Morris: Consulting, Advisory role, Speakers bureaus: Janssen, Dendreon, GenomeDx, Myriad, Pacific Edge Diagnostics, Astellas; Support for scientific study or clinical trial: Janssen, Dendreon, Bayer, Myriad, Clovis Oncology, and Astellas. A. Hussain: Consulting, Advisory role: Bayer, Bristol-Myers Squibb, AstraZeneca. E. Pintus: Consulting or advisory role: Clovis Oncology; Honoraria: Astellas, travel, grant support: Clovis, Janssen, Astellas. A. Benjelloun: Consulting, Advisory role: Janssen, Astellas, Bristol-Myers Squibb. M.E. Gross: Research support: Clovis Oncology, Myriad, Janssen. A. Loehr, A.D. Simmons, S.P. Watkins: Employee, Stock owner, Stock option Owner: Clovis Oncology. W. Abida: Consulting, Advisory role: Clovis Oncology; Honoraria: Caret Healthcare; Research funding: AstraZeneca, Zenith Epigenetics. All other authors have declared no conflicts of interest.