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Poster Discussion session - Genitourinary tumours, prostate

3724 - Genomic profiling of circulating tumour DNA (ctDNA) and tumour tissue for the evaluation of rucaparib in metastatic castration-resistant prostate cancer (mCRPC)

Date

21 Oct 2018

Session

Poster Discussion session - Genitourinary tumours, prostate

Topics

Cytotoxic Therapy;  Translational Research

Tumour Site

Prostate Cancer

Presenters

Simon Chowdhury

Citation

Annals of Oncology (2018) 29 (suppl_8): viii271-viii302. 10.1093/annonc/mdy284

Authors

S. Chowdhury1, R. McDermott2, J.M. Piulats3, J.D. Shapiro4, I. Mejlholm5, D. Morris6, P. Ostler7, A. Hussain8, I. Dumbadze9, E.R. Goldfischer10, E. Pintus11, A. Benjelloun12, M.E. Gross13, S. Tejwani14, G. Chatta15, A. Font16, A. Loehr17, A.D. Simmons18, S.P. Watkins19, W. Abida20

Author affiliations

  • 1 Medical Oncology, Guy's Hospital and Sarah Cannon Research Institute, SE1 9RT - London/GB
  • 2 Genito-urinary Oncology, AMNCH Adelaide and Meath Hospital, 24 - Dublin/IE
  • 3 Medical Oncology, Instituto Catalan de Oncologia, Barcelona/ES
  • 4 Medical Oncology, Cabrini Hospital, 3186 - Malvern/AU
  • 5 Oncology, Vejle Sygehus, 7100 - Vejle/DK
  • 6 Oncology, Urology Associates Clinical research, Nashville/US
  • 7 Clinical Oncology, Mount Vernon Cancer Centre, HA6 2RN - Northwood/GB
  • 8 Department Of Medicine, University of Maryland Greenebaum Cancer Center, Baltimore/US
  • 9 Urology, The Urology Group, Cincinnati/US
  • 10 Urology, Premier Medical Group of the Hudson Valley, Poughkeepsie/US
  • 11 Medical Oncology, Frimley Health NHS Foundation Trust, RG1 5AN - Slough/GB
  • 12 Medical Oncology, Centre Hospitalier Universitaire Dr-Georges-L.-Dumont, E1C 8X3 - Moncton/CA
  • 13 Department Of Medicine, University of Southern California, Los Angeles/US
  • 14 Medical Oncology, Henry Ford Health System, 48202 - Detroit/US
  • 15 Genitourinary Medicine, Roswell Park Comprehensive Cancer Center, Buffalo/US
  • 16 Medical Oncology, Hospital Universitari Germans Trias i Pujol, 08916 - Badalona/ES
  • 17 Translational Medicine, Clovis Oncology, Inc., 80301 - Boulder/US
  • 18 Translational Medicine, Clovis Oncology, 94158 - Boulder/US
  • 19 Clinical Science, Clovis Oncology, Inc., Boulder/US
  • 20 Genitourinary Oncology, Memorial Sloan Kettering Cancer Center, New York/US
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Resources

Abstract 3724

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.

Legal entity responsible for the study

Clovis Oncology, Inc.

Funding

Clovis Oncology, Inc.

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).

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.

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