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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

2834 - Multimodal detection of homologous recombination repair gene mutations (HRRm) in a Phase II trial of olaparib plus abiraterone in metastatic castrate resistant prostate cancer (mCRPC)

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Presenters

Thomas Carr

Citation

Annals of Oncology (2018) 29 (suppl_8): viii14-viii57. 10.1093/annonc/mdy269

Authors

T.H. Carr1, C. Adelman2, A. Barnicle2, I. Kozarewa2, S. Luke2, Z. Lai3, S. Menon2, S. Hollis4, B. Dougherty3, E.A. Harrington2, J.C. Barrett3, C. Goessl3, F. Saad5, N. Sala6, N.W. Clarke7, D. Hodgson2

Author affiliations

  • 1 ,, AstraZeneca, SG86HB - Cambridge/GB
  • 2 ,, AstraZeneca, Cambridge/GB
  • 3 ,, AstraZeneca, Gaithersburg/US
  • 4 ,, Phastar, London/GB
  • 5 ,, University of Montreal Hospital Research Centre, Montreal/CA
  • 6 ,, Catalan Institute of Oncology, Hospital Josep Trueta, Girona/ES
  • 7 ,, The Christie NHS Foundation Trust, Manchester/GB
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Resources

Abstract 2834

Background

Study 8 [NCT01972217] was a randomized Phase II trial that tested the hypothesis that the combination of PARP inhibition plus abiraterone benefits unselected patients (pts) with mCRPC. The primary endpoint was progression-free survival. A key secondary objective was to understand the relationship between HRRm status and outcome, which was challenged by low-tissue acquisition and high-test failure. The primary biomarker analysis focused on testing plasma when tumour data were not available and germline mutations were not evident. Here we describe additional analyses of circulating tumour DNA (ctDNA) to further characterize HRRm status and evaluate concordance between different testing modalities.

Methods

Tumour specimens were sequenced via Foundation Medicine. Germline analysis was performed via Color Genomics. An inhouse (RUO) sequencing assay was used for baseline ctDNA analysis. A subset of plasma samples was analyzed via GuardantOMNI™ and a custom assay (Resolution Bioscience). CtDNA libraries were also subjected to shallow whole genome sequencing (∼4–5x). From 142 enrolled pts, we obtained HRRm data for 136 (from any source).

Results

Previous tumour/germline analyses identified 8 HRRm pts: 1 somatic, 7 germline (tumour success rate 38/68 [56%]; germline success rate 102/102). CtDNA analyses yielded a success rate of 93% (127/136 pts with plasma analyzed), with tumour variants detectable with high confidence in 79% (100/127). Plasma sequencing identified additional HRRm pts, including homozygous deletions, approximately tripling the number known to have a HRRm. Plasma testing in pts with tumour data revealed high concordance between tumour and ctDNA.

Conclusions

Comprehensive, sensitive sequencing of ctDNA for HRRm is feasible in mCRPC pts with a high success rate. Both targeted and whole genome approaches add value. There was good concordance across testing modalities where gene coverage overlapped, highlighting the considerable value of ctDNA testing in mCRPC where access to tissue of sufficient quality for molecular analysis is challenging, and somatic alterations are common. The first two authors contributed equally.

Clinical trial identification

NCT01972217.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Editorial Acknowledgement

n/a

Disclosure

T.H. Carr, C. Adelman, A. Barnicle, I. Kozarewa, S. Luke, Z. Lai, S. Menon, B. Dougherty, E.A. Harrington, J.C. Barrett, C. Goessl, D. Hodgson: Employee and stockholder: AstraZeneca. S. Hollis: Contracted: AstraZeneca and own stock. F. Saad: Grants and personal fees: AstraZeneca, Janssen, Astellas, Sanofi, Bayer. N. Sala: Personal fees: Astellas, Janssen, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

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