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.
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).
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.
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.
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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.