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Practice Guideline
. 2020 Dec;31(12):1606-1622.
doi: 10.1016/j.annonc.2020.08.2102. Epub 2020 Sep 28.

ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer

R E Miller  1 , A Leary  2 , C L Scott  3 , V Serra  4 , C J Lord  5 , D Bowtell  3 , D K Chang  6 , D W Garsed  3 , J Jonkers  7 , J A Ledermann  8 , S Nik-Zainal  9 , I Ray-Coquard  10 , S P Shah  11 , X Matias-Guiu  12 , E M Swisher  13 , L R Yates  14
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Free article
Practice Guideline

ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer

R E Miller et al. Ann Oncol. 2020 Dec.
Free article

Abstract

Background: Homologous recombination repair deficiency (HRD) is a frequent feature of high-grade serous ovarian, fallopian tube and peritoneal carcinoma (HGSC) and is associated with sensitivity to PARP inhibitor (PARPi) therapy. HRD testing provides an opportunity to optimise PARPi use in HGSC but methodologies are diverse and clinical application remains controversial.

Materials and methods: To define best practice for HRD testing in HGSC the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project that incorporated a systematic review approach. The main aims were to (i) define the term 'HRD test'; (ii) provide an overview of the biological rationale and the level of evidence supporting currently available HRD tests; (iii) provide recommendations on the clinical utility of HRD tests in clinical management of HGSC.

Results: A broad range of repair genes, genomic scars, mutational signatures and functional assays are associated with a history of HRD. Currently, the clinical validity of HRD tests in ovarian cancer is best assessed, not in terms of biological HRD status per se, but in terms of PARPi benefit. Clinical trials evidence supports the use of BRCA mutation testing and two commercially available assays that also incorporate genomic instability for identifying subgroups of HGSCs that derive different magnitudes of benefit from PARPi therapy, albeit with some variation by clinical scenario. These tests can be used to inform treatment selection and scheduling but their use is limited by a failure to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies. Existing tests lack negative predictive value and inadequately address the complex and dynamic nature of the HRD phenotype.

Conclusions: Currently available HRD tests are useful for predicting likely magnitude of benefit from PARPis but better biomarkers are urgently needed to better identify current homologous recombination proficiency status and stratify HGSC management.

Keywords: BRCA; genomic scar assays; homologous recombination deficiency (HRD); poly-ADP ribose inhibitors (PARPi).

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Conflict of interest statement

Disclosures REM receives consultancy fees from Merck, TESARO-GSK and Clovis Oncology, speaker bureau from Roche and TESARO and travel grants from AstraZeneca and TESARO. LRY receives research funding from the Wellcome Trust (Clinical Career Development Fellowship 214584/Z/18/Z). AL receives consultancy fees from Ability, Astra Zeneca, Clovis, GamaMabs, GSK, MSD, Merck Serono, and TESARO, research funding from Merus, GamaMabs, Inivata, and Sanofi Investigator and fees for trials with Ability, Agenus, AstraZeneca, BMS, Boehringer. IRC is the principal investigator of PAOLA1 trial; receives honoraria from AstraZeneca, Clovis, TESARO and Pharma Mar; consulting/advisory board fees from AstraZeneca, Roche, Clovis, TESARO, Genmab, Pharma Mar, MSD and Pfizer; research funding from MSD; travel expenses from AstraZeneca, GSK and Roche. JAL received fees for Advisory Boards and Lectures for AstraZeneca; Clovis Oncology; GSK. Advisory Boards from MSD/Merck; Eisai; Artios; Amgen; Regeneron. Grants AstraZeneca; MSD/Merck. SPS is a founder and shareholder of Canexia Health Inc. VS developed EP3502700A1: methods based on the detection of rad51 foci in tumour cells and developed EP3502700A1: methods based on the detection of rad51 foci in tumour cells and receives research funding from AstraZeneca and Tesaro; received consultancy, SAB membership or honoraria payments from Abbvie. CJL receives research funding from AstraZeneca, Merck KGaA, and Artios; received consultancy, SAB membership or honoraria payments from Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, and Artios. CJL has stock in Tango and OVIBIO and is also a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from the development as part of the ICR ‘Rewards to Inventors’ scheme. JJ is an advisory board member of Artios Pharma. DKC received research funding from Cancer Research UK (C51058/A25407), Celgene and Astra Zeneca, and speaker bureau from Celgene. DB receives research grant funding from Astra Zeneca, Genentech/Roche, Beigene, and paid consultancy from Exo Therapeutics. SNZ holds multiple patents on mutational-signature-based clinical algorithms and is a current or past recipient of honoraria from Astra Zeneca, Artios Pharma and the Scottish Genomics Partnership. JJ is an advisory board member of Artios Pharma and receives research funding from Artios Pharma, Cancer Research UK, Dutch Cancer Society and Oncode Institute. All remaining authors have declared no conflicts of interest. CLS acts in an honorary advisory capacity for AstraZeneca, Clovis Oncology, Roche, Eisai Inc, Sierra Oncology, Takeda, MSD.; receives grant/research support from Clovis Oncology, Eisai Inc, Sierra Oncology, Roche, Beigene; travel support from AstraZeneca.

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