755P - Beyond HRD status: Unraveling genetic variants impacting PARP inhibitor sensitivity in advanced ovarian cancer

Background

The management of advanced ovarian cancer (AOC) has evolved with the advent of molecular diagnostics, particularly in predicting responses to poly (ADP-ribose) polymerase inhibitors (PARPi) based on homologous recombination deficiency (HRD) status. Despite this, a comprehension of PARPi sensitivity in HRD negative (HRDneg) tumors and resistance in HRD positive (HRDpos) tumors has not yet been fully achieved.

Methods

We conducted post hoc translational analysis of formalin-fixed paraffin-embedded tumor samples from the ENGOT-ov24/NSGO-AVANOVA part 1 and 2 trial (AVANOVA1&2; NCT02354131), focusing on alterations with regards to progressions-free survival (PFS) and radiological response. DNA sequencing was performed using the TruSight Oncology 500 HT gene panel, and variants were classified according to recent guidelines. HRD status had been assessed by Myriad MyChoice® CDx.

Results

Among samples collected from 92 patients included in the AVANOVA1&2 trial, 151 oncogenic or likely oncogenic variants were identified across 81 samples. In terms of PFS, PARPi sensitizing variants were identified in two out of ten HRDneg samples from patients with clinical benefit (PFS ≥ 12 months), and with PARPi resistance in three out of ten HRDpos samples from patients having no benefit (PFS ≤ 6 months). Moreover, studying the location of pathogenic variants in BRCA1 revealed, that truncating variants in exon 11 were associated with clinical benefit, only when niraparib was combined with bevacizumab in this study.

Conclusions

Our findings highlight the complexity of PARPi response in AOC and underscore the importance of exploring somatic variants beyond HRD status. Further investigation into exon 11 variants of BRCA1 and the potential role of combination treatment is warranted.

Clinical trial identification

ENGOT-ov24/NSGO-AVANOVA1&2; NCT02354131.

Editorial acknowledgement

During the preparation of this work the first author used ChatGPT for language editing support. After using this tool, all authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Legal entity responsible for the study

NSGO-CTU.

Funding

GSK provided a research grant covering analysis costs in this study and reviewed the preliminary version of the abstract. The authors are solely responsible for final content and interpretation.

Disclosure

M.K. Kjeldsen: Financial Interests, Institutional, Research Grant: GSK. C.A. Haslund: Financial Interests, Personal, Invited Speaker: MSD, GSK, BMS; Financial Interests, Institutional, Local PI: BMS, Tesaro, MSD, IO Biotech, Chimerix, Incyte; Financial Interests, Institutional, Coordinating PI: GSK, Celgene Aps. S. Hietanen: Financial Interests, Personal, Advisory Role: AstraZeneca, GSK, MSD, Eisai, Orion; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, GSK. H. Dahlstrand: Financial Interests, Advisory Board: AstraZeneca; Financial Interests, Invited Speaker: Roche, GSK. L. Bjorge: Financial Interests, Personal, Advisory Board, Expert testimony regarding a patent application: Onsagers, Oslo; Financial Interests, Personal, Advisory Board, Expert testimony for an application to The National System for Managed Introduction of New Health Technologies within the Specialist Health Service in Norway: AstraZeneca; Financial Interests, Personal, Advisory Board, Part of an ad hoc advisory board for ovarian cancer: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker at at national meeting for gynaecologist: GSK; Financial Interests, Personal, Member of Board of Directors, Oslo Cancer Cluster is an oncology research and industry cluster dedicated to improving the lives of cancer patients by accelerating the development of new cancer diagnostics and treatment. Been part of the board during the period 2015-2022 (elected): Oslo Cancer Cluster; Financial Interests, Personal, Full or part-time Employment, I hold a full-time position as Medical Director and consultant in gynecologic oncology at this institution: Helse Bergen HF; Financial Interests, Personal, Full or part-time Employment, I hold a part-time position as Professor in Obstetrics and Gynecology: University of Bergen; Financial Interests, Institutional, Research Grant, Financial support for a researcher-initiated trial: AstraZeneca; Non-Financial Interests, Leadership Role, Onkologisk Forum is the interest organization for all groups of personal working with cancer patients or cancer treatment or cancer research in Norway, https://onkologiskforum.org/om-onkologisk-forum. During the period 2018-2022 I been the leader for the organization (elected position): Onkologisk Forum; Non-Financial Interests, Leadership Role, From March 2021 hold the position as president for the organization: Nordic Society for Gynecological Oncology; Non-Financial Interests, Leadership Role, Leader of the board since March 2021: Nordic Society of Gynecologic Oncology-Clinical Trial Unit; Non-Financial Interests, Advisory Role, Member of the specialist group in oncology, Sykehusinnkjøp HF, Representing Helse Vest RHF.: Sykehus Innkjøp HF; Non-Financial Interests, Leadership Role, Since March 2021 I have hold the position as president for the organization. I have been a member of the organization since 2012, and a board member since 2014.: Nordic Society of Gynecologic Oncology; Non-Financial Interests, Member, I have been a member since 2011: ESGO; Non-Financial Interests, Member, I have been a member since 2015: ASCO; Other, I have been evaluating grant applications from different national and international research institutions and grant providers: Different academic institutions; Other, Member of the scientific advisory board for different Norwegian and Nordic Research centres: Different academic institutions; Other, Board member (non-profil activity): KinN Therapeutics. M.R. Mirza: Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Karyopharm, Merck, Zailab, BioNTech, Deiichi Sankyo, Eisai, ImmunoGen/AbbVie, Incyte, Regeneron; Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK; Financial Interests, Personal, Member of Board of Directors: Karyopharm; Financial Interests, Personal, Stocks/Shares: Karyopharm; Financial Interests, Institutional, Research Grant: GSK, AstraZeneca, Ultimovacs, Apexigen; Financial Interests, Institutional, Trial Chair: Deciphera; Non-Financial Interests, Advisory Role: Ultimovacs; Non-Financial Interests, Member, Member of Prix Galien Awards Committee: Prix Galien Foundation. All other authors have declared no conflicts of interest.