4592 - Analysis of tumor samples from SOLO1: frequency of BRCA specific loss of heterozygosity (LOH) and progression-free survival (PFS) according to homologous recombination repair deficiency (HRD)-LOH score

Background

In SOLO1 (NCT01844986; GOG-3004), maintenance olaparib significantly improved PFS vs placebo (HR 0.30; 95% CI 0.23–0.41; Moore et al. NEJM 2018) in patients (pts) with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 mutation (BRCAm), who were in clinical complete or partial response after first line treatment, which includes surgery and platinum-based chemotherapy. We analyzed BRCA LOH and PFS by genome-wide HRD-LOH score in SOLO1.

Methods

Archival diagnostic tumour samples from 341/391 pts from SOLO1 were analysed using the Foundation Medicine F1CDx clinical trial assay. Tumour BRCA1 and BRCA2 LOH was determined using the SGZ-computational method (Sun et al. 2018). HRD-LOH score (genomic instability scar) was also generated and compared with PFS using a Cox Proportional Hazards model.

Results

Of evaluable tumours, 99% (275/277) had BRCA1 or BRCA2 LOH, including 2 pts with a somatic BRCAm. Two germline BRCA2m tumours lacked LOH. 283/341 (83.0%) tumours sequenced at FMI were evaluable for HRDLOH score. Using established cut-offs of 14 and 16 (Swisher et al. 2017); 84% (237/283) and 77% (218/283), respectively, would be considered HRD-LOH high. BRCAm pts with HRD-LOH scores <14 or < 16 derived similar benefit with olaparib compared to those with high scores (Table).Table: 998PD

Conclusions

As surgery is part of first-line treatment, platinum sensitivity cannot be determined in all pts. However, our results show that in patients with BRCAm tumours, BRCAm LOH is almost universal in ovarian cancer in the first-line setting. The majority of BRCAm tumours also have high HRD-LOH scores at diagnosis, with significant olaparib benefit demonstrated in pts with both high and low HRD-LOH scores. Assessing BRCA LOH and HRD-LOH scores does not discriminate the extent of olaparib benefit in newly diagnosed BRCAm advanced OC.

Clinical trial identification

NCT01844986.

Editorial acknowledgement

Emma Robinson, PhD, from Mudskipper Business Ltd, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD).

Legal entity responsible for the study

AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD).

Funding

AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD).

Disclosure

C. Gourley: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Tesaro; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Nucana; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: Foundation One; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Sierra Oncology; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Aprea. J.S. Brown: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Z. Lai: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Lao-Sirieix: Shareholder / Stockholder / Stock options, Full / Part-time employment, Spouse / Financial dependant, Spouse full-time employee: AstraZeneca; Licensing / Royalties, Named inventor on patent licensed to Medtronic. Not related to the topic of the abstract: Medtronic. C.E. Elks: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. H. McGarvey: Full / Part-time employment: AstraZeneca. T. French: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. T. Milenkova: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. R. Bloomfield: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Rowe: Full / Part-time employment: AstraZeneca. D. Hodgson: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J.C. Barrett: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. K. Moore: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Financial conflict of interest with AstraZeneca for 2018 related to speaking engagements following SOLO-1 and travel: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Tesaro; Honoraria (self): Prime Oncology; Honoraria (self): Research to Practice; Honoraria (self): PER; Advisory / Consultancy: Advaxis; Advisory / Consultancy: Immunogen; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Janssen; Advisory / Consultancy: Oncomed; Advisory / Consultancy: Samumed; Advisory / Consultancy: Aravive; Advisory / Consultancy: VBL Therapeutics; Advisory / Consultancy: Eisai; Research grant / Funding (self): Lilly; Research grant / Funding (self): PTC Therapeutics; Research grant / Funding (institution): LEAP, AbbVie, Boehringer Ingelheim, Regeneron. P. DiSilvestro: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro. E.A. Harrington: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca.