1936P - Analysis of BRCA genes and homologous recombination deficiency (HRD) scores in tumours from patients (pts) with metastatic breast cancer (mBC) in the OlympiAD trial

Abstract

BackgroundWe conducted tumour testing in pts with germline mutations in BRCA1 and/or BRCA2 (gBRCAm) and HER2-negative mBC in the OlympiAD study (NCT02000622). MethodsTumour tissue of gBRCAm pts was analysed with Myriad myChoice HRD Plus, including determination of tumor (t) BRCAm, HRD score and gene-specific loss of heterozygosity (LOH). ResultsTissue was available from 161/302 pts: tBRCAm status n=143 (47%); HRD score n=129 (43%); LOH n=125 (41%). Concordance of gBRCAm and tBRCAm was 99% (141/142). Absence of LOH was observed in 7/125 pts (6%): 4/49 (8%) BRCA2m, 3/76 (4%) BRCA1m; 2 had a 2nd mutation event (Table). Low HRD scores (<42) were seen in 16% of pts (21/129), with higher rates in BRCA2m vs BRCA1m pts (14/51 [27%] vs 7/78 [9%]) and hormone receptor positive (HR+) vs triple negative (TN; 13/59 [22%] vs 8/70 [11%]). In olaparib (ola) pts with a BRCAm, ORR was 60% (6/10) and 57% (37/65) in pts with HRD score <42 and ≥42, respectively. Hazard ratio for PFS favoured ola vs treatment of physician’s choice (TPC) when HRD score was <42 or≥42.Table: 1936PPts with absence of LOHTable: 1936PTreatmentBiopsyGeneVariantHRD scoreHormone receptor status2nd eventRECIST responsePFS (months)†OlaPriBRCA2c.9097dupA (p.Thr3033Asnfs*11)31HR+PR11.0‡OlaPriBRCA2c.5946del (p.Ser1982Argfs*22)28HR+PD1.3§OlaMetBRCA2c.658_659del (p.Val220Ilefs*4)12HR+SD8.2§OlaPriBRCA2c.7977-1G>C34HR+CR11.0‡OlaMet¶BRCA1c.188T>A (p.Leu63*)56HR+S1580fs*2PR6.5§TPCMet¶BRCA1c.5266dupC (p.Gln1756Profs*74)73HR+494dupT and 528_535delins25PR5.9§TPCPriBRCA1c.1931del (p.Cys644Phefs*7)41TNSD8.1§†Overall median PFS was 7.0 months for ola vs 4.2 months for TPC;‡Censor;§Event;¶Diagnosis to sample interval was ≥7 years. CR, complete response; Met, metastatic; PD, progressive disease; PR, partial response; Pri, primary; SD, stable disease ConclusionsTumour testing detected almost all gBRCAm in the study. In this mBC population, absence of LOH was uncommon, indicating a high rate of biallelic inactivation. There was no evidence for a reduction in ola efficacy in the small number of pts with BRCAm HER2-negative mBC whose tumors lack LOH and/or have HRD score <42. Clinical trial identificationNCT02000622. Editorial acknowledgementMedical writing assistance was provided by Debbi Gorman, 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 studyAstraZeneca. FundingThis study was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck & Co, Inc. DisclosureM. Robson: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Uncompensated: Daiichi-Sankyo; Advisory / Consultancy: McKesson; Advisory / Consultancy, Uncompensated: Merck; Advisory / Consultancy, Research grant / Funding (institution), Consulting/advisory: Uncompensated; other transfer of value (editorial services): Pfizer; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Invitae; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Myriad; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution), Funded in part: Grant P30 CA008748: NIH/NCI Cancer Center Support. Z. Lai: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. S. Dearden: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J.C. Barrett: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. E.A. Harrington: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. K. Timms: Shareholder / Stockholder / Stock options, Full / Part-time employment: Myriad. J. Lanchbury: Shareholder / Stockholder / Stock options, Full / Part-time employment: Myriad. W. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Allen: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Goessl: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. E. Senkus: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): Clinigen; Honoraria (self), Travel / Accommodation / Expenses: Egis; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self): Sandoz; Honoraria (self), Research grant / Funding (institution): Samsung; Honoraria (self), Research grant / Funding (institution): Merck; Research grant / Funding (institution): Boehringer. S. Domchek: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Clovis Oncology; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (institution): PharmaMar. D. Hodgson: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca.