Olaparib in HR-deficient, metastatic triple-negative breast and platinum-sensitive relapsed ovarian cancers without germline mutations in BRCA1/2: phase 2 EMBRACE trial

Sjoquist, KM; Mccarthy, N; Dobrovic, A; Bedo, J; Robledo, KP; Nesic, K; Baron-Hay, S; Ananda, S; Goh, J; Steer, C; Murray, N; Yip, S; Mileshkin, LR; Fink, JL; Chang, G; Bailey, L; Lee, Y; Zebic, DS; Kariyawasam, Ugiu; Shield-Artin, K; Jarratt, A; Papenfuss, AT; Kondrashova, O; Wakefield, MJ; Vandenberg, CJ; Stockler, MR; Scott, CL; Waring, PM

Author(s): Sjoquist, KM; Mccarthy, N; Dobrovic, A; Bedo, J; Robledo, KP; Nesic, K; Baron-Hay, S; Ananda, S; Goh, J; Steer, C; Murray, N; Yip, S; Mileshkin, LR; Fink, JL; Chang, G; Bailey, L; Lee, Y; Zebic, DS; Kariyawasam, Ugiu; Shield-Artin, K; Jarratt, A; Papenfuss, AT; Kondrashova, O; Wakefield, MJ; Vandenberg, CJ; Stockler, MR; Scott, CL; Waring, PM;
Details: Publication Year 2026-10,Volume 135,Issue #7,Page 1152-1163
Journal Title: British Journal of Cancer
Publication Type: Jul 8
Abstract: BACKGROUND: Homologous recombination (HR) deficiency (HRD) from germline BRCA1/2 mutations (gBRCAm) sensitizes high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) to PARP inhibitors (PARPi), as may promoter methylation of BRCA1 (meBRCA1) or RAD51C (meRAD51C) or mutation of non-BRCA HR genes. This trial evaluated olaparib in platinum-sensitive, relapsed HGSOC (PSROC) and metastatic TNBC (mTNBC) with non-gBRCA HRD. METHODS: Single-arm phase 2 trial of olaparib 300 mg orally twice daily. Tumour meBRCA1/meRAD51C determined by methylation-sensitive, high-resolution melting PCR and targeted sequencing. Unmethylated cases underwent HR gene mutation testing. PRIMARY OUTCOME: objective tumour response rate (OTRR) at 6 months(m). SECONDARY OUTCOMES: progression-free survival (PFS), OTRR according to HR gene aberration, and safety. RESULTS: Total 22 enrolled: promoter methylation detected in 8/15 HGSOC and 5/7 TNBC, and pathogenic variants (PV) in non-BRCA HR genes. OTRR at 6 m was 40% HGSOC and 0% TNBC. OTRR was 38% in methylated cases vs 43% for other HRD. 6 m/12 m PFS were 53% / 25% (HGSOC), and 17% / 0% (TNBC). CONCLUSIONS: Olaparib demonstrated activity in HGSOC beyond gBRCAm, including with meBRCA1 or gRAD51C PV. Olaparib had limited activity in pre-treated TNBC. Effects of prior chemotherapy on meBRCA1/meRAD51C require exploration to improve patient selection for PARPi. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry Registration number ACTRN 12617000855325.
Publisher: Springer Nature
Keywords: Humans; Female; *Phthalazines/therapeutic use/adverse effects/administration & dosage; *Piperazines/therapeutic use/adverse effects/administration & dosage; *Ovarian Neoplasms/drug therapy/genetics/pathology; *Triple Negative Breast Neoplasms/drug therapy/genetics/pathology; Middle Aged; Germ-Line Mutation; Aged; Adult; BRCA1 Protein/genetics; Neoplasm Recurrence, Local/drug therapy/genetics; BRCA2 Protein/genetics; DNA Methylation; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use; Homologous Recombination
Research Division(s): Cancer Biology and Stem Cells; Bioinformatics and Computational Biology
PubMed ID: 42420629
Publisher's Version: https://doi.org/10.1038/s41416-026-03535-6
Open Access at Publisher's Site: https://doi.org/10.1038/s41416-026-03535-6
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-07-15 09:14:54

Last Modified: 2026-10-02 08:19:43