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

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 (me BRCA1 ) or RAD51C (me RAD51C ) 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 me BRCA1/ me RAD51C 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 me BRCA1 or gRAD51C PV. Olaparib had limited activity in pre-treated TNBC. Effects of prior chemotherapy on me BRCA1/ me RAD51C require exploration to improve patient selection for PARPi. Clinical trials registration Australian New Zealand Clinical Trials Registry Registration number ACTRN 12617000855325.