Olaparib in HR-deficient, metastatic triple-negative breast and platinum-sensitive relapsed ovarian cancers without germline mutations in BRCA1/2: phase 2 EMBRACE trial
Mené sur 22 patientes ne présentant pas de mutation constitutionnelle BRCA et atteintes d'un cancer du sein triple négatif de stade métastatique ou d'un cancer séreux de l'ovaire de haut grade, sensible aux sels de platine et récidivant, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective à 6 mois, et la toxicité de l'olaparib
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.
British Journal of Cancer , article en libre accès, 2026