British journal of cancer · 2026
Olaparib in HR-deficient, metastatic triple-negative breast and platinum-sensitive relapsed ovarian cancers without germline mutations in BRCA1/2: phase 2 EMBRACE trial.
СтатьяКлиническое исследование II фазыНазвание и аннотация: Перевод в очереди
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Sjoquist Katrin M, Dobrovic Alexander, Robledo Kristy P, Nesic Ksenija, Baron-Hay Sally, Ananda Sumitra, McCarthy Nicole, Goh Jeffrey, Steer Christopher, Murray Nick, Yip Sonia, Mileshkin Linda R, Fink J Lynn, Chang Garry, Bailey Lisa, Lee Yvonne, Zebic Danka S, Kariyawasam U G Imalki U, Shield-Artin Kristy, Jarratt Andrew, Bedő Justin, Papenfuss Anthony T, Kondrashova Olga, Wakefield Matthew J, Vandenberg Cassandra J, Stockler Martin R, Scott Clare L, Waring Paul M
Аннотация
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.
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.