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Background <p>Homologous recombination (HR) deficiency (HRD) from germline <i>BRCA1/2</i> mutations (gBRCAm) sensitizes high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) to PARP inhibitors (PARPi), as may promoter methylation of <i>BRCA1</i> (me<i>BRCA1</i>) or <i>RAD51C</i> (me<i>RAD51C</i>) 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.</p> Methods <p>Single-arm phase 2 trial of olaparib 300 mg orally twice daily. Tumour me<i>BRCA1/</i>me<i>RAD51C</i> 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.</p> Results <p>Total 22 enrolled: promoter methylation detected in 8/15 HGSOC and 5/7 TNBC, and pathogenic variants (PV) in non-<i>BRCA</i> 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).</p> Conclusions <p>Olaparib demonstrated activity in HGSOC beyond gBRCAm, including with me<i>BRCA1</i> or <i>gRAD51C</i> PV. Olaparib had limited activity in pre-treated TNBC. Effects of prior chemotherapy on me<i>BRCA1/</i>me<i>RAD51C</i> require exploration to improve patient selection for PARPi.</p> Clinical trials registration <p>Australian New Zealand Clinical Trials Registry Registration number ACTRN 12617000855325.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Katrin M. Sjoquist,
  • Alexander Dobrovic,
  • Kristy P. Robledo,
  • Ksenija Nesic,
  • Sally Baron-Hay,
  • Sumitra Ananda,
  • Nicole McCarthy,
  • Jeffrey Goh,
  • Christopher Steer,
  • Nick Murray,
  • Sonia Yip,
  • Linda R. Mileshkin,
  • J. Lynn Fink,
  • Garry Chang,
  • Lisa Bailey,
  • Yvonne Lee,
  • Danka S. Zebic,
  • U. G. Imalki U. Kariyawasam,
  • Kristy Shield-Artin,
  • Andrew Jarratt,
  • Justin Bedő,
  • Anthony T. Papenfuss,
  • Olga Kondrashova,
  • Matthew J. Wakefield,
  • Cassandra J. Vandenberg,
  • Martin R. Stockler,
  • Clare L. Scott,
  • Paul M. Waring

摘要

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.