TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes

Nadine M. Tung, Mark E. Robson, Steffen Ventz, Cesar A. Santa-Maria, Rita Nanda, Paul K. Marcom, Payal D. Shah, Tarah J. Ballinger, Eddy S. Yang, Shaveta Vinayak, Michelle Melisko, Adam Brufsky, Michelle DeMeo, Colby Jenkins, Susan Domchek, Alan D’Andrea, Nancy U. Lin, Melissa E. Hughes, Lisa A. Carey, Nick WagleGerburg M. Wulf, Ian E. Krop, Antonio C. Wolff, Eric P. Winer, Judy E. Garber

Research output: Contribution to journalArticlepeer-review

268 Scopus citations


PURPOSE Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer (MBC) in germline (g)BRCA1/2 mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)BRCA1/2 mutations or g/s mutations in homologous recombination (HR)–related genes other than BRCA1/2. METHODS Eligible patients had MBC with measurable disease and germline mutations in non-BRCA1/2 HR-related genes (cohort 1) or somatic mutations in these genes or BRCA1/2 (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (# 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS). RESULTS Fifty-four patients enrolled. Seventy-six percent had estrogen receptor–positive HER2-negative disease. Eighty-seven percent had mutations in PALB2, sBRCA1/2, ATM, or CHEK2. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with gPALB2 (ORR, 82%) and sBRCA1/2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for gPALB2 and 6.3 months (90% CI, 4.4 months to NA) for sBRCA1/ 2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone. CONCLUSION PARP inhibition is an effective treatment for patients with MBC and gPALB2 or sBRCA1/2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond gBRCA1/2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.

Original languageEnglish
Pages (from-to)4274-4282
Number of pages9
JournalJournal of Clinical Oncology
Issue number36
StatePublished - Dec 20 2020

Bibliographical note

Publisher Copyright:
Copyright © 2020 American Society of Clinical Oncology. All rights reserved.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes'. Together they form a unique fingerprint.

Cite this