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

Publication ,  Journal Article
Tung, NM; Robson, ME; Ventz, S; Santa-Maria, CA; Nanda, R; Marcom, PK; Shah, PD; Ballinger, TJ; Yang, ES; Vinayak, S; Melisko, M; Brufsky, A ...
Published in: J Clin Oncol
December 20, 2020

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.

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Published In

J Clin Oncol

DOI

EISSN

1527-7755

Publication Date

December 20, 2020

Volume

38

Issue

36

Start / End Page

4274 / 4282

Location

United States

Related Subject Headings

  • Poly(ADP-ribose) Polymerase Inhibitors
  • Piperazines
  • Phthalazines
  • Oncology & Carcinogenesis
  • Neoplasm Metastasis
  • Mutation
  • Middle Aged
  • Humans
  • Homologous Recombination
  • Female
 

Citation

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Tung, N. M., Robson, M. E., Ventz, S., Santa-Maria, C. A., Nanda, R., Marcom, P. K., … Garber, J. E. (2020). TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes. J Clin Oncol, 38(36), 4274–4282. https://doi.org/10.1200/JCO.20.02151
Tung, Nadine M., Mark E. Robson, Steffen Ventz, Cesar A. Santa-Maria, Rita Nanda, Paul K. Marcom, Payal D. Shah, et al. “TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes.J Clin Oncol 38, no. 36 (December 20, 2020): 4274–82. https://doi.org/10.1200/JCO.20.02151.
Tung NM, Robson ME, Ventz S, Santa-Maria CA, Nanda R, Marcom PK, et al. TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes. J Clin Oncol. 2020 Dec 20;38(36):4274–82.
Tung, Nadine M., et al. “TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes.J Clin Oncol, vol. 38, no. 36, Dec. 2020, pp. 4274–82. Pubmed, doi:10.1200/JCO.20.02151.
Tung NM, Robson ME, Ventz S, Santa-Maria CA, Nanda R, Marcom PK, Shah PD, Ballinger TJ, Yang ES, Vinayak S, Melisko M, Brufsky A, DeMeo M, Jenkins C, Domchek S, D’Andrea A, Lin NU, Hughes ME, Carey LA, Wagle N, Wulf GM, Krop IE, Wolff AC, Winer EP, Garber JE. TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes. J Clin Oncol. 2020 Dec 20;38(36):4274–4282.

Published In

J Clin Oncol

DOI

EISSN

1527-7755

Publication Date

December 20, 2020

Volume

38

Issue

36

Start / End Page

4274 / 4282

Location

United States

Related Subject Headings

  • Poly(ADP-ribose) Polymerase Inhibitors
  • Piperazines
  • Phthalazines
  • Oncology & Carcinogenesis
  • Neoplasm Metastasis
  • Mutation
  • Middle Aged
  • Humans
  • Homologous Recombination
  • Female