Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation

N Engl J Med. 2017 Aug 10;377(6):523-533. doi: 10.1056/NEJMoa1706450. Epub 2017 Jun 4.

Abstract

Background: Olaparib is an oral poly(adenosine diphosphate-ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation.

Methods: We conducted a randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single-agent chemotherapy of the physician's choice (capecitabine, eribulin, or vinorelbine in 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review and was analyzed on an intention-to-treat basis.

Results: Of the 302 patients who underwent randomization, 205 were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the olaparib group than in the standard-therapy group (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% confidence interval, 0.43 to 0.80; P<0.001). The response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard-therapy group, and the rate of treatment discontinuation due to toxic effects was 4.9% and 7.7%, respectively.

Conclusions: Among patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, olaparib monotherapy provided a significant benefit over standard therapy; median progression-free survival was 2.8 months longer and the risk of disease progression or death was 42% lower with olaparib monotherapy than with standard therapy. (Funded by AstraZeneca; OlympiAD ClinicalTrials.gov number, NCT02000622 .).

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / mortality
  • Chemotherapy, Adjuvant
  • Disease-Free Survival
  • Female
  • Genes, BRCA1*
  • Genes, BRCA2*
  • Germ-Line Mutation*
  • Humans
  • Kaplan-Meier Estimate
  • Middle Aged
  • Neoplasm Metastasis / drug therapy
  • Phthalazines / adverse effects
  • Phthalazines / therapeutic use*
  • Piperazines / adverse effects
  • Piperazines / therapeutic use*
  • Poly(ADP-ribose) Polymerase Inhibitors / adverse effects
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use*
  • Receptor, ErbB-2
  • Young Adult

Substances

  • Antineoplastic Agents
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • olaparib

Associated data

  • ClinicalTrials.gov/NCT02000622
  • ClinicalTrials.gov/NCT02000622