EORTC, BIG and TESARO launch registration trial with niraparib for patients with metastatic BRCA mutated breast cancer

The overall breast cancer death rate has dropped steadily in recent years as meaningful improvements in survival have resulted from the introduction of newer systemic therapies. Even so, it is unlikely that metastatic disease will be cured any time soon. Patients with metastatic disease currently receive systemic therapy consisting of chemotherapy, endocrine therapy and /or biologic therapies as well as supportive care measures. The median overall survival for patients receiving this treatment is approximately two years and ranges from a few months to many years. In this setting, alleviation of symptoms and improvement in quality of life apart from prolongation of survival remain the main goals.

The EORTC (European Organisation for Research and Treatment of Cancer), BIG (Breast International Group), and Tesaro (an oncology-focused biopharmaceutical company), have launched the phase III EORTC 1307 registration trial for already pretreated patients with metastatic HER2 negative breast cancer and germline BRCA mutations in order to test the efficacy and safety of niraparib over the standard chemotherapy (chosen by the physician and patient together before randomization) of eribulin, vinorelbine, gemcitabine, or capecitabine. The study will randomize a total of 306 patients, two thirds of whom will receive treatment with niraparib, while one third will be treated with the physician’s choice.

Dr. Nicholas Turner of the Royal Marsden Hospital in London and Coordinator of the study says, “The poly ADP-ribose polymerases, PARP 1 and PARP 2, play an essential role in DNA repair; PARP binds DNA strands resulting in efficient repair of DNA breaks. Cells treated with PARP inhibitors are not able to repair these defects, and convert pre-existing single strand breaks to double strand breaks as the replication machinery passes. Cells with BRCA1 or BRCA2 mutations cannot repair these replication associated double strand breaks, and so they end up accumulating defects that ultimately lead to their death.”

Niraparib, an orally active potent and selective PARP-1 and PARP-2 inhibitor developed by Tesaro, has demonstrated selective anti- proliferative activity for cancer cell lines that have been silenced or mutated for BRCA1 or BRCA2 as compared to their wild type counterparts.

Dr. David Cameron of the NHS Lothian – Western General Hospital, Edinburgh, Chair of the EORTC Breast Cancer Group, and Co-Coordinator of this study adds, “BRCA deficient cancer cells have been shown to be hypersensitive to single agent PARP inhibitors, and there are several PARP inhibitors now in clinical development. Treatment with this class of agents represents a novel opportunity to selectively kill a subset of cancer cell types by exploiting their deficiencies in DNA repair.”

Germline BRCA1 and BRCA2 gene mutations are found in the majority of patients with hereditary breast or ovarian cancer, but data regarding the impact of BRCA1/2 mutational status on treatment of breast cancer are currently inconclusive. These genes do not affect the decision making process regarding the choice of systemic therapy at this time.

This intergroup trial is sponsored by TESARO, co-led by the EORTC and BIG, and will be conducted in approximately 70 sites in 13 countries: Belgium, Canada, Germany, Spain, France, the United Kingdom, Hungary, Iceland, Israel, Italy, Poland, Portugal, and the United States of America. Niraparib, the investigational drug, will be supplied by TESARO, who are fully supporting this trial.

Konstantinos Tryfonidis, MD
EORTC Clinical Research Physician

John Bean, PhD
EORTC Medical Science Writer

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