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BCC 2021 | Phase III trial of denosumab for breast cancer risk reduction in BRCA1 carriers

Denosumab is a monoclonal antibody targeting RANK ligand (RANKL). Evidence has implicated RANKL in the development of BRCA1-associated breast cancer and thus, its inhibition may reduce the risk of developing breast cancer in women with a germline BRCA1 mutation. Judy Garber, MD, MPH, Dana-Farber Cancer Institute, Boston, MA, outlines the details of the upcoming BRCA-P Phase III prevention trial (NCT04711109) of denosumab in BRCA1 carriers. The randomized, double-blind, placebo-controlled trial will be run internationally, using breast cancer development as an endpoint to determine the risk reduction associated with denosumab use. This interview took place during the 17th St. Gallen International Breast Cancer Conference.

Transcript (edited for clarity)

BRCA-P is the breast cancer prevention trial for BRCA1 carriers who have never had breast cancer. The study drug in this Phase III prevention trial, so the endpoint is breast cancer, the study drug is denosumab, which is a RANK ligand inhibitor. This is based on the work of Geoff Lindeman in Australia, showing that RANK ligand itself was important in the development of BRCA1-associated breast cancer, and therefore its inhibition should reduce risk...

BRCA-P is the breast cancer prevention trial for BRCA1 carriers who have never had breast cancer. The study drug in this Phase III prevention trial, so the endpoint is breast cancer, the study drug is denosumab, which is a RANK ligand inhibitor. This is based on the work of Geoff Lindeman in Australia, showing that RANK ligand itself was important in the development of BRCA1-associated breast cancer, and therefore its inhibition should reduce risk.

You can see in their primary publication by Nolan et al. that inhibition of RANK ligand blocks proliferation in animal models and in some early human tissue. The trial is open already in Austria, where it is led by Christian Singer through the ABCSG, Australia, Israel, Spain, Germany and the UK. The US is coming on board this summer.

We have a large grant for translational work to be part of the study. Hopefully this will change what we can offer women with BRCA1 mutations, at least to allow them to delay their consideration of prophylactic mastectomy, and hopefully permanently.

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Disclosures

Prof. Garber reports being the co-PI of the OlympiA trial, supported by Astra-Zeneca/Merck, Co-PI of the BRCA-P trial, supported by AmGen and by a grant from the Department of Defense.

Prof. Garber reports research support from Myriad, Ambry and Invitae Genetics Laboratories, and unpaid consulting for Konica Minolta.