BRCA-P: Can denosumab reduce breast cancer risk in BRCA1 mutation carriers?

TPS10630 Background: The likely ‘cell-of-origin’ that leads to breast cancer in BRCA1 mutation carriers is a progenitor cell that is highly proliferative and prone to DNA damage. This progenitor cell expresses RANK ligand receptor RANK and is hyper-responsive to progesterone through paracrine signaling mediated by RANK ligand RANKL. Notably, high tissue expression of RANKL has recently been found in mechanosensitive (stiff) breast tissue and is associated with increased breast density, a recognized breast cancer risk factor. Methods: The BRCA-P trial is a randomized, double-blinded, placebo-controlled multi-centre international phase 3 trial evaluating the RANKL inhibitor denosumab as a possible breast cancer risk-reducing agent (EudraCT 2017-002505-35; NCT04711109). The safety profile of denosumab is generally well understood, as it is currently approved for the treatment of osteoporosis, bone metastases and giant cell tumor of bone. The study is led by the ABCSG (Austria), in collaboration with individual country sponsors in seven participating countries. Eligible participants include women age 25-55 years who carry a BRCA1 pathogenic variant, are unaffected by breast or ovarian cancer, and are not pregnant or currently trying to become pregnant. Participants must also have not undergone prophylactic bilateral mastectomy or be currently taking a chemopreventive agent such as tamoxifen. They are randomised 1:1 to receive either denosumab 120 mg or placebo subcutaneously every 6 months for 5 years. The study primary objective is to evaluate the reduction in the risk of any breast cancer (invasive or DCIS). The safety profile and tolerability of denosumab in this setting will be also studied. Secondary and exploratory objectives include reduction in risk of ovarian, fallopian tube and other cancers, reduction in mammographic breast density, reduction in clinical fractures, effects on bone health and bone turnover markers and quality of life. BRCA-P completed its recruitment phase in December 2024, with 364 participants randomised globally. This investigator-initiated study is supported by Amgen. Clinical trial information: NCT04711109 .