A phase 3 study to determine the breast cancer risk reducing effect of denosumab in women carrying a germline BRCA1 mutation (BRCA-P Study).
Authors: Bhulani Nizar , Wood Marie , Tsai Joy , Bedrosian Isabelle , Hopkins Judith O. , Brunet Joan , Michaelson-Cohen Rachel , Schmutzler Rita K. , Evans Gareth D , Gnant Michael , Fesl Christian , Mystek Aleksandra , Lindeman Geoffrey J , Singer Christian F. , Garber Judy Ellen 
Published: June 2022

TPS10616 Background: Women with BRCA1 mutations have a 50-70% lifetime risk of developing breast cancer. Currently, prophylactic mastectomy is the only strategy that significantly reduces breast cancer risk. Recent evidence suggests that the RANK/RANKL signaling pathway plays a pivotal role in the development of BRCA1-mutated tumors. Targeting the RANK pathway has been shown to attenuate breast epithelial proliferation in vitro and in vivo, and to profoundly reduce mammary tumor formation in mouse models. The RANKL inhibitor, denosumab, an FDA approved drug for the treatment of osteoporosis, is potentially an ideal chemopreventive agent for women with a germline BRCA1 mutation because it: (a) could potentially reduce breast cancer risk, and (b) concomitantly protect bone health in women who have already undergone bilateral salpingo-oophorectomy or in naturally postmenopausal women. The BRCA-P study will evaluate the reduction in the risk of any breast cancer (invasive or DCIS) in women with a germline BRCA1 mutation who are treated with denosumab compared to placebo. Sub-studies include measurement of bone turnover markers; epigenetic profiling of tumor tissues; measuring denosumab’s effect on bone and breast density; measurement of serum RANK, RANKL, OPG, progesterone, LH and FSH; and measurement of quality of life. Methods: This is a randomized, double-blind, placebo-controlled, multi-center international phase 3 study to determine the breast cancer risk reducing effect of denosumab in women carrying a germline BRCA1 mutation. Eligibility: Women with a confirmed BRCA1 germline mutation; ages ≥ 25 years and ≤ 55 years; no evidence of breast or ovarian cancer; no preventive breast surgery planned at randomization; ECOG performance status 0-1. Eligible participants will be randomized 1:1 to receive 120 mg of subcutaneous denosumab or placebo every 6 months for 5 years. Thereafter, all participants will be followed up for 5 years. Primary endpoints: Time to the occurrence of any breast cancer (invasive or DCIS). Secondary endpoints: Time to invasive triple negative breast cancer; time to other BRCA1 mutation associated malignancies, time to clinical fractures. Statistically, a 35% reduction in breast cancer risk would be detected with an 80% power and a two-sided significance level of 5% if 167 breast cancer cases are observed. We expect to observe the number of events needed if 1459 subjects per group (2918 in total) are randomized. The study is currently enrolling participants in Austria, Australia, Israel and Spain. The study will shortly begin accrual in Germany, United Kingdom, and at more than 30 sites across the United States. Globally, the trial is coordinated by the Austrian Breast & Colorectal Cancer Study Group and by the Alliance for Clinical Trial in Oncology in the US. EudraCT: 2017-02505-35. Clinical trial information: NCT04711109.