Background: Denosumab is a monoclonal antibody that inhibits RANKL and is approved for the prevention of fractures in patients with osteoporosis or bone metastases. The RANKL signaling pathway is also involved in BRCA1-associated mammary tumorigenesis via a progesterone-induced paracrine effect of RANKL on luminal progenitor cells. Pre-clinical studies have demonstrated that RANKL inhibition resulted in reduced proliferation of mammary tumors. Early findings from an ongoing pre-surgical study demonstrated that denosumab treatment resulted in decreased Ki67 proliferation index in benign breast tissue. Based on these data, denosumab is being pursued as a potential preventive agent for breast cancer in BRCA1 mutation carriers. While promising, the effect of RANKL inhibition on gynecologic tissues such as the ovaries and fallopian tubes, in which progesterone has a protective effect, is unknown.

Trial design: We will conduct a multicenter, open-label randomized pilot study of presurgical administration of denosumab versus no treatment in premenopausal women with BRCA1/2 mutations undergoing risk-reducing salpingo-oophorectomy (RRSO). A total of 60 women will be randomized 1:1 to Arm 1) 3-4 doses of 120 mg denosumab subcutaneously every 4 weeks or Arm 2) No treatment. Participants will be stratified by 1) BRCA1 versus BRCA2 mutation status and 2) Use of hormonal contraceptives within the past 3 months (yes/no). Assuming a 10% unevaluable rate, we expect to have 54 evaluable participants (27 per arm).

Eligibility criteria: 1) Premenopausal women (defined as < 3 months since last menstrual period OR serum follicle-stimulating hormone (FSH) < 20 mIU/mL), age > 18 years; 2) Documented germline pathogenic mutation or likely pathogenic variant in the BRCA1 or BRCA2 gene; 3) Plan for RRSO with or without hysterectomy; 4) ECOG performance status ≤ 1 (Karnofsky ≥ 70%); 5) Normal organ and marrow function; 6) Negative pregnancy test and use of adequate contraception; 7) Willingness to take supplemental oral calcium and vitamin D3; 8) Dental examination within 6 months of enrollment and no evidence of active dental issues; 9) Ability to understand and willingness to provide informed consent.

Specific aims: Our primary objective is to compare the effect of denosumab to no treatment on Ki67 expression in the fimbrial end of the fallopian tube. Secondary objectives are to assess Ki67 in ovary and endometrium; cleaved caspase-3, RANK/RANKL, ER/PR, CD44, and STAT3/pSTAT3 expression in fallopian tube, ovary, and endometrium; gene expression profiling in the fallopian tube and ovary; serum markers (progesterone, estradiol, C-terminal telopeptide) and denosumab levels; and toxicity.

Statistical methods: The primary endpoint is post-treatment Ki67 expression in the fimbrial end of the fallopian tube in the denosumab arm compared to the no treatment arm. Assuming a standard deviation of 5.0%, we will have 82% power to detect a 4.0% absolute difference (or effect size of 0.8) in Ki67 proliferation index between the denosumab and no treatment groups by applying a 2-sample t-test at a 0.05 significance level.

Target accrual: 60 participants, to be activated in Summer 2018.

Citation Format: Trivedi MS, Samimi G, Wright JD, Holcomb K, Garber JE, Horowitz NS, Arber N, Friedman E, Wenham RM, House M, Parnes H, Lee JJ, Abutaseh S, Vornik LA, Heckman-Stoddard BM, Brown PH, Crew KD. Pilot study of denosumab in BRCA1/2 mutation carriers scheduling for risk-reducing salpingo-oophorectomy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-09-01.