Pilot Study of Denosumab in BRCA1/2 Mutation Carriers Scheduled for Risk-Reducing Salpingo-Oophorectomy

Inclusion Criteria

• Participants must be premenopausal (defined as < 3 months since last menstrual period OR serum follicle-stimulating hormone [FSH] < 20 mIU/mL)
• Documented germline pathogenic or likely pathogenic variant in the BRCA1 or BRCA2 genes
• Participants must be scheduled for or in the process of scheduling a risk-reducing salpingo-oophorectomy with or without hysterectomy – either bilateral or unilateral (if prior unilateral oophorectomy or salpingectomy for benign condition)
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
• Leukocytes >= 3,000/microliter
• Absolute neutrophil count >= 1,500/microliter
• Platelets >= 100,000/microliter
• Total bilirubin =< 2 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])) =< 1.5 x institutional ULN
• Creatinine clearance >= 30 mL/min
• Serum calcium or albumin adjusted >= 8.0 mg/dL and =< 11.5 mg/dL
• Participant must have a negative urine or serum pregnancy test 14 days prior to randomization or drug administration; the effects of denosumab on the developing human fetus at the recommended therapeutic dose may cause fetal harm when administered to pregnant women; women of childbearing potential must agree to use adequate contraception from time of drug administration to time of surgery; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
• Women currently on hormonal contraception (i.e., oral contraceptives, Mirena intrauterine device [IUD]) are eligible to participate if they have been on a stable dose for at least 3 months; women who have undergone bilateral tubal ligation are also eligible to participate in this study; there will be stratification for hormonal contraceptive use within 3 months prior to registration
• Participants must be willing to take supplemental oral calcium 1000 mg (two 500 mg tablets) and vitamin D3 1000 IU daily for six months (which will be supplied by the research study) after receiving denosumab treatment or no treatment
• Ability to understand and the willingness to sign a written informed consent document in English or Spanish or Hebrew
• Participants must have a dental examination =< 6 months of study registration
• Willing to not undergo any other elective surgery procedure with general anesthesia or conscious sedation during the treatment period; the treatment period is completed after the last injection of denosumab is administered

Exclusion Criteria

• History of ovarian cancer; history of breast cancer or any other malignancy is permitted if last chemotherapy treatment was greater than 6 months prior to registration and participant is not using endocrine therapy
• Previous treatment with denosumab (including Prolia for osteoporosis or Xgeva for bone metastases) or use of bisphosphonate within 3 months of registration to the study
• Participants receiving any other investigational agents
• History of allergic reactions or hypersensitivity attributed to denosumab or any components of denosumab or compounds of similar chemical or biologic composition to denosumab, such as other RANKL inhibitors
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant and breastfeeding women are excluded from this study because denosumab is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with denosumab, breastfeeding should be discontinued if the mother is treated with denosumab; there is no minimum amount of time since pregnancy/breastfeeding required before enrolling into the study; however, the date of delivery, pregnancy termination, or weaning from breastfeeding will be documented on case report forms; female subjects of child bearing potential and not willing to use, in combination with her partner, highly effective contraception during treatment will be excluded
• Use of endocrine therapy (selective estrogen receptor modulator, aromatase inhibitor, gonadotrophin releasing hormone [GnRH] agonist) within 6 months of registration to the study
• Prior history or current evidence of osteonecrosis or osteomyelitis of the jaw, evidence of untreated local gum or oral infection, or non-healed dental or oral surgery
• Active dental or jaw conditions which require oral surgery/dental procedures, including tooth extraction within 6 months of registration to the study; dental fillings are permitted within 6 months of study registration
• Other risk factors for the development of osteonecrosis of the jaw (ONJ) including poor oral hygiene, use of a dental appliance, immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, or gingival infections
• Known sensitivity to any of the products to be administered during the study (e.g., calcium or vitamin D)
• Known serious infections, including a history of active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV); screening for these infections is not required for study enrollment
• Hypocalcemia (serum calcium or albumin adjusted calcium < 8.0 mg/dL) or renal dysfunction (creatinine clearance < 30 mL/min)
• Women with known osteoporosis or history of osteoporotic (fragility) fracture of the spine