This phase III trial compares denosumab to placebo for the prevention of breast cancer in women with a BRCA1 germline mutation. A germline mutation is an inherited gene change which, in the BRCA1 gene, is associated with an increased risk of breast and other cancers. Denosumab is a monoclonal antibody that is used to treat bone loss in order to reduce the risk of bone fractures in healthy people, and to reduce new bone growths in cancer patients whose cancer has spread to their bones. Research has shown that denosumab may also reduce the risk of developing breast cancer in women carrying a BRCA1 germline mutation.
PRIMARY OBJECTIVE: I. To evaluate the reduction in the risk of any breast cancer (invasive or ductal carcinoma in situ \[DCIS\]) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo. SECONDARY OBJECTIVES: I. To determine the reduction in the risk of invasive breast cancer in women with germline BRCA1 mutation who are treated with denosumab compared to placebo. II. To determine the reduction in the risk of invasive triple negative breast cancer (TNBC) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo. III. To determine the reduction in risk of ovarian, fallopian and peritoneal cancers (in women who have not undergone prophylactic bilateral salpingo-oophorectomy \[PBSO\]) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo. IV. To determine the reduction in risk of other (i.e. non-breast and nonovarian) malignancies, including those known to be associated with BRCA1 germline mutations in women with germline BRCA1 mutation who are treated with denosumab compared to placebo. V. To determine the reduction in the risk of clinical fractures in pre- and postmenopausal women with germline BRCA1 mutation who are treated with denosumab compared to placebo. VI. To compare rates of breast biopsies and rate of benign breast lesions in women with germline BRCA1 mutation who are treated with denosumab compared to placebo. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive denosumab subcutaneously (SC) every 6 months (q6m) for up to 5 years in the absence of the development of breast cancer or unacceptable toxicity. ARM B: Patients receive placebo SC q6m for up to 5 years in the absence of the development of breast cancer. After completion of study treatment, patients are followed up every 12 months for 5 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
DOUBLE
Enrollment
300
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
UCSF Medical Center-Mount Zion
San Francisco, California, United States
Rocky Mountain Cancer Centers-Aurora
Aurora, Colorado, United States
UCHealth University of Colorado Hospital
Aurora, Colorado, United States
Rocky Mountain Cancer Centers-Boulder
Boulder, Colorado, United States
Time to the occurrence of any breast cancer (invasive or ductal carcinoma in situ [DCIS])
Time to breast cancer (invasive or DCIS) will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.
Time frame: From randomization to the occurrence of breast cancer (invasive or DCIS), assessed up to 5 years
Time to invasive breast cancer
Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.
Time frame: Up to 5 years post treatment
Time to invasive triple negative breast cancer
Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.
Time frame: Up to 5 years post treatment
Time to ovarian, fallopian and peritoneal cancer (in women who have not undergone prophylactic bilateral salpingo-oophorectomy)
Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model. Time to ovarian cancer will be analyzed in the overall group and in different strata (oral contraceptive use, hormone replacement therapy use, and menopausal status).
Time frame: Up to 5 years post treatment
Time to other (nonbreast or ovarian cancer) malignancies, including those known to be associated with BRCA1 mutations
Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.
Time frame: Up to 5 years post treatment
Time to clinical fractures in pre- and postmenopausal women
Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.
Time frame: Up to 5 years post treatment
Frequency of breast biopsies
May be recommended as part of care based on a finding on mammogram, MRI, ultrasound or physical exam performed as part of monitoring for breast cancer. Will be compared between the two treatment arms via chi-square analysis.
Time frame: Up to 5 years post treatment
Frequency of benign breast lesions
May be recommended as part of care based on a finding on mammogram, MRI, ultrasound or physical exam performed as part of monitoring for breast cancer. Will be compared between the two treatment arms via chi-square analysis.
Time frame: Up to 5 years post treatment
Assess incidence, nature and severity of adverse events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment will be reported per treatment arm.
Time frame: Up to 5 years post treatment
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