Evaluation of Denosumab for Breast Cancer Prevention in Women with BRCA1 Germline Mutation: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

Trial ID: 2024-513734-38-00
Protocol: BRCA-P/ABCSG 50
Sponsor: Alliance Foundation Trials LLC

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Diseases & Conditions

Breast cancer Prophylaxis BRCA1 gene mutation

Objectives

The primary objective of this study is to evaluate the reduction in the risk of any **breast cancer** (invasive or ductal carcinoma in situ, DCIS) in women with a germline **BRCA1 mutation** who are treated with **denosumab** compared to placebo. This is clinically relevant as women with BRCA1 mutations have a significantly increased risk of developing breast cancer, and effective preventive strategies are crucial for this high-risk population.

Secondary objectives include:

To determine the reduction in risk of invasive breast cancer.
To determine the reduction in risk of invasive triple-negative breast cancer (TNBC).
To determine the reduction in risk of ovarian, fallopian tube cancers (in women who have not undergone prophylactic bilateral salpingo-oophorectomy) and primary peritoneal cancers in women with germline BRCA1 mutation treated with denosumab compared to placebo.
To determine the reduction in the risk of other malignancies, including those associated with BRCA1 germline mutations, in women treated with denosumab compared to placebo.
To compare rates of breast biopsies and rate of benign breast lesions in women with germline BRCA1 mutation treated with denosumab compared to placebo.
To determine the reduction in the risk of clinical fractures in pre- and postmenopausal women with germline BRCA1 mutation treated with denosumab compared to placebo.

Participants

The clinical trial involves a total of **1768 participants**, specifically targeting women with a confirmed deleterious or likely deleterious **BRCA1 germline mutation**. The study population is comprised exclusively of female subjects, aged between 25 and 55 years, who exhibit no evidence of breast cancer as confirmed by MRI or mammography, and no clinical evidence of ovarian cancer at the time of randomization. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on these criteria, ensuring that all participants are women with a high risk of developing breast cancer due to their genetic mutation. Lifestyle considerations such as diet and physical activity are not specified, but participants must not have any preventive breast surgery planned at the time of randomization. The study does not include male subjects and is focused on a vulnerable population due to the genetic predisposition to breast cancer.

Plans and Procedures

The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to evaluate the preventive effect of **denosumab** on breast cancer in women carrying a **BRCA1 germline mutation**. The trial is a Phase III study, with an estimated duration from May 2019 to July 2030. Participants will be randomly assigned to receive either denosumab or a placebo, with the primary objective being to assess the reduction in the risk of any breast cancer, including invasive or ductal carcinoma in situ (DCIS), in the target population.

Study visits are structured to ensure comprehensive monitoring and data collection. The initial visit, known as the inclusion or screening visit, will confirm eligibility based on criteria such as age, genetic mutation status, and absence of breast cancer evidence. Following randomization, participants will undergo regular follow-up visits to monitor health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will conclude the participant's involvement, with a final assessment of health outcomes and data collection.

The expected length of participant involvement is up to 60 months, with conditions for early termination including the development of breast cancer, withdrawal of consent, or any significant adverse events that compromise participant safety. The primary endpoint is the time to the occurrence of any breast cancer, while secondary endpoints include time to invasive breast cancer, time to invasive triple-negative breast cancer, and time to other malignancies associated with BRCA1 mutations. The study also monitors the frequency of breast biopsies and benign breast lesions.

Treatment

The clinical trial involves the administration of **Denosumab**, marketed under the name XGEVA, which is a **solution for injection**. The active substance, Denosumab, is a protein of biological/biotechnological origin. The pharmaceutical form is a solution intended for **subcutaneous use**. The dosage is set at 120 mg per administration, with a maximum daily dose of 120 mg and a total maximum dose of 1200 mg over the treatment period. The treatment is administered once every four weeks, over a maximum treatment period of 60 weeks. The product is manufactured by Amgen Europe B.V. and is authorized under the marketing authorization number EU/1/11/703/001. The product has been repackaged and relabelled for the purposes of the trial.

The study also includes a **placebo** group, which receives an identical formulation to the test product, but without the active substance, Denosumab. The placebo is administered in the same pharmaceutical form, dosage, and route as the experimental treatment to ensure blinding and maintain the integrity of the study design. The placebo is used to evaluate the preventive effect of Denosumab on breast cancer in women carrying a BRCA1 germline mutation, as compared to no active treatment.

Efficacy

Efficacy in this clinical trial will be assessed by evaluating the primary endpoint, which is the time to the occurrence of any breast cancer, including invasive or ductal carcinoma in situ (DCIS), in women with a germline **BRCA1** mutation treated with denosumab compared to placebo. Secondary endpoints include the time to invasive breast cancer, time to invasive triple-negative breast cancer, time to ovarian, fallopian tube, or primary peritoneal cancer in women who have not undergone prophylactic bilateral salpingo-oophorectomy (PBSO), time to other malignancies associated with **BRCA1** mutations, time to clinical fractures in pre- and postmenopausal women, and the frequency of breast biopsies and benign breast lesions.

The measurement and collection of these efficacy parameters will be conducted at specified intervals throughout the trial duration, with the primary focus on the time to event analysis. The trial is designed as a randomized, double-blind, placebo-controlled, multi-center, international Phase 3 study. The data collected will be analyzed to determine the preventive effect of denosumab on breast cancer in the specified population. The trial is expected to conclude by July 2030, with recruitment having started in May 2019.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Women with a confirmed deleterious or likely deleterious BRCA 1 germline mutation (Variant class 4 or 5)
Age ≥ 25 years and ≤ 55 years at randomization
No evidence of breast cancer by MRI or MG and clinical breast examination within the last 6 months prior to randomization
No clinical evidence of ovarian cancer at randomization
Negative pregnancy test at randomization for women of childbearing potential
No preventive breast surgery planned at time of randomization
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Written informed consent before any study-specific procedure is performed

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Exclusion Criteria

Prior bilateral mastectomy
History of ovarian cancer (including fallopian tube and primary peritoneal cancer)
History of breast cancer
History of invasive cancer except for basal cell or squamous cell skin cancer. History of the following are also allowed: carcinoma in situ of the cervix, stage 1 papillary or follicular thyroid cancer, atypical hyperplasia or LCIS (Lobular Carcinoma In Situ)
Pregnant or lactating women (within the last 2 months prior to randomization)
Unwillingness to use highly effective contraception method during and within at least 5 months after cessation of denosumab/placebo therapy in women of childbearing potential
Clinically relevant hypocalcaemia (history and current condition), or serum calcium <2.0 mmol/L (<8.0 mg/dL) or corrected calcium (<2.1 mmol/L) Hypocalcemia defined by calcium below the normal range (a single value below the normal range does not necessarily constitute hypocalcemia, but should be 'corrected' before dosing the participant). Monitoring of calcium level in regular intervals (usually prior to IP administration) is highly recommended
Tamoxifen, raloxifene or aromatase inhibitor use during the last 3 months prior to randomization or for a duration of more than 3 years in total (current and prior HRT is permitted)
Any prior use of denosumab
Participant has a known prior history or current evidence of osteonecrosis or osteomyelitis of the jaw, or an active dental/jaw condition which requires oral surgery including tooth extraction ≤ 3 months prior enrollment
Concurrent treatment with a bisphosphonate or an anti-angiogenic agent
Concurrent therapy with other Investigational Products
Any major medical or psychiatric condition that may prevent the participant from completing the study
Known active infection with Hepatitis B virus or Hepatitis C virus
Known infection with human immunodeficiency virus (HIV)
Hypersensitivity to the active substance or to any of the excipients
Known rare hereditary problems of fructose intolerance