Denosumab to Prevent Breast Cancer in Women With BRCA1 Mutation

(BRCA-P Trial)

Recruiting at 48 trial locations

Overseen By Judy E. Garber, MD, MPH

Age: 18 - 65

Sex: Female

Trial Phase: Phase 3

Sponsor: Alliance for Clinical Trials in Oncology

Must not be taking: Tamoxifen, Raloxifene, Aromatase inhibitors

Disqualifiers: Bilateral mastectomy, Ovarian cancer, Breast cancer, Invasive cancer, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 15

Duration: 5 years

300 Participants Needed

Trial Summary

Do I have to stop taking my current medications for this trial?

The trial does not specify if you must stop all current medications, but you cannot use tamoxifen, raloxifene, aromatase inhibitors, bisphosphonates, or anti-angiogenic agents. If you've used tamoxifen, raloxifene, or aromatase inhibitors in the last 3 months or for more than 3 years total, you cannot participate. Current or prior use of aspirin or NSAIDs is allowed.

Will I have to stop taking my current medications?

The trial requires that you stop using tamoxifen, raloxifene, or aromatase inhibitors if you've used them in the last 3 months or for more than 3 years in total. You also cannot be on bisphosphonates or anti-angiogenic agents. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

What data supports the idea that Denosumab to Prevent Breast Cancer in Women With BRCA1 Mutation is an effective drug?

The available research shows that Denosumab is effective in delaying bone-related issues in breast cancer patients. In a large study, Denosumab was compared to another drug, zoledronic acid, and was found to delay bone problems by over 8 months in patients with cancer that had spread to the bones. This suggests that Denosumab might be a better option for preventing bone complications in these patients. ^{1 2 3 4 5}

What data supports the effectiveness of the drug denosumab in preventing breast cancer in women with BRCA1 mutation?

Denosumab has been shown to significantly delay bone-related complications in breast cancer patients with bone metastases and increase bone density in early breast cancer patients. Preclinical data also suggest it may affect tumor growth and development. ^{1 2 3 4 5}

What safety data is available for Denosumab?

Denosumab, marketed as Prolia and Xgeva, has been studied for safety in various contexts. In the FREEDOM trial, it was associated with some adverse events like back pain, musculoskeletal pain, and hypercholesterolemia, but no increasing trends in adverse events were observed over six years. A systematic review and meta-analysis found an increased risk of cardiovascular adverse events compared to bisphosphonates, but not compared to placebo. Overall, Denosumab's safety profile includes common adverse reactions and some cardiovascular risks, particularly when compared to bisphosphonates. ^{1 5 6 7 8}

Is denosumab generally safe for humans?

Denosumab has been used in various conditions, including osteoporosis and cancer-related bone issues, and is generally considered safe, but some people have experienced side effects like back pain, high cholesterol, and bladder infections. There is also a potential increase in cardiovascular events compared to some other treatments, but not compared to a placebo. ^{1 5 6 7 8}

Is the drug Denosumab a promising treatment to prevent breast cancer in women with BRCA1 mutation?

Denosumab is a promising drug because it has been shown to delay bone problems in breast cancer patients and increase bone strength. It may also help slow down tumor growth and cancer development. ^{1 3 4 5 9}

How is the drug denosumab unique in preventing breast cancer in women with BRCA1 mutation?

Denosumab is unique because it is a fully human monoclonal antibody that targets RANKL, a protein involved in bone resorption, and it is administered as an injection under the skin. While it is primarily used to prevent bone-related issues in cancer patients, its potential effect on tumor growth and cancer prevention is being explored, making it a novel approach for women with BRCA1 mutations. ^{1 3 4 5 9}

What is the purpose of this trial?

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.

Research Team

Judy E. Garber, MD, MPH

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Women aged 25-55 with a BRCA1 gene mutation, no breast or ovarian cancer, and not planning preventive breast surgery can join. They must have normal recent breast exams, not be pregnant or breastfeeding, agree to use contraception, and have good physical health.

Inclusion Criteria

Written informed consent before any study-specific procedure is performed

I am fully active or restricted in physically strenuous activity but can do light work.

I have a harmful BRCA1 gene mutation.

Exclusion Criteria

I have low calcium levels or a history of low calcium that's relevant to my health.

Any major medical or psychiatric condition that may prevent the subject from completing the study

I am currently taking medication for bone health or to stop new blood vessels from forming.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive denosumab or placebo subcutaneously every 6 months for up to 5 years

5 years

10 visits (in-person, every 6 months)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

5 visits (in-person, annually)

Treatment Details

Interventions

• Denosumab
• Quality-of-Life Assessment

Trial Overview The trial is testing if Denosumab can prevent breast cancer in women with the BRCA1 mutation compared to a placebo. It's a phase III study where participants are randomly given either Denosumab or an inactive substance while their quality of life is monitored.

Participant Groups

Group I: Arm A (denosumab) Experimental Treatment 2 Interventions

Patients receive denosumab SC q6m for up to 5 years in the absence of disease progression or unacceptable toxicity.

Group II: Arm B (placebo) Placebo Group 2 Interventions

Patients receive placebo SC q6m for up to 5 years in the absence of disease progression.

Denosumab is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Prolia for:

• Osteoporosis in postmenopausal women
• Bone loss associated with hormone ablation therapy for prostate cancer
• Bone loss associated with hormone ablation therapy for breast cancer

Approved in United States as Prolia for:

• Treatment of postmenopausal women with osteoporosis at high risk for fracture
• Treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer
• Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer

Approved in Canada as Prolia for:

• Treatment of osteoporosis in postmenopausal women at high risk for fracture
• Treatment to increase bone mass in men with osteoporosis at high risk for fracture

Approved in Japan as Prolia for:

• Treatment of osteoporosis in postmenopausal women
• Treatment of bone loss associated with hormone ablation therapy for prostate cancer

Who Is Running the Clinical Trial?

Alliance for Clinical Trials in Oncology

Lead Sponsor

Trials

521

Recruited

224,000+

Austrian Breast & Colorectal Cancer Study Group (ABCSG)

Collaborator

Trials

1

Recruited

300+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Denosumab, a monoclonal antibody that inhibits RANKL, shows consistent pharmacokinetics across a large population of 1,076 subjects, including both healthy individuals and cancer patients, indicating its effectiveness in preventing osteoclast activation and survival.

The study found that after administering denosumab, over 95% of patients achieved more than 97% RANKL occupancy, suggesting that dosage adjustments based on body weight, age, race, or tumor type are unnecessary for patients with bone metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours. Gibiansky, L., Sutjandra, L., Doshi, S., et al.[2021]

In a systematic review of two large trials involving 7929 patients, adjuvant denosumab did not improve disease-free survival (DFS), bone-metastasis-free survival (BMFS), or overall survival (OS) in early breast cancer patients overall, but showed a DFS benefit in hormone receptor positive/HER2 negative patients.

Denosumab improved bone health outcomes by reducing fracture incidence and delaying time to first fracture without increasing overall toxicity, indicating it can be safely added to standard anticancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant denosumab in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials. Mastrantoni, L., Garufi, G., Di Monte, E., et al.[2023]

In a large phase III study, denosumab significantly delayed the time to the first skeletal-related event in patients with breast cancer bone metastases compared to zoledronic acid, highlighting its efficacy as a targeted bone therapy.

Denosumab also increased bone mineral density in patients receiving aromatase inhibitors, suggesting additional benefits in the adjuvant setting beyond just managing metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Denosumab in breast cancer treatment. Drooger, JC., van der Padt, A., Sleijfer, S., et al.[2015]

Denosumab (XGEVA®) is a monoclonal antibody that effectively inhibits bone resorption by preventing the activation of osteoclasts, making it a targeted treatment for patients with bone metastases.

In Phase 3 clinical studies, denosumab was found to be superior to zoledronic acid in delaying skeletal-related events (SREs) by a median of 8.2 months, suggesting it may be a more effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative pharmacology of denosumab in patients with bone metastases from solid tumors. Perez Ruixo, JJ., Doshi, S., Sohn, W., et al.[2015]

Denosumab, a monoclonal antibody used to treat skeletal-related events in advanced cancer patients, shows dose-dependent pharmacokinetics, meaning its absorption and effects vary with the dose given, particularly at doses below 60 mg.

In patients with solid tumors and bone metastases, denosumab effectively reduces bone turnover markers quickly, and its pharmacokinetics and pharmacodynamics remain consistent across different tumor types and cancer treatments, indicating its broad applicability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacokinetics and pharmacodynamics of denosumab in patients with advanced solid tumours and bone metastases: a systematic review. Sohn, W., Simiens, MA., Jaeger, K., et al.[2022]

LY01011, a biosimilar to denosumab, showed pharmacokinetic (PK) and pharmacodynamic (PD) similarity to denosumab in a study involving 168 healthy Chinese subjects, indicating it may be an effective alternative for preventing skeletal-related events in patients with bone metastases.

The safety profiles of LY01011 and denosumab were comparable, with only a small number of treatment-emergent adverse events reported, none of which were related to the study drug, suggesting that LY01011 is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized trial comparing LY01011, biosimilar candidate, with the reference product denosumab (Xgeva®) in healthy Chinese subjects. Ding, Y., Liu, Y., Dou, C., et al.[2023]

Denosumab, a monoclonal antibody that targets RANKL, significantly reduces the risk of fractures in postmenopausal women with osteoporosis, showing a 68% reduction in new vertebral fractures and a 40% reduction in hip fractures over a 3-year trial.

Long-term treatment with denosumab did not show increasing trends in adverse events, indicating that its safety profile remains stable over 6 years, even when comparing data from initial placebo recipients who later received the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension. Watts, NB., Brown, JP., Papapoulos, S., et al.[2018]

In a systematic review of 49 randomized controlled trials involving 13,202 postmenopausal women, denosumab was associated with a 46% increase in cardiovascular adverse events (CAEs) compared to bisphosphonates, indicating potential cardiovascular safety concerns with denosumab.

However, when compared to placebo, denosumab did not show a significant difference in total CAEs, suggesting that the increased risk may be specific to comparisons with bisphosphonates rather than a general risk associated with the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular Safety of Denosumab Across Multiple Indications: A Systematic Review and Meta-Analysis of Randomized Trials. Seeto, AH., Abrahamsen, B., Ebeling, PR., et al.[2021]

Denosumab, a drug used to prevent bone loss, was linked to a non-healing area in the lower jaw after a tooth extraction, highlighting a potential complication associated with its use.

After stopping denosumab, the non-healing area healed successfully, suggesting that discontinuation of the drug may be necessary to allow for healing in similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Denosumab: a case of MRONJ with resolution. Lyttle, CV., Patterson, H.[2018]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Adjuvant denosumab in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Denosumab in breast cancer treatment. [2015]

4. England pubmed.ncbi.nlm.nih.gov

Quantitative pharmacology of denosumab in patients with bone metastases from solid tumors. [2015]

5. England pubmed.ncbi.nlm.nih.gov

The pharmacokinetics and pharmacodynamics of denosumab in patients with advanced solid tumours and bone metastases: a systematic review. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

A randomized trial comparing LY01011, biosimilar candidate, with the reference product denosumab (Xgeva®) in healthy Chinese subjects. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Cardiovascular Safety of Denosumab Across Multiple Indications: A Systematic Review and Meta-Analysis of Randomized Trials. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Denosumab: a case of MRONJ with resolution. [2018]