Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Adenocarcinoma

Breast Neoplasms

Breast Diseases

Skin Diseases

All Drugs and Chemicals

Antineoplastic Agents

Bone Density Conservation Agents

Estrogens

Anastrozole

Zoledronic Acid

Denosumab

Aromatase Inhibitors

Progesterone

Enzyme Inhibitors

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Eligible participants who completed the open-label phase could be enrolled into the zoledronic acid substudy and randomized to receive a single 5 mg intravenous dose of zoledronic acid 8 months after the last open-label dose of denosumab.

Eligible participants who completed the open-label phase could be enrolled into the zoledronic acid substudy and randomized to receive standard of care 8 months after the last open-label dose of denosumab.

Placebo

An approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting

Non-steroidal aromatase inhibitor therapy

5 mg zoledronic acid administered at a constant infusion rate

Standard of care (SoC) as recommended by the treating physician, depending on individual factors such as bone density, lifestyle recommendations by the Investigator such as diet, physical activities and sun exposure, as well as local treatment standards.

Standard of Care

The purpose of this study is to determine whether denosumab compared to placebo, will reduce the rate of first clinical fracture in women with non-metastatic breast cancer receiving (non-steroidal) aromatase inhibitor therapy.

Participants will remain on treatment until the required number of events (where an event is defined as first clinical fracture) is reached and all participants have had the opportunity to receive a minimum of at least 2 doses of study drug, whichever occurs later. The primary analysis data cut-off date (PADCD) is defined as the time at which the required number of events is reached and all participants have had the opportunity to receive at least 2 doses of study drug. When the PADCD is reached, all participants will discontinue study drug.

Following the study PADCD, participants will be followed every 12 months starting from their last study visit until a maximum of 66 months after PADCD.

After approval of Amendment 4, willing and eligible participants randomized to placebo during the double-blind phase may participate in an open-label phase (OLP) and receive denosumab 60 mg Q6M for up to 36 months (maximum of 7 doses).

After approval of Amendment 6 in 2019 a zoledronic acid (ZA) substudy was added to the protocol. Willing and eligible participants who participated in the OLP of the study and completed open-label denosumab may opt in to this ZA substudy and either receive a single dose of ZA (Therapy Arm), or be managed according to the current standard of care for this patient population (Control Arm).

Study to Determine Treatment Effects of Denosumab in Patients With Breast Cancer Receiving Aromatase Inhibitor Therapy

A Randomised, Double-Blind, Placebo-Controlled, Multi-Centre Phase 3 Study to Determine the Treatment Effect of Denosumab in Subjects With Non-Metastatic Breast Cancer Receiving Aromatase Inhibitor Therapy.

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request

The time to first on-study clinical fracture was defined as the number of days from randomization to the date of the x-ray confirming the clinical fracture. A clinical fracture is any clinically evident fracture with associated symptoms and confirmed by x-ray. Participants who died or withdrew without experiencing a clinical fracture were censored at the date of last contact or study termination whichever was earlier.

Bone mineral density was assessed by dual x-ray absorptiometry.

Assessment of vertebral fractures was performed by an expert radiologist at the central imaging center using a semiquantitative grading scale: Grade 1, 20% to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2, 25% to 40% reduction in height; Grade 3, greater than 40% reduction in height.

A new vertebral fracture was defined as a fracture in a previously undeformed vertebrae including new compression fractures, defined as those compression fractures having a decrease in total anterior or posterior height of at least 25% from baseline. New vertebral fractures includes morphometric vertebral fractures identified from on study x-rays and clinical vertebral fractures confirmed by x-rays.

Assessment of vertebral fractures was performed by an expert radiologist at the central imaging center using a semiquantitative grading scale: Grade 1, 20% to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2, 25% to 40% reduction in height; Grade 3, greater than 40% reduction in height.

A new vertebral fracture was defined as a fracture in a previously undeformed vertebrae including new compression fractures, defined as those compression fractures having a decrease in total anterior or posterior height of at least 25% from baseline. New vertebral fractures includes morphometric vertebral fractures identified from on study x-rays and clinical vertebral fractures confirmed by x-rays. Worsening of pre-existing fractures was defined as an increase in fracture severity of at least 1 grade on the semiquantitative scale.

DFS was defined as the time interval from the randomization date to the date of first evidence of local or distant metastases, contra-lateral breast cancer, secondary carcinoma, or death from any cause (whichever occurred first). Participants last known to be alive, who did not experience recurrence of disease, were censored at their last contact date or at the data cut-off date whichever came first.

BMFS was defined as the time interval from randomization to first occurrence of bone metastasis or death from any cause, whichever comes first. Participants last known to be alive, who did not experience bone metastasis, were censored at their last assessment (i.e., bone scan) date or at the last contact date, whichever comes first.

OS was defined as the time from randomization to death from any cause.

Austrian Breast and Colorectal Cancer Study Group

Amgen

All randomized participants who received \>1 dose of treatment; participants were analyzed according to the actual treatment received in double-blind phase. 9 participants randomized to the placebo in the DB phase incorrectly received denosumab. Per protocol, only AEs of special interest and SAEs were collected in the open-label phase. MedDRA 17.1 used in double-blind phase and 24.0 in the open-label phase.

Participants received the matching placebo SC Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Double-blind Phase: Placebo

Participants received 60 mg denosumab SC Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Double-blind Phase: Denosumab

Participants who received the matching placebo during the double-blind phase, who continued into the open-label phase where they received denosumab 60 mg SC Q6M for up to a maximum of 7 additional doses.

Open-label Phase: Placebo/Denosumab

Participants who received denosumab during the double-blind phase, who continued into the open-label phase where they received denosumab 60 mg SC Q6M for up to a maximum of 7 additional doses.

Open-label Phase: Denosumab/Denosumab

Participants randomized to receive the matching placebo subcutaneously (SC) once every 6 months (Q6M) in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

Major Academic Center

Other Center

Stratification Factor: Type of Hospital

Stratification Factor: Prior Aromatase inhibitor Use

T-scores are standardized scores that reflect the standard deviations (SDs) above/below the normal mean for young adults.

T-score ≥ -1.0: BMD is considered normal.

T-score \< -1.0: Low BMD.

Stratification Factor: Total Lumbar Spine BMD T-score

Study Director

The efficacy clinical hypothesis is that denosumab, when administered subcutaneously at a dose of 60 mg every 6 months, will be considered efficacious in patients with non-metastatic breast cancer receiving AIT if the rate of first clinical fracture in denosumab-treated patients is lower than that in placebo-treated patients. It is anticipated that denosumab will reduce the rate by 30% compared with placebo (ie, the true hazard ratio of denosumab compared with placebo is 0.70).

Full Analysis Set: all randomized participants

Time to First Clinical Fracture

BMD Analysis Set: all participants with evaluable lumbar spine BMD values at Baseline and Month 36

Percent Change From Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36 at Pre-selected Sites

BMD Analysis Set: all participants with total hip BMD evaluable values at Baseline and Month 36

Percent Change From Baseline in Total Hip BMD at Month 36 at Pre-selected Sites

BMD Analysis Set: all participants with evaluable femoral neck BMD values at Baseline and Month 36

Percent Change From Baseline in Femoral Neck BMD at Month 36 at Pre-selected Sites

Vertebral Fracture Analysis Set: all participants with a Baseline and at least one post-baseline vertebral x-ray prior to or at Month 36

Spots Global Cancer Trial Database for postmenopausal woman