Breast Cancer
Conditions
Keywords
confirmed adenocarcinoma, non-metastatic breast cancer, estrogen receptor positive, progesterone receptor positive, non-steroidal aromatase, aromatase inhibitor therapy, postmenopausal woman, adjuvant chemotherapy, neoadjuvant chemotherapy
Brief summary
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.
Detailed description
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).
Interventions
DRUGPlacebo
BIOLOGICALDenosumab
Administered as a subcutaneous injection
DRUGNon-steroidal aromatase inhibitor therapy
An approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting
DRUGZoledronic Acid
5 mg zoledronic acid administered at a constant infusion rate
OTHERStandard of Care
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.
Sponsors
Austrian Breast and Colorectal Cancer Study Group
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
for Double Blinded Phase: * Histologically or cytologically confirmed adenocarcinoma of the breast; * Female subjects with non-metastatic disease who are estrogen receptor (ER) and/or progesterone receptor (PR) positive, and who have completed their treatment pathway; * Subjects who are currently on, or will initiate an approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting; * Postmenopausal woman, defined as a woman fulfilling any one of the following criteria: * Having undergone a bilateral oophorectomy; * Age ≥ 60 years; * Aged \< 60 years meeting the following requirements: * Follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range; * A negative pregnancy test within 7 days prior to randomization. Subjects who have undergone a hysterectomy do not require a pregnancy test. * More criteria may apply.
Exclusion criteria
for Double Blinded Phase: * Aromatase inhibitor therapy for more than 24 months; * Prior or concurrent treatment with Selective Estrogen Receptor Modulators (eg, tamoxifen); * Evidence of metastatic disease; * Current or prior intravenous (IV) bisphosphonate administration; * Oral bisphosphonate treatment greater than or equal to 3 years continuously OR greater than 3 months but less than 3 years unless there was a washout period of at least 1 year prior to randomization OR any use during the 3-month period prior to randomization; * Prior administration of denosumab; * Known liver or renal deficiency; * Recurrence of the primary malignancy (e.g., during the allowed interval of pretreatment with aromatase inhibitor); * Diagnosis of any second non-breast malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or for in situ carcinoma of the cervix uteri; * Any kind of disorder that compromises the ability to give written informed consent and/or comply with study procedures. Inclusion Criteria to Receive Open-label Phase Denosumab: * Obtain signed and dated written informed consent prior to performing any study-specific procedure; * Subjects currently taking an approved non-steroidal AIT (eg, anastrazole) or who have completed or discontinued AIT within 12 months prior to participation in the OLP; * Randomized to placebo arm during the double-blind phase (as determined by unblinding procedures);
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Clinical Fracture | From randomization until the primary analysis cut-off date of 26 March 2014; maximum time on main study at the cut-off was 87 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Total Hip BMD at Month 36 at Pre-selected Sites | Baseline and Month 36 | Bone mineral density was assessed by dual x-ray absorptiometry. |
| Percent Change From Baseline in Femoral Neck BMD at Month 36 at Pre-selected Sites | Baseline and Month 36 | Bone mineral density was assessed by dual x-ray absorptiometry. |
| Number of Participants With New Vertebral Fractures | 36 months | 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. |
| Percent Change From Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36 at Pre-selected Sites | Baseline and Month 36 | Bone mineral density was assessed by dual x-ray absorptiometry. |
| Disease-free Survival (DFS) | From randomization until the DFS data cut-off date of 15 September 2015; maximum time on main study at the cut-off was 102 months | 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. |
| Bone Metastases-free Survival (BMFS) | From randomization until end of main study, maximum time on main study was 152 months | 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. |
| Overall Survival (OS) | Randomization until end of main study, maximum duration of main study was 152 months | OS was defined as the time from randomization to death from any cause. |
| Number of Participants With New or Worsening Vertebral Fractures | 36 months | 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. |
Countries
Austria, Sweden
Participant flow
Recruitment details
Participants were enrolled at 58 centers in Austria and Sweden from December 2006 to August 2020. Data collected during the exploratory ZA substudy were not used for the final analysis of the main study.
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive either denosumab or placebo in the double-blind phase. Randomization was stratified by type of hospital (major academic centers or other centers), prior aromatase inhibitor usage (Yes/No) and total lumbar spine bone mineral density (BMD) score at baseline (T-score \< -1.0 or ≥ -1.0). Willing and eligible participants continued into the open-label phase and receive denosumab for a maximum of 7 doses once Q6M.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 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. | 1,709 |
| Denosumab 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. | 1,711 |
| Total | 3,420 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Continuing into Zoledronic Acid Substudy | 50 | 0 |
| Overall Study | Death | 158 | 127 |
| Overall Study | Lost to Follow-up | 24 | 17 |
| Overall Study | Withdrawal by Subject | 235 | 205 |
Baseline characteristics
| Characteristic | Denosumab | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 64.0 years STANDARD_DEVIATION 7.9 | 64.3 years STANDARD_DEVIATION 8 | 64.6 years STANDARD_DEVIATION 8 |
| Race/Ethnicity, Customized Asian | 5 Participants | 12 Participants | 7 Participants |
| Race/Ethnicity, Customized Black/Afro-Caribbean | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 3 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White/Caucasian | 1702 Participants | 3402 Participants | 1700 Participants |
| Sex: Female, Male Female | 1711 Participants | 3420 Participants | 1709 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Stratification Factor: Prior Aromatase inhibitor Use No | 270 Participants | 539 Participants | 269 Participants |
| Stratification Factor: Prior Aromatase inhibitor Use Yes | 1441 Participants | 2881 Participants | 1440 Participants |
| Stratification Factor: Total Lumbar Spine BMD T-score T-score < -1.0 | 773 Participants | 1548 Participants | 775 Participants |
| Stratification Factor: Total Lumbar Spine BMD T-score T-score ≥ -1.0 | 938 Participants | 1872 Participants | 934 Participants |
| Stratification Factor: Type of Hospital Major Academic Center | 633 participants | 1265 participants | 632 participants |
| Stratification Factor: Type of Hospital Other Center | 1078 participants | 2155 participants | 1077 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 838 / 1,690 | 882 / 1,709 | 0 / 245 | 0 / 1 |
| serious Total, serious adverse events | 515 / 1,690 | 521 / 1,709 | 40 / 245 | 0 / 1 |
Outcome results
Primary
Time to First Clinical Fracture
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.
Time frame: From randomization until the primary analysis cut-off date of 26 March 2014; maximum time on main study at the cut-off was 87 months
Population: Full Analysis Set: all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Clinical Fracture | NA Days |
| Denosumab | Time to First Clinical Fracture | NA Days |
Comparison: 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).p-value: <0.000195% CI: [0.39, 0.65]Cox Proportional Hazards Model
Secondary
Bone Metastases-free Survival (BMFS)
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.
Time frame: From randomization until end of main study, maximum time on main study was 152 months
Population: Full Analysis Set: all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Bone Metastases-free Survival (BMFS) | NA Days |
| Denosumab | Bone Metastases-free Survival (BMFS) | NA Days |
95% CI: [0.654, 0.997]
Secondary
Disease-free Survival (DFS)
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.
Time frame: From randomization until the DFS data cut-off date of 15 September 2015; maximum time on main study at the cut-off was 102 months
Population: Full Analysis Set: all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Disease-free Survival (DFS) | NA Days |
| Denosumab | Disease-free Survival (DFS) | NA Days |
p-value: 0.051595% CI: [0.66, 1]Cox Proportional Hazards Model
Secondary
Number of Participants With New or Worsening Vertebral Fractures
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.
Time frame: 36 months
Population: Vertebral Fracture Analysis Set: all participants with a Baseline and at least one post-baseline vertebral x-ray prior to or at Month 36
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With New or Worsening Vertebral Fractures | 55 Participants |
| Denosumab | Number of Participants With New or Worsening Vertebral Fractures | 31 Participants |
p-value: 0.00795% CI: [0.34, 0.84]Regression, Logistic
Secondary
Number of Participants With New Vertebral Fractures
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.
Time frame: 36 months
Population: Vertebral Fracture Analysis Set: all participants with a Baseline and at least one post-baseline vertebral x-ray prior to or at Month 36
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With New Vertebral Fractures | 49 Participants |
| Denosumab | Number of Participants With New Vertebral Fractures | 27 Participants |
p-value: 0.008895% CI: [0.33, 0.85]Regression, Logistic
Secondary
Overall Survival (OS)
OS was defined as the time from randomization to death from any cause.
Time frame: Randomization until end of main study, maximum duration of main study was 152 months
Population: Full analysis set: all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Overall Survival (OS) | NA Days |
| Denosumab | Overall Survival (OS) | NA Days |
95% CI: [0.635, 1.013]
Secondary
Percent Change From Baseline in Femoral Neck BMD at Month 36 at Pre-selected Sites
Bone mineral density was assessed by dual x-ray absorptiometry.
Time frame: Baseline and Month 36
Population: BMD Analysis Set: all participants with evaluable femoral neck BMD values at Baseline and Month 36
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline in Femoral Neck BMD at Month 36 at Pre-selected Sites | -3.10 Percent Change in BMD |
| Denosumab | Percent Change From Baseline in Femoral Neck BMD at Month 36 at Pre-selected Sites | 3.41 Percent Change in BMD |
p-value: <0.000195% CI: [5.62, 7.39]ANCOVA
Secondary
Percent Change From Baseline in Total Hip BMD at Month 36 at Pre-selected Sites
Bone mineral density was assessed by dual x-ray absorptiometry.
Time frame: Baseline and Month 36
Population: BMD Analysis Set: all participants with total hip BMD evaluable values at Baseline and Month 36
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline in Total Hip BMD at Month 36 at Pre-selected Sites | -3.32 Percent Change in BMD |
| Denosumab | Percent Change From Baseline in Total Hip BMD at Month 36 at Pre-selected Sites | 4.60 Percent Change in BMD |
p-value: <0.000195% CI: [6.87, 8.97]ANCOVA
Secondary
Percent Change From Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36 at Pre-selected Sites
Bone mineral density was assessed by dual x-ray absorptiometry.
Time frame: Baseline and Month 36
Population: BMD Analysis Set: all participants with evaluable lumbar spine BMD values at Baseline and Month 36
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36 at Pre-selected Sites | -2.75 Percent Change in BMD |
| Denosumab | Percent Change From Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36 at Pre-selected Sites | 7.27 Percent Change in BMD |
p-value: <0.000195% CI: [9.04, 11.01]ANCOVA