Breast Cancer
Conditions
Keywords
recurrent breast cancer, stage IV breast cancer, stage IIIB breast cancer, stage IIIC breast cancer
Brief summary
RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant, anastrozole, or exemestane may fight breast cancer by blocking the use of estrogen by the tumor cells or by lowering the amount of estrogen the body makes. It is not yet known whether giving fulvestrant together with anastrozole is more effective than giving fulvestrant together with a placebo or exemestane alone in treating breast cancer. PURPOSE: This randomized phase III trial is studying fulvestrant and anastrozole to see how well they work compared to fulvestrant and a placebo or exemestane alone in treating postmenopausal women with locally advanced or metastatic breast cancer.
Detailed description
OBJECTIVES: Primary * Compare progression-free survival of postmenopausal women with estrogen receptor- and/or progesterone receptor-positive, locally advanced or metastatic breast cancer that relapsed or progressed during prior treatment with nonsteroidal aromatase inhibitors treated with fulvestrant with vs without anastrozole vs exemestane alone. Secondary * Compare the objective complete response (CR) and partial response (PR) rate and duration of response in patients treated with these regimens. * Compare the clinical benefit (i.e., 6-month CR, PR, and stable disease) rate and duration of clinical benefit in patients treated with these regimens. * Compare time to treatment failure in patients treated with these regimens. * Compare the overall survival of patients treated with these regimens. * Compare the tolerability of these regimens in these patients. OUTLINE: This is a randomized, partially double-blind and placebo-controlled, multicenter study. Patients are stratified according to the setting in which prior nonsteroidal aromatase-inhibitor therapy was given (adjuvant therapy vs first-line therapy) and participating center. Patients are randomized to 1 of 3 treatment arms. * Arm I (fulvestrant and anastrozole): Patients receive fulvestrant intramuscularly (IM) on days 1, 15, and 29 and then once monthly. Patients receive oral anastrozole once daily. * Arm II (fulvestrant and placebo): Patients receive fulvestrant as in arm I and oral placebo once daily. * Arm III (exemestane alone): Patients receive oral exemestane once daily. In all arms, treatment repeats every month in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for survival. PROJECTED ACCRUAL: A total of 750 patients (250 per treatment arm) will be accrued for this study.
Interventions
DRUGAnastrozole
This may be Anastrazole OR a placebo
DRUGExemestane
DRUGFulvestrant
Sponsors
Royal Marsden NHS Foundation Trust
Institute of Cancer Research, United Kingdom
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Arimidex vs Arimidex-placebo component is double-blinded. Faslodex is not blinded Exemestane is not blinded
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed adenocarcinoma of the breast * Locally advanced or metastatic disease * Metastatic disease must be measurable or evaluable * Patients with bone only metastases are eligible provided there is an evaluable site of bone metastasis that can be followed by x-ray, MRI, or CT scan * Relapsed or progressed during prior treatment with single-agent nonsteroidal aromatase inhibitor (NSAI)\*, meeting either of the following criteria: * NSAI given as adjuvant therapy that lasted ≥ 12 months * Achieved an objective complete response, partial response, or stable disease that lasted ≥ 6 months after prior first-line therapy with NSAI for locally advanced or metastatic disease * Chemotherapy as part of the first-line therapy given before initiation of NSAI allowed NOTE: \*Patients are required to continue to take NSAI until beginning of study treatment. * No rapidly progressive visceral disease (i.e., lymphangitis carcinomatosa or diffuse hepatic involvement) * Hormone receptor status: * Estrogen receptor (ER) and/or progesterone receptor positive tumor * No ER-unknown disease PATIENT CHARACTERISTICS: Sex * Female Menopausal status * Postmenopausal, as defined by 1 of the following criteria: * Age 60 and over * Age 45 to 59 AND ≥ 12 months since last menstrual period with no prior hysterectomy * Any age with prior bilateral oophorectomy Performance status * WHO 0-2 Life expectancy * More than 3 months Hematopoietic * Neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * No thrombocytopenia * Hemoglobin ≥ 10 g/dL Hepatic * AST and ALT ≤ 2.5 times upper limit of normal (ULN) * Alkaline phosphatase ≤ 5 times ULN (unless due to bone metastases) * No liver disease Renal * Creatinine \< 1.97 mg/dL Other * No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Chemotherapy * See Disease Characteristics * Prior neoadjuvant or adjuvant chemotherapy allowed Endocrine therapy * See Disease Characteristics * Prior tamoxifen as neoadjuvant or adjuvant therapy allowed * No systemic corticosteroids that lasted \> 15 days within the past 4 weeks Other * More than 4 weeks since prior investigational drugs * Concurrent bisphosphonates for bone metastases allowed provided bisphosphonate therapy has been established for ≥ 6 months * Concurrent initiation of bisphosphonate allowed provided patient has soft tissue or visceral metastases as the measurable or evaluable target lesion * No concurrent anticoagulant therapy * No concurrent unlicensed noncancer investigational agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Assessed up to 190 months | defined as time from randomisation to progression of existing disease, new sites of disease, second primary cancer if change in systemic treatment was necessary, or death from any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | Assessed up to 190 months | time from first assessment of response to progression or death. Response is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as either disappearance of all lesions or a \>=30% decrease in the sum of the longest diameter of target lesions with no progressing non-target lesions and no new lesions. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Clinical Benefit Rate | Assessed up to 190 months | Complete or partial response or stable disease for at least six months prior to progression. Response is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as either disappearance of all lesions or a \>=30% decrease in the sum of the longest diameter of target lesions with no progressing non-target lesions and no new lesions. Stable disease is neither responding or progressing. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Duration of Clinical Benefit | Assessed up to 190 months | Time from first assessment of clinical benefit to progression or death. Response is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as either disappearance of all lesions or a \>=30% decrease in the sum of the longest diameter of target lesions with no progressing non-target lesions and no new lesions. Stable disease is neither responding or progressing. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Clinical benefit = (CR+PR)+(SD\>=6months). |
| Objective Response Rate | From start of treatment, every 3 months to treatment discontinuation and/or up to 190 months | The proportion of patients identified as having a complete response (CR) or partial response (PR) at any time whilst on study treatment. Response is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as either disappearance of all lesions or a \>=30% decrease in the sum of the longest diameter of target lesions with no progressing non-target lesions and no new lesions. Objective Response (OR) = CR + PR |
| Overall Survival | To death assessed up to 190 months. | Time from randomisation until death from any cause. |
| Tolerability of Treatment | From start of treatment to discontinuation of treatment/progression assessed up to 190 months | To evaluate the overall safety and tolerability. The number of patients experiencing at least one adverse event. Refer to adverse event section for more details. |
| Time to Treatment Failure | To discontinuation of protocol treatment for any reason, or progression of disease assessed up to 190 months | Time from randomisation to discontinuation of protocol treatment for any reason, or progression of disease |
Countries
United Kingdom
Participant flow
Recruitment details
Patients were recruited between 26 March 2004 and 6 August 2010 from 82 hospitals in the UK.
Pre-assignment details
Prior to randomisation patients were assessed for medical history and had a clinical examination, haematology and biochemistry and tumour staging to assess eligibility.
Participants by arm
| Arm | Count |
|---|---|
| Faslodex + Placebo Arimidex/placebo comparator is blinded Faslodex (fulvestrant) IM on day 1,15,29 and monthly thereafter Placebo orally once a day
Anastrozole: This may be Anastrazole OR a placebo
Fulvestrant | 226 |
| Faslodex + Arimidex Arimidex/placebo comparator is blinded Faslodex (fulvestrant) IM on day 1,15,29 and monthly thereafter Arimidex (anastrozole) orally once a day
Anastrozole: This may be Anastrazole OR a placebo
Fulvestrant | 233 |
| Exemestane exemestane orally once a day
Exemestane | 239 |
| Total | 698 |
Baseline characteristics
| Characteristic | Faslodex + Placebo | Faslodex + Arimidex | Exemestane | Total |
|---|---|---|---|---|
| Age, Continuous | 63.2 years | 64.1 years | 66.1 years | 64.7 years |
| Age, Customized 50 to 64 years | 102 Participants | 104 Participants | 100 Participants | 306 Participants |
| Age, Customized <50 years | 17 Participants | 21 Participants | 7 Participants | 45 Participants |
| Age, Customized 65 to 74 years | 61 Participants | 65 Participants | 70 Participants | 196 Participants |
| Age, Customized >=75 years | 46 Participants | 43 Participants | 62 Participants | 151 Participants |
| HER2 Status of primary disease HER2 unknown | 76 Participants | 101 Participants | 90 Participants | 267 Participants |
| HER2 Status of primary disease HER2 -ve | 136 Participants | 117 Participants | 134 Participants | 387 Participants |
| HER2 Status of primary disease HER2 +ve | 14 Participants | 15 Participants | 15 Participants | 44 Participants |
| Hormone Receptor Status of primary disease ER unknown PR unknown | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Hormone Receptor Status of primary disease ER+ve PR unknown | 71 Participants | 83 Participants | 91 Participants | 245 Participants |
| Hormone Receptor Status of primary disease ER-ve PR-ve | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Hormone Receptor Status of primary disease ER+ve PR -ve | 31 Participants | 38 Participants | 22 Participants | 91 Participants |
| Hormone Receptor Status of primary disease ER+ve PR+ve | 121 Participants | 111 Participants | 123 Participants | 355 Participants |
| Hormone Receptor Status of primary disease ER-ve/unknown PR+ve | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Region of Enrollment United Kingdom | 226 participants | 233 participants | 239 participants | 698 participants |
| Sex: Female, Male Female | 226 Participants | 233 Participants | 239 Participants | 698 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Time from primary diagnosis to first relapse | 5.1 years | 5.0 years | 5.2 years | 5.1 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 221 / 226 | 225 / 233 | 227 / 239 |
| other Total, other adverse events | 221 / 225 | 227 / 231 | 230 / 237 |
| serious Total, serious adverse events | 31 / 225 | 39 / 231 | 37 / 237 |
Outcome results
Primary
Progression-free Survival
defined as time from randomisation to progression of existing disease, new sites of disease, second primary cancer if change in systemic treatment was necessary, or death from any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Assessed up to 190 months
Population: Intention to treat (ITT). This population contains all people randomised into the study (regardless of whether they were later found to be ineligible, a protocol deviator, given the wrong treatment allocation, never treated etc.). Comparisons are made by randomised treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Faslodex + Placebo | Progression-free Survival | 4.8 Months |
| Faslodex + Arimidex | Progression-free Survival | 4.1 Months |
| Exemestane | Progression-free Survival | 3.5 Months |
p-value: 0.7695% CI: [0.86, 1.24]Log Rank
p-value: 195% CI: [0.83, 1.2]Log Rank
Secondary
Clinical Benefit Rate
Complete or partial response or stable disease for at least six months prior to progression. Response is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as either disappearance of all lesions or a \>=30% decrease in the sum of the longest diameter of target lesions with no progressing non-target lesions and no new lesions. Stable disease is neither responding or progressing. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Assessed up to 190 months
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Faslodex + Placebo | Clinical Benefit Rate | 55 Participants |
| Faslodex + Arimidex | Clinical Benefit Rate | 66 Participants |
| Exemestane | Clinical Benefit Rate | 57 Participants |
p-value: 0.33Chi-squared
p-value: 0.94Chi-squared
Secondary
Duration of Clinical Benefit
Time from first assessment of clinical benefit to progression or death. Response is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as either disappearance of all lesions or a \>=30% decrease in the sum of the longest diameter of target lesions with no progressing non-target lesions and no new lesions. Stable disease is neither responding or progressing. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Clinical benefit = (CR+PR)+(SD\>=6months).
Time frame: Assessed up to 190 months
Population: The number of patients that had clinical benefit, defined as complete or partial response, or stable disease for at least 6 months prior to progression.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Faslodex + Placebo | Duration of Clinical Benefit | 11.2 months |
| Faslodex + Arimidex | Duration of Clinical Benefit | 11.5 months |
| Exemestane | Duration of Clinical Benefit | 12.2 months |
Secondary
Duration of Response
time from first assessment of response to progression or death. Response is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as either disappearance of all lesions or a \>=30% decrease in the sum of the longest diameter of target lesions with no progressing non-target lesions and no new lesions. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Assessed up to 190 months
Population: The number of patients that had an objective response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Faslodex + Placebo | Duration of Response | 10.2 Months |
| Faslodex + Arimidex | Duration of Response | 8.7 Months |
| Exemestane | Duration of Response | 12.8 Months |
Secondary
Objective Response Rate
The proportion of patients identified as having a complete response (CR) or partial response (PR) at any time whilst on study treatment. Response is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as either disappearance of all lesions or a \>=30% decrease in the sum of the longest diameter of target lesions with no progressing non-target lesions and no new lesions. Objective Response (OR) = CR + PR
Time frame: From start of treatment, every 3 months to treatment discontinuation and/or up to 190 months
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Faslodex + Placebo | Objective Response Rate | 16 Participants |
| Faslodex + Arimidex | Objective Response Rate | 17 Participants |
| Exemestane | Objective Response Rate | 10 Participants |
p-value: 0.99Chi-squared
p-value: 0.12Chi-squared
Secondary
Overall Survival
Time from randomisation until death from any cause.
Time frame: To death assessed up to 190 months.
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Faslodex + Placebo | Overall Survival | 20.1 Months |
| Faslodex + Arimidex | Overall Survival | 20.2 Months |
| Exemestane | Overall Survival | 22.5 Months |
p-value: 0.9195% CI: [0.82, 1.19]Log Rank
p-value: 0.3195% CI: [0.91, 1.32]Log Rank
Secondary
Time to Treatment Failure
Time from randomisation to discontinuation of protocol treatment for any reason, or progression of disease
Time frame: To discontinuation of protocol treatment for any reason, or progression of disease assessed up to 190 months
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Faslodex + Placebo | Time to Treatment Failure | 3.8 Months |
| Faslodex + Arimidex | Time to Treatment Failure | 3.9 Months |
| Exemestane | Time to Treatment Failure | 3.4 Months |
p-value: 0.9595% CI: [0.84, 1.21]Log Rank
p-value: 0.6695% CI: [0.87, 1.25]Log Rank
Secondary
Tolerability of Treatment
To evaluate the overall safety and tolerability. The number of patients experiencing at least one adverse event. Refer to adverse event section for more details.
Time frame: From start of treatment to discontinuation of treatment/progression assessed up to 190 months
Population: Number of patients that received at least one dose of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Faslodex + Placebo | Tolerability of Treatment | 221 Participants |
| Faslodex + Arimidex | Tolerability of Treatment | 227 Participants |
| Exemestane | Tolerability of Treatment | 230 Participants |