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.

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.

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

De-identified individual participant data, together with a data dictionary defining each field in the set, will be made available to other researchers on request, subject to the approval of a formal data access request in accordance with the ICR-CTSU data and sample access policy. Trial documentation including the protocol are available on request by contacting Formal requests for data sharing are considered in line with ICR-CTSU procedures. Requests are via a standard proforma describing the nature of the proposed research and extent of data requirements. Contact sofea-icrctsu@icr.ac.uk or visit the link below for further information.

Data will become available to researchers following the formal review and approval of a data access request in accordance with the ICR-CTSU data and sample access policy.

Completion and approval of a data access request form as stated above

ITT

Collected from the date each patient commenced treatment. AEs were collected every month for the first six months of the protocol and then every three months until disease progression/treatment discontinuation (assessed up to 190 months).

All events were graded according to CTCAE V3.0.

For (S)AEs the analysis population was "as treated", i.e. all patients receiving at least one dose of treatment. For all cause mortality the analysis population is ITT.

Arimidex vs Arimidex-placebo component is double-blinded. Faslodex is not blinded Exemestane is not blinded