S0226 Anastrozole With or Without Fulvestrant as First-Line Therapy in Postmenopausal Women With Metastatic Breast Cancer

OBJECTIVES:

- Compare the time to tumor progression in postmenopausal women with metastatic breast
cancer treated with anastrozole with or without fulvestrant as first-line therapy.

- Compare the clinical benefit (complete or partial response, confirmed or unconfirmed, or
stable disease ≥ 24 weeks) and overall survival of patients treated with these regimens.

- Compare adverse events in patients treated with these regimens.

- Determine the prognostic significance of estrogen receptor positivity and HER2/neu
status in patients treated with these regimens.

- Determine parameters of estrogen and clinical pharmacology and estrogen levels in
patients treated with these regimens.

- Compare anastrozole plasma levels at 8, 16, and 24 weeks in patients treated with these
regimens (closed as of 4/16/2009).

- Compare estradiol serum levels at 8, 16, and 24 weeks in patients treated with these
regimens (closed as of 4/16/2009).

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prior
adjuvant tamoxifen therapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive oral anastrozole once daily on days 1-28.

- Arm II: Patients receive oral anastrozole as in arm I. Patients also receive fulvestrant
intramuscularly on days 1, 14, and 28 during course 1 and then on day 28 of the
subsequent courses.

In both arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

Patients are followed for up to 4 years.

PROJECTED ACCRUAL: A total of 690 patients (345 per treatment arm) will be accrued for this
study within 3 years.

DISEASE CHARACTERISTICS:

- Histologically confirmed breast cancer meeting 1 of the following criteria:

- Metastatic disease (M1)

- Multiple sites of new disease that is clinically obvious metastatic disease
(e.g., multiple sites of new osseous disease)

- Measurable or nonmeasurable disease

- No known brain or CNS metastases

- Hormone receptor status:

- Estrogen-receptor positive* AND/OR

- Progesterone-receptor positive* NOTE: *Positivity defined as estrogen binding of
> 10 fmol/mg cytosol protein by ligand binding assay or positive by
immunohistochemistry

PATIENT CHARACTERISTICS:

Age

- Not specified

Sex

- Female

Menopausal status

- Postmenopausal, as defined by 1 of the following:

- Prior bilateral oophorectomy

- More than 12 months since last menstrual period with no prior hysterectomy

- At least 55 years of age with prior hysterectomy

- Under 55 years of age with a prior hysterectomy without oophorectomy and with
estradiol and follicle-stimulating hormone levels consistent with menopause

Performance status

- Zubrod 0-2

Life expectancy

- Not specified

Hematopoietic

- No bleeding diathesis (e.g., disseminated intravascular coagulation or clotting factor
deficiency)

Hepatic

- INR ≤ 1.6

Renal

- Not specified

Other

- HIV negative

- No other malignancy within the past 5 years except adequately treated basal cell or
squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated
stage I or II cancer currently in complete remission

PRIOR CONCURRENT THERAPY:

Biologic therapy

- No prior immunotherapy for recurrent or metastatic disease

Chemotherapy

- No prior chemotherapy for recurrent or metastatic disease

- More than 12 months since prior adjuvant or neoadjuvant chemotherapy

- No concurrent chemotherapy for malignancy

Endocrine therapy

- Prior adjuvant hormonal therapy allowed

- At least 12 months since prior adjuvant luteinizing hormone-releasing hormone (LHRH)
analogues

- Menstrual periods must not have resumed since LHRH therapy

- More than 12 months since prior adjuvant or neoadjuvant aromatase inhibitors (e.g.,
anastrozole, letrozole, or exemestane)

- More than 12 months since prior fulvestrant

- No prior hormonal therapy for recurrent or metastatic disease

- No other concurrent hormonal therapy for malignancy

- No concurrent hormone replacement therapy

Radiotherapy

- Not specified

Surgery

- Not specified

Other

- No long-term anticoagulant therapy (except antiplatelet therapy)