CLINICAL PHARMACOLOGY
Mechanism of Action
Many breast cancers have estrogen receptors and growth of these tumors can be stimulated by estrogen. In postmenopausal women, the principal source of circulating estrogen (primarily estradiol) is conversion of adrenally-generated androstenedione to estrone by aromatase in peripheral tissues, such as adipose tissue, with further conversion of estrone to estradiol. Many breast cancers also contain aromatase; the importance of tumor-generated estrogens is uncertain.
Treatment of breast cancer has included efforts to decrease estrogen levels, by ovariectomy premenopausally and by use of anti-estrogens and progestational agents both pre- and post-menopausally; and these interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.
Anastrozole is a potent and selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.
Pharmacokinetics
Inhibition of aromatase activity is primarily due to anastrozole, the parent drug. Studies with radiolabeled drug have demonstrated that orally administered anastrozole is well absorbed into the systemic circulation with 83 to 85% of the radiolabel recovered in urine and feces. Food does not affect the extent of absorption. Elimination of anastrozole is primarily via hepatic metabolism (approximately 85%) and to a lesser extent, renal excretion (approximately 11%), and anastrozole has a mean terminal elimination half-life of approximately 50 hours in postmenopausal women. The major circulating metabolite of anastrozole, triazole, lacks pharmacologic activity. The pharmacokinetic parameters are similar in patients and in healthy postmenopausal volunteers. The pharmacokinetics of anastrozole are linear over the dose range of 1 to 20 mg and do not change with repeated dosing. Consistent with the approximately 2-day terminal elimination half-life, plasma concentrations approach steady-state levels at about 7 days of once daily dosing and steady-state levels are approximately three- to four-fold higher than levels observed after a single dose of ARIMIDEX. Anastrozole is 40% bound to plasma proteins in the therapeutic range.
Metabolism and Excretion
Studies in postmenopausal women demonstrated that anastrozole is extensively metabolized with about 10% of the dose excreted in the urine as unchanged drug within 72 hours of dosing, and the remainder (about 60% of the dose) is excreted in urine as metabolites. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. Three metabolites of anastrozole have been identified in human plasma and urine. The known metabolites are triazole, a glucuronide conjugate of hydroxy-anastrozole, and a glucuronide of anastrozole itself. Several minor (less than 5% of the radioactive dose) metabolites have not been identified.
Because renal elimination is not a significant pathway of elimination, total body clearance of anastrozole is unchanged even in severe (creatinine clearance less than 30 mL/min/1.73m2) renal impairment, dosing adjustment in patients with renal dysfunction is not necessary (see Special Populations and DOSAGE AND ADMINISTRATION sections). Dosage adjustment is also unnecessary in patients with stable hepatic cirrhosis (see Special Populations and DOSAGE AND ADMINISTRATION sections).
Special Populations
Geriatric
Anastrozole pharmacokinetics have been investigated in postmenopausal female volunteers and patients with breast cancer. No age related effects were seen over the range <50 to >80 years.
Race
Estradiol and estrone sulfate levels were similar between Japanese and Caucasian postmenopausal women who received 1 mg of anastrozole daily for 16 days. Anastrozole mean steady-state minimum plasma concentrations in Caucasian and Japanese postmenopausal women were 25.7 and 30.4 ng/mL, respectively.
Renal Insufficiency
Anastrozole pharmacokinetics have been investigated in subjects with renal insufficiency. Anastrozole renal clearance decreased proportionally with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment (creatinine clearance < 30 mL/min/1.73m2) compared to controls. Since only about 10% of anastrozole is excreted unchanged in the urine, the reduction in renal clearance did not influence the total body clearance (See DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency
Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Anastrozole pharmacokinetics have been investigated in subjects with hepatic cirrhosis related to alcohol abuse. The apparent oral clearance (CL/F) of anastrozole was approximately 30% lower in subjects with stable hepatic cirrhosis than in control subjects with normal liver function. However, plasma anastrozole concentrations in the subjects with hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials (see DOSAGE AND ADMINISTRATION), so that no dosage adjustment is needed.
Drug-Drug Interactions
Anastrozole inhibited reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cmax values observed following a 1 mg daily dose. Anastrozole had no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg/kg or multiple 10 mg/kg doses of anastrozole to healthy subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites. Based on these in vitro and in vivo results, it is unlikely that co-administration of ARIMIDEX 1 mg with other drugs will result in clinically significant inhibition of cytochrome P450 mediated metabolism.
In a study conducted in 16 male volunteers, anastrozole did not alter the pharmacokinetics as measured by Cmax and AUC, and anticoagulant activity as measured by prothrombin time, activated partial thromboplastine time, and thrombin time of both R- and S-warfarin.
Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole alone; however, the coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen (see PRECAUTIONS -Drug Interactions).
Pharmacodynamics
Effect on Estradiol
Mean serum concentrations of estradiol were evaluated in multiple daily dosing trials with 0.5, 1, 3, 5, and 10 mg of ARIMIDEX in postmenopausal women with advanced breast cancer. Clinically significant suppression of serum estradiol was seen with all doses. Doses of 1 mg and higher resulted in suppression of mean serum concentrations of estradiol to the lower limit of detection (3.7 pmol/L). The recommended daily dose, ARIMIDEX 1 mg, reduced estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of daily dosing. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing with ARIMIDEX 1 mg.
The effect of ARIMIDEX on estradiol levels in premenopausal women has not been studied. Because aromatization of adrenal androgens is not a significant source of estradiol in premenopausal women (women with functioning ovaries as evidenced by menstruation and/or premenopausal LH, FSH and estradiol levels), ARIMIDEX would not be expected to lower estradiol levels in premenopausal women.
Effect on Corticosteroids
In multiple daily dosing trials with 3, 5, and 10 mg, the selectivity of anastrozole was assessed by examining effects on corticosteroid synthesis. For all doses, anastrozole did not affect cortisol or aldosterone secretion at baseline or in response to ACTH. No glucocorticoid or mineralocorticoid replacement therapy is necessary with anastrozole.
Other Endocrine Effects
In multiple daily dosing trials with 5 and 10 mg, thyroid stimulating hormone (TSH) was measured; there was no increase in TSH during the administration of ARIMIDEX. ARIMIDEX does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens.
Clinical Studies
Adjuvant Treatment of Breast Cancer in Postmenopausal Women
A multicenter, double-blind trial (ATAC) randomized 9,366 postmenopausal women with operable breast cancer to adjuvant treatment with ARIMIDEX 1 mg daily, tamoxifen 20 mg daily, or a combination of the two treatments for five years or until recurrence of the disease.
The primary endpoint of the trial was disease-free survival (ie, time to occurrence of a distant or local recurrence, or contralateral breast cancer or death from any cause). Secondary endpoints of the trial included distant disease-free survival, the incidence of contralateral breast cancer and overall survival. At a median follow-up of 33 months, the combination of ARIMIDEX and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial.
Demographic and other baseline characteristics were similar among the three treatment groups (see Table 1).
Table 1 - Demographic and Baseline Characteristics for ATAC Trial |
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Demographic Characteristic
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ARIMIDEX
1 mg (N=3125)
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Tamoxifen
20 mg
(N=3116)
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ARIMIDEX 1 mg
plus Tamoxifen
20 mg
(N=3125)
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Mean age (yrs.)
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64.1
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64.1
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64.3
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Age Range (yrs.)
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38.1 - 92.8
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32.8 − 94.9
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37.0 - 92.2
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Age Distribution (%)
| | | |
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45 yrs.
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0.7
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0.4
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0.5
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5-60 yrs.
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34.6
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35.0
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34.5
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60 <70 yrs.
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38.0
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37.1
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37.7
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70 yrs.
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26.7
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27.4
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27.3
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Mean Weight (kg)
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70.8
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71.1
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71.3
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Receptor Status (%)
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Positive
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83.5
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83.1
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84.0
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Negative
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7.4
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8.0
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7.0
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Other
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8.8
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8.6
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9.0
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Other Treatment (%) prior to Randomization
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Mastectomy
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47.8
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47.3
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48.1
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Breast conservation
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52.3
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52.8
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51.9
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Axillary surgery
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95.5
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95.7
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95.2
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Radiotherapy
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63.3
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62.5
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61.9
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Chemotherapy
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22.3
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20.8
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20.8
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Neoadjuvant Tamoxifen
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1.6
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1.6
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1.7
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Primary Tumor Size (%)
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T1 (≤2 cm)
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63.9
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62.9
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64.1
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T2 (>2 cm and ≤5 cm)
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32.6
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34.2
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32.9
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T3 (>5 cm)
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2.7
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2.2
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2.3
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Nodal Status (%)
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Node positive
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34.9
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33.6
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33.5
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1-3 (# of nodes)
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24.4
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24.4
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24.3
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4-9
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7.5
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6.4
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6.8
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>9
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2.9
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2.7
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2.3
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Tumor Grade (%)
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Well-differentiated
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20.8
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20.5
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21.2
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Moderately differentiated
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46.8
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47.8
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46.5
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Poorly/undifferentiated
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23.7
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23.3
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23.7
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Not assessed/recorded
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8.7
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8.4
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8.5
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Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127 in the ARIMIDEX arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 84% of the trial patients, disease-free survival was also statistically significantly improved (HR =0.83, 95% CI: 0.73, 0.94, p=0.0049) in the ARIMIDEX arm compared to the tamoxifen arm.
 Figure 1 - Disease-free Survival Kaplan Meier Survival Curve for all Patients Randomized to ARIMIDEX or Tamoxifen Monotherapy in the ATAC trial (Intent-to-treat)  Figure 2 - Disease-free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to ARIMIDEX or Tamoxifen Monotherapy in the ATAC Trial
The survival data with 68 months follow-up is presented in Table 3.
In the group of patients who had previous adjuvant chemotherapy (N=698 for ARIMIDEX and N=647 for tamoxifen), the hazard ratio for disease-free survival was 0.91 (95% CI: 0.73 to 1.13) in the Arimidex arm compared to the tamoxifen arm. For patients who were 65 years of age and older (N=1413 for ARIMIDEX and N=1410 for tamoxifen), the hazard ratio for disease-free survival was 0.93 (95% CI: 0.80 to1.08) in the Arimidex arm compared to the tamoxifen arm.
The frequency of individual events in the intent-to-treat population and the hormone receptor-positive subpopulation are described in Table 2.
Table 2 - All Recurrence and Death Events |
Intent-To-Treat
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Hormone Receptor-Positive Subpopulation
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ARIMIDEX
1mg
(N=3125)
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Tamoxifen
20 mg
(N=3116)
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ARIMIDEX
1 mg
(N=2618)
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Tamoxifen
20 mg
(N=2598)
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Number (%) of Patients
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Number (%) of Patients
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Median Duration of Therapy (mo)
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60
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60
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60
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60
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Median Efficacy Follow-up (mo)
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68
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68
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68
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68
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Loco-regional recurrence
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119 (3.8)
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149 (4.8)
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76 (2.9)
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101 (3.9)
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Contralateral breast cancer
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35 (1.1)
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59 (1.9)
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26 (1.0)
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54 (2.1)
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Invasive
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27 (0.9)
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52 (1.7)
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21 (0.8)
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48 (1.8)
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Ductal carcinoma in situ
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8 (0.3)
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6 (0.2)
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5 (0.2)
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5 (0.2)
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Unknown
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0
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1 (<0.1)
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0
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1 (<0.1)
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Distant recurrence a
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324 (10.4)
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375 (12.0)
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226 (8.6)
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265 (10.2)
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Death from Any Cause
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411 (13.2)
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420 (13.5)
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296 (11.3)
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301 (11.6)
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Death breast cancer
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218 (7.0)
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248 (8.0)
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138 (5.3)
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160 (6.2)
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Death other reason (including unknown)
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193 (6.2)
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172 (5.5)
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158 (6.0)
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141 (5.4)
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A summary of the study efficacy results is provided in Table 3.
Table 3 - ATAC Efficacy Summary |
Intent-To-Treat Population
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Hormone Receptor-Positive Subpopulation
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ARIMIDEX
1mg
(N=3125)
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Tamoxifen
20 mg
(N=3116)
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ARIMIDEX
1 mg
(N=2618)
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Tamoxifen
20 mg
(N=2598)
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Number of Events
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Number of Events
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Disease-free Survival
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575
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651
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424
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497
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Hazard ratio
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0.87
0.78 to 0.97
0.0127
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0.83
0.73 to 0.94
0.0049
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2-sided 95% CI
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p-value
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Distant Disease-free Survival
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500
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530
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370
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394
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Hazard ratio
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0.94
0.83 to 1.06
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0.93
0.80 to 1.07
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2-sided 95% CI
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Overall Survival
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411
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420
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296
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301
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Hazard ratio
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0.97
0.85 to 1.12
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0.97
0.83 to 1.14
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2-sided 95% CI
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First Line Therapy in Postmenopausal Women with Advanced Breast Cancer
Two double-blind, well-controlled clinical studies of similar design (0030, a North American study and 0027, a predominately European study) were conducted to assess the efficacy of ARIMIDEX compared with tamoxifen as first-line therapy for hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer in postmenopausal women. A total of 1021 patients between the ages of 30 and 92 years old were randomized to receive trial treatment. Patients were randomized to receive 1 mg of ARIMIDEX once daily or 20 mg of tamoxifen once daily. The primary end points for both trials were time to tumor progression, objective tumor response rate, and safety.
Demographics and other baseline characteristics, including patients who had measurable and no measurable disease, patients who were given previous adjuvant therapy, the site of metastatic disease and ethnic origin were similar for the two treatment groups for both trials. The following table summarizes the hormone receptor status at entry for all randomized patients in trials 0030 and 0027.
Table 4 |
Number (%) of subjects
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Trial 0030
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Trial 0027
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Receptor status
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ARIMIDEX
1mg
(N=171)
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Tamoxifen
20 mg
(N=182)
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ARIMIDEX
1 mg
(N=340)
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Tamoxifen
20 mg
(N=328)
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ER+ and/or PgR+
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151 (88.3)
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162 (89.0)
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154 (45.3)
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144 (43.9)
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ER unknown, PgR Unknown
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19 (11.1)
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20 (11.0)
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185 (54.4)
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183 (55.8)
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For the primary endpoints, trial 0030 showed ARIMIDEX was at least as effective as tamoxifen for objective tumor response rate. ARIMIDEX had a statistically significant advantage over tamoxifen (p=0.006) for time to tumor progression (see Table 5 and Figure 3). Trial 0027 showed ARIMIDEX was at least as effective as tamoxifen for objective tumor response rate and time to tumor progression (See Table 5 and Figure 4).
Table 5 below summarizes the results of trial 0030 and trial 0027 for the primary efficacy endpoints.
Table 5 |
End point
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Trial 0030
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Trial 0027
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ARIMIDEX
1 mg
(n=171)
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Tamoxifen
20 mg
(n=182)
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ARIMIDEX
1 mg
(n=340)
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Tamoxifen
20 mg
(n=328)
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Time to progression (TTP)
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Median TTP (months)
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11.1
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5.6
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8.2
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8.3
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Number (%) of subjects who progressed
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114 (67%)
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138 (76%)
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249 (73%)
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247 (75%)
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Hazard ratio (LCL)1
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1.42 (1.15)
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1.01 (0.87)
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2-sided 95% CI
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(1.11, 1.82)
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(0.85, 1.20)
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p-value2
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0.006
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0.920
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Best objective response rate
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Number (%) of subjects wth CR + PR
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36 (21.1%)
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31 (17.0%)
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112 (32.9%)
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107 (32.6%)
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Odds Ratio (LCL)3
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1.30 (0.83)
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1.01 (0.77)
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 Figure 3 - Kaplan-Meier probability of time to disease progression for all randomized patients (intent-to-treat) in Trial 0030  Figure 4 Kaplan-Meier probability of time to progression for all randomized patients (intent-to-treat) in Trial 0027
Results from the secondary endpoints of time to treatment failure, duration of tumor response, and duration of clinical benefit were supportive of the results of the primary efficacy endpoints. There were too few deaths occurring across treatment groups of both trials to draw conclusions on overall survival differences.
Second Line Therapy in Postmenopausal Women with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy
Anastrozole was studied in two well-controlled clinical trials (0004, a North American study; 0005, a predominately European study) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. Some of the patients had also received previous cytotoxic treatment. Most patients were ER-positive; a smaller fraction were ER-unknown or ER-negative; the ER-negative patients were eligible only if they had had a positive response to tamoxifen. Eligible patients with measurable and non-measurable disease were randomized to receive either a single daily dose of 1 mg or 10 mg of ARIMIDEX or megestrol acetate 40 mg four times a day. The studies were double-blinded with respect to ARIMIDEX. Time to progression and objective response (only patients with measurable disease could be considered partial responders) rates were the primary efficacy variables. Objective response rates were calculated based on the Union Internationale Contre le Cancer (UICC) criteria. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also calculated.
Both trials included over 375 patients; demographics and other baseline characteristics were similar for the three treatment groups in each trial. Patients in the 0005 trial had responded better to prior tamoxifen treatment. Of the patients entered who had prior tamoxifen therapy for advanced disease (58% in Trial 0004; 57% in Trial 0005), 18% of these patients in Trial 0004 and 42% in Trial 0005 were reported by the primary investigator to have responded. In Trial 0004, 81% of patients were ER-positive, 13% were ER-unknown, and 6% were ER-negative. In Trial 0005, 58% of patients were ER-positive, 37% were ER-unknown, and 5% were ER-negative. In Trial 0004, 62% of patients had measurable disease compared to 79% in Trial 0005. The sites of metastatic disease were similar among treatment groups for each trial. On average, 40% of the patients had soft tissue metastases; 60% had bone metastases; and 40% had visceral (15% liver) metastases.
As shown in the table below, similar results were observed among treatment groups and between the two trials. None of the within-trial differences were statistically significant.
Table 6 |
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ARIMIDEX
1 mg
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ARIMIDEX
10 mg
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Megestrol Acetate
160 mg
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Trial 0004
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(N. America)
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(n=128)
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(N=130)
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(n=128)
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Median Fol1ow-up (months)*
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31.3
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30.9
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32.9
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Median Time to Death (months)
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29.6
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25.7
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26.7
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2 Year Survival Probability (%)
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62.0
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58.0
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53.1
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Median Time to Progression (months)
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5.7
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5.3
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5.1
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Objective Response (all patients) (%)
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12.5
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10.0
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10.2
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Stable Disease for >24 weeks (%)
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35.2
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29.2
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32.8
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Progression (%)
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86.7
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85.4
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90.6
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Trial 0005
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(Europe, Australia, S. Africa)
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(n=135)
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(n=118)
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(n=125)
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Median Follow-up (months)*
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31.0
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30.9
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31.5
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Median Time to Death (months)
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24.3
|
24.8
|
19.8
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2 Year Survival Probability (%)
|
50.5
|
50.9
|
39.1
|
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Median Time to Progression (months)
|
4.4
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5.3
|
3.9
|
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Objective Response (all patients) (%)
|
12.6
|
15.3
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14.4
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Stable Disease for >24 weeks (%)
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24.4
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25.4
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23.2
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Progression (%)
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91.9
|
89.8
|
92.0
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More than 1/3 of the patients in each treatment group in both studies had either an objective response or stabilization of their disease for greater than 24 weeks. Among the 263 patients who received ARIMIDEX 1 mg, there were 11 complete responders and 22 partial responders. In patients who had an objective response, more than 80% were still responding at 6 months from randomization and more than 45% were still responding at 12 months from randomization.
When data from the two controlled trials are pooled, the objective response rates and median times to progression and death were similar for patients randomized to ARIMIDEX 1 mg and megestrol acetate. There is, in this data, no indication that ARIMIDEX 10 mg is superior to ARIMIDEX 1 mg.
Table 7 |
Trials 0004 & 0005
(Pooled Data)
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ARIMIDEX
1 mg
N=263
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ARIMIDEX
10 mg
N=248
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Megestrol Acetate
160 mg
N=253
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Median Time to Death (months)
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26.7
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25.5
|
22.5
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2 Year Survival Probability (%)
|
56.1
|
54.6
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46.3
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Median Time to Progression
|
4.8
|
5.3
|
4.6
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Objective Response (all patients) (%)
|
12.5
|
12.5
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12.3
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Objective response rates and median times to progression and death for ARIMIDEX 1 mg were similar to megestrol acetate for women over or under 65. There were too few non-white patients studied to draw conclusions about racial differences in response.
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