Anastrozole (Page 4 of 8)
13.2 Animal Pharmacology and/or Toxicology
Reproductive Toxicology
Anastrozole has been found to cross the placenta following oral administration of 0.1 mg/kg in rats and rabbits (about 1 and 1.9 times the recommended human dose, respectively, on a mg/m2 basis). Studies in both rats and rabbits at doses equal to or greater than 0.1 and 0.02 mg/kg/day, respectively (about 1 and 1/3, respectively, the recommended human dose on a mg/m 2 basis), administered during the period of organogenesis showed that anastrozole increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption, and decreased numbers of live fetuses); effects were dose related in rats. Placental weights were significantly increased in rats at doses of 0.1 mg/kg/day or more. Evidence of fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), was observed in rats administered doses of 1 mg/kg/day (which produced plasma anastrozole CSS max and AUC0-24 hr that were 19 times and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose). There was no evidence of teratogenicity in rats administered doses up to 1.0 mg/kg/day. In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 1.0 mg/kg/day (about 16 times the recommended human dose on a mg/m 2 basis); there was no evidence of teratogenicity in rabbits administered 0.2 mg/kg/day (about 3 times the recommended human dose on a mg/m 2 basis).
14 CLINICAL STUDIES
14.1 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 Anastrozole 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 (i.e., 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 Anastrozole 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. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole. [see Drug Interactions ( 7.1)]
Demographic and other baseline characteristics were similar among the three treatment groups (see Table 7).
Demographic Characteristic | Anastrozole 1 mg (N *=3125) | Tamoxifen 20 mg (N *=3116) | Anastrozole 1 mg plus Tamoxifen 20 mg † (N *=3125) |
| |||
Mean age (yrs.) | 64.1 | 64.1 | 64.3 |
Age Range (yrs.) | 38.1 to 92.8 | 32.8 to 94.9 | 37 to 92.2 |
Age Distribution (%) | |||
<45 yrs. | 0.7 | 0.4 | 0.5 |
45 to 60 yrs. | 34.6 | 35.0 | 34.5 |
>60 <70 yrs. | 38.0 | 37.1 | 37.7 |
>70 yrs. | 26.7 | 27.4 | 27.3 |
Mean Weight (kg) | 70.8 | 71.1 | 71.3 |
Receptor Status (%) | |||
Positive ‡ | 83.5 | 83.1 | 84.0 |
Negative § | 7.4 | 8.0 | 7.0 |
Other ¶ | 8.8 | 8.6 | 9.0 |
Other Treatment (%) prior to Randomization | |||
Mastectomy | 47.8 | 47.3 | 48.1 |
Breast conservation # | 52.3 | 52.8 | 51.9 |
Axillary surgery | 95.5 | 95.7 | 95.2 |
Radiotherapy | 63.3 | 62.5 | 61.9 |
Chemotherapy | 22.3 | 20.8 | 20.8 |
Neoadjuvant Tamoxifen | 1.6 | 1.6 | 1.7 |
Primary Tumor Size (%) | |||
T1 (≤2 cm) | 63.9 | 62.9 | 64.1 |
T2 (>2 cm and ≤5 cm) | 32.6 | 34.2 | 32.9 |
T3 (>5 cm) | 2.7 | 2.2 | 2.3 |
Nodal Status (%) | |||
Node positive | 34.9 | 33.6 | 33.5 |
1 to 3 (# of nodes) | 24.4 | 24.4 | 24.3 |
4 to 9 | 7.5 | 6.4 | 6.8 |
>9 | 2.9 | 2.7 | 2.3 |
Tumor Grade (%) | |||
Well-differentiated | 20.8 | 20.5 | 21.2 |
Moderately differentiated | 46.8 | 47.8 | 46.5 |
Poorly/undifferentiated | 23.7 | 23.3 | 23.7 |
Not assessed/recorded | 8.7 | 8.4 | 8.5 |
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 Anastrozole 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 Anastrozole arm compared to the tamoxifen arm.
Figure 1 — Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC trial (Intent-to-Treat)
Figure 2 — Disease-free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC Trial
The survival data with 68 months follow-up is presented in Table 9.
In the group of patients who had previous adjuvant chemotherapy (N=698 for Anastrozole and N=647 for tamoxifen), the hazard ratio for disease-free survival was 0.91 (95% CI: 0.73 to 1.13) in the Anastrozole 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 8.
Intent-To-Treat Population † | Hormone Receptor-Positive Subpopulation † | |||
Anastrozole 1 mg (N ‡=3125) | Tamoxifen 20 mg (N ‡=3116) | Anastrozole 1 mg (N ‡=2618) | Tamoxifen 20 mg (N ‡=2598 | |
Median Duration of Therapy (mo) | 60 | 60 | 60 | 60 |
Median Efficacy Follow-up (mo) | 68 | 68 | 68 | 68 |
Loco-regional recurrence | 119 (3.8) | 149 (4.8) | 76 (2.9) | 101 (3.9) |
Contralateral breast cancer | 35 (1.1) | 59 (1.9) | 26 (1.0) | 54 (2.1) |
Invasive | 27 (0.9) | 52 (1.7) | 21 (0.8) | 48 (1.8) |
Ductal carcinoma in situ | 8 (0.3) | 6 (0.2) | 5 (0.2) | 5 (0.2) |
Unknown | 0 | 1 (<0.1) | 0 | 1 (<0.1) |
Distant recurrence | 324 (10.4) | 375 (12.0) | 226 (8.6) | 265 (10.2) |
Death from Any Cause | 411 (13.2) | 420 (13.5) | 296 (11.3) | 301 (11.6) |
Death breast cancer | 218 (7.0) | 248 (8.0) | 138 (5.3) | 160 (6.2) |
Death other reason (including unknown) | 193 (6.2) | 172 (5.5) | 158 (6.0) | 141 (5.4) |
A summary of the study efficacy results is provided in Table 9.
Intent-To-Treat Population | Hormone Receptor-Positive Subpopulation | |||
Anastrozole 1 mg (N=3125) | Tamoxifen 20 mg (N=3116) | Anastrozole 1 mg (N=2618) | Tamoxifen 20 mg (N=2598) | |
Number of Events | Number of Events | |||
| ||||
Disease-free Survival | 575 | 651 | 424 | 497 |
Hazard ratio | 0.87 0.78 to 0.97 0.0127 | 0.83 0.73 to 0.94 0.0049 | ||
2-sided 95% CI | ||||
p-value | ||||
Distant Disease-free Survival | 500 | 530 | 370 | 394 |
Hazard ratio | 0.94 0.83 to 1.06 | 0.93 0.80 to 1.07 | ||
2-sided 95% CI | ||||
Overall Survival | 411 | 420 | 296 | 301 |
Hazard ratio | 0.97 0.85 to 1.12 | 0.97 0.83 to 1.14 | ||
2-sided 95% CI |
10-year median follow-up Efficacy Results from the ATAC Trial
In a subsequent analysis of the ATAC trial, patients in the two monotherapy arms were followed for a median of 120 months (10 years). Patients received study treatment for a median of 60 months (5 years) (see Table 10).
Intent-To-Treat Population | Hormone Receptor-Positive Subpopulation | |||
Anastrozole 1 mg (N=3125) | Tamoxifen 20 mg (N=3116) | Anastrozole 1 mg (N=2618) | Tamoxifen 20 mg (N=2598) | |
Number of Events | Number of Events | |||
Disease-free Survival | 953 | 1022 | 735 | 924 |
Hazard ratio | 0.91 | 0.86 | ||
2-sided 95% CI | 0.83 to 0.99 | 0.78 to 0.95 | ||
p-value | 0.0365 | 0.0027 | ||
Overall Survival | 734 | 747 | 563 | 586 |
Hazard ratio | 0.91 0.88 to 1.08 | 0.95 0.84 to 1.06 | ||
2-sided 95% CI |
a The proportion of patients with 120 months’ follow-up was 29.4%.
Figure 3 — Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC Trial (Intent-to-Treat) (a)
a The proportion of patients with 120 months’ follow-up was 29.4%.
Figure 4 — Disease-Free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC Trial (b)
b The proportion of patients with 120 months’ follow-up was 29.8%.
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