Anastrozole (Page 4 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A conventional carcinogenesis study in rats at doses of 1.0 to 25 mg/kg/day (about 10 to 243 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed an increase in the incidence of hepatocellular adenoma and carcinoma and uterine stromal polyps in females and thyroid adenoma in males at the high dose. A dose-related increase was observed in the incidence of ovarian and uterine hyperplasia in females. At 25 mg/kg/day, plasma AUC0-24 hr levels in rats were 110 to 125 times higher than the level exhibited in postmenopausal volunteers at the recommended dose. A separate carcinogenicity study in mice at oral doses of 5 to 50 mg/kg/day (about 24 to 243 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years produced an increase in the incidence of benign ovarian stromal, epithelial and granulosa cell tumors at all dose levels. A dose-related increase in the incidence of ovarian hyperplasia was also observed in female mice. These ovarian changes are considered to be rodent-specific effects of aromatase inhibition and are of questionable significance to humans. The incidence of lymphosarcoma was increased in males and females at the high dose. At 50 mg/kg/day, plasma AUC levels in mice were 35 to 40 times higher than the level exhibited in postmenopausal volunteers at the recommended dose.

Anastrozole tablets has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests, CHO-K1 gene mutation assay) or clastogenic either in vitro (chromosome aberrations in human lymphocytes) or in vivo (micronucleus test in rats).

Oral administration of anastrozole to female rats (from 2 weeks before mating to pregnancy day 7) produced significant incidence of infertility and reduced numbers of viable pregnancies at 1 mg/kg/day (about 10 times the recommended human dose on a mg/m2 basis and 9 times higher than the AUC0-24 hr found in postmenopausal volunteers at the recommended dose). Pre-implantation loss of ova or fetus was increased at doses equal to or greater than 0.02 mg/kg/day (about one-fifth the recommended human dose on a mg/m2 basis). Recovery of fertility was observed following a 5-week non-dosing period which followed 3 weeks of dosing. It is not known whether these effects observed in female rats are indicative of impaired fertility in humans.

Multiple-dose studies in rats administered anastrozole for 6 months at doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 19 and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose) resulted in hypertrophy of the ovaries and the presence of follicular cysts. In addition, hyperplastic uteri were observed in 6-month studies in female dogs administered doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 22 times and 16 times higher than the respective values found in postmenopausal women at the recommended dose). It is not known whether these effects on the reproductive organs of animals are associated with impaired fertility in premenopausal women.

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 tablets 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 tablets 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).

Table 7 Demographic and Baseline Characteristics for ATAC Trial

* N=Number of patients randomized to the treatment

The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up

Includes patients who were estrogen receptor (ER) positive or progesterone receptor (PgR) positive, or both positive

§ Includes patients with both ER negative and PgR negative receptor status

Includes all other combinations of ER and PgR receptor status unknown

# Among the patients who had breast conservation, radiotherapy was administered to 95.0% of patients in the anastrozole tablets arm, 94.1% in the tamoxifen arm and 94.5% in the anastrozole tablets plus tamoxifen arm.

Demographic Characteristic Anastrozole Tablets 1 mg (N* =3125) Tamoxifen 20 mg (N* =3116) Anastrozole Tablets 1 mg plus Tamoxifen 20 mg (N* =3125)
Mean age (yrs.) 64.1 64.1 64.3
Age Range (yrs.) 38.1 — 92.8 32.8 — 94.9 37.0 – 92.2
Age Distribution (%)
<45 yrs. 0.7 0.4 0.5
45-60 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
1-3 (# of nodes) 24.4 24.4 24.3
4-9 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 tablets 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 tablets arm compared to the tamoxifen arm.

Figure 1

Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Anastrozole Tablets or Tamoxifen Monotherapy in the ATAC Trial (Intent-to-Treat)

Structured formula for Anastrozole Tablets
(click image for full-size original)

Figure 2

Disease-Free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anastrozole Tablets or Tamoxifen Monotherapy in the ATAC Trial

Structured formula for Anastrozole Tablets
(click image for full-size original)

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 tablets 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 tablets 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.

Table 8 All Recurrence and Death Events *
*
The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up.
Patients may fall into more than one category.
N=Number of patients randomized
Header$ Intent-To-Treat Population Hormone Receptor-Positive Subpopulation
Anastrozole Tablets Tamoxifen Anastrozole Tablets Tamoxifen
1 mg 20 mg 1 mg 20 mg
(N =3125) (N =3116) (N =2618) (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 8 (0.3) 6 (0.2) 5 (0.2) 5 (0.2)
in situ
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.

Table 9ATAC Efficacy Summary*

* The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up.

Intent To Treat Population Hormone Receptor Positive Subpopulation
Anastrozole tablets Tamoxifen Anastrozole tablets Tamoxifen
1 mg 20 mg 1 mg 20 mg
( N = 3125 ) ( N = 3116 ) ( N = 2618 ) ( N = 2598 )
Number of Events Number of Events
Disease free Survival 575651424497
Hazard ratio0.870.83
2-sided 95% CI0.78 to 0.970.73 to 0.94
p-value0.01270.0049
Distant Disease free Survival 500530370394
Hazard ratio0.940.93
2-sided 95% CI0.83 to 1.060.80 to 1.07
Overall Survival 411420296301
Hazard ratio0.970.97
2-sided 95% CI0.85 to 1.120.83 to 1.14

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).

Table 10 Efficacy Summary
Intent-To-Treat Population Hormone Receptor-Positive Subpopulation
Anastrozole tablets Tamoxifen Anastrozole tablets Tamoxifen
1 mg 20 mg 1 mg 20 mg
(N=3125) (N=3116) (N=2618) (N=2598)
Number of Events Number of Events
Disease-free Survival 953 1022 735 924
Hazard ratio 0.91 0.83 to 0.99 0.0365 0.86 0.78 to 0.95 0.0027
2-sided 95% CI
p-value
Overall Survival 734 747 563 586
Hazard ratio 0.97 0.88 to 1.08 0.95 0.84 to 1.06
2-sided 95% CI

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)

Anastrozole Tablets
(click image for full-size original)

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)

Anastrozole Tablets
(click image for full-size original)

b The proportion of patients with 120 months’ follow-up was 29.8%.

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