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).

Table 7 — Demographic and Baseline Characteristics for ATAC Trial

Demographic Characteristic

Anastrozole

1 mg

(N *=3125)

Tamoxifen

20 mg

(N *=3116)

Anastrozole 1 mg

plus Tamoxifen

20 mg

(N *=3125)

*
N=Number of patients randomized to the treatment
The combination arm was discontinued due to lack of efficacy benefit at 33 months to 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 arm, 94.1% in the tamoxifen arm and 94.5% in the Anastrozole plus tamoxifen arm.

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-1
(click image for full-size original)

Figure 2 — Disease-free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC Trial

figure-2
(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 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.

Table 8-All Recurrence and Death Events *

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

*
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

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.

Table 9 — ATAC Efficacy Summary *

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

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

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).

Table 10 — Efficacy Summary

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)

figure-3
(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)

figure-4
(click image for full-size original)

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

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