Prescription Drug Information: Anastrozole (Page 4 of 6)

14.2 First-Line Therapy in Postmenopausal Women with Advanced Breast Cancer

Two double-blind, controlled clinical studies of similar design (0030, a North American study and 0027, a predominately European study) were conducted to assess the efficacy of anastrozole tablets 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 anastrozole tablets once daily or 20 mg of tamoxifen once daily. The primary endpoints 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 11

Demographic and Other Baseline Characteristics
Number (%) of subjects
* ER=Estrogen receptor
PgR=Progesterone receptor

Trial 0030

Trial 0027

Receptor status

Anastrozole Tablets

Tamoxifen

Anastrozole Tablets

Tamoxifen

1 mg

20 mg

1 mg

20 mg

(N=171)

(N=182)

(N=340)

(N=328)

ER* and/or PgR

151 (88.3)

162 (89.0)

154 (45.3)

144 (43.9)

ER* unknown, PgR unknown

19 (11.1)

20 (11.0)

185 (54.4)

183 (55.8)

For the primary endpoints, trial 0030 showed that anastrozole tablets had a statistically significant advantage over tamoxifen (p=0.006) for time to tumor progression; objective tumor response rates were similar for anastrozole tablets and tamoxifen. Trial 0027 showed that anastrozole tablets and tamoxifen had similar objective tumor response rates and time to tumor progression (see Table 12 and Figures 5 and 6).

Table 12 below summarizes the results of trial 0030 and trial 0027 for the primary efficacy endpoints.

Table 12

Efficacy Results of First-line Treatment
Endpoint Trial 0030 Trial 0027
* LCL=Lower Confidence Limit
Tamoxifen: anastrozole tablets
CI=Confidence Interval
§ Two-sided Log Rank
CR=Complete Response
# PR=Partial Response
anastrozole tablets:Tamoxifen

Anastrozole Tablets

Tamoxifen

Anastrozole Tablets

Tamoxifen

1 mg

20 mg

1 mg

20 mg

(N=171)

(N=182)

(N=340)

(N=328)

Time to progression (TTP)

Median TTP (months)

Number (%) of subjects Who progressed

11.1

114 (67%)

5.6

138 (76%)

8.2

249 (73%)

8.3

247 (75%)

Hazard ratio (LCL*)

2-sided 95% CI

p-value§

1.42 (1.15)

(1.11, 1.82)

0.006

1.01 (0.87)

(0.85, 1.20)

0.920

Best objective response rate

Number (%) of subjects With CR + PR#

36 (21.1%)

31 (17.0%)

112 (32.9%)

107 (32.6%)

Odds Ratio (LCL* )

1.30 (0.83)

1.01 (0.77)

Figure 5

Kaplan-Meier probability of time to disease progression for all randomized patients (intent-to-treat) in Trial 0030

Figure 5
(click image for full-size original)

Figure 6

Kaplan-Meier probability of time to progression for all randomized patients (intent-to-treat) in Trial 0027

Figure 6
(click image for full-size original)

Results from the secondary endpoints 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.

14.3 Second-Line Therapy in Postmenopausal Women with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy

Anastrozole was studied in two 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 anastrozole tablets or megestrol acetate 40 mg four times a day. The studies were double-blinded with respect to anastrozole tablets. 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.

Efficacy results from the two studies were similar as presented in Table 13. In both studies there were no significant differences between treatment arms with respect to any of the efficacy parameters listed in the table below.

Table 13

Efficacy Results of Second-line Treatment
Anastrozole Tablets Anastrozole Tablets Megestrol Acetate

1 mg

10 mg

160 mg

Trial 0004

(N. America)

(N=128)

(N=130)

(N=128)

Median Follow-up (months)*

31.3

30.9

32.9

Median Time to Death (months)

29.6

25.7

26.7

2 Year Survival Probability (%)

62.0

58.0

53.1

Median Time to Progression (months)

5.7

5.3

5.1

Objective Response (all patients) (%)

12.5

10.0

10.2

Stable Disease for >24 weeks (%)

35.2

29.2

32.8

Progression (%)

86.7

85.4

90.6

Trial 0005

(Europe, Australia, S. Africa)

(N=135)

(N=118)

(N=125)

Median Follow-up (months)*

31.0

30.9

31.5

Median Time to Death (months)

24.3

24.8

19.8

2 Year Survival Probability (%)

50.5

50.9

39.1

Median Time to Progression (months)

4.4

5.3

3.9

Objective Response(all patients) (%)

12.6

15.3

14.4

Stable Disease for >24 weeks (%)

24.4

25.4

23.2

Progression (%)

91.9

89.8

92.0

*Surviving Patients

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 anastrozole tablets 1 mg and megestrol acetate. There is, in this data, no indication that anastrozole tablets 10 mg is superior to anastrozole tablets 1 mg.

Table 14

Pooled Efficacy Results of Second-line Treatment
Trials 0004 & 0005 Anastrozole Tablets Anastrozole Tablets Megestrol Acetate

(Pooled Data)

1 mg

10 mg

160 mg

N=263

N=248

N=253

Median Time toDeath (months)

26.7

25.5

22.5

2 Year SurvivalProbability (%)

56.1

54.6

46.3

Median Time toProgression

4.8

5.3

4.6

Objective Response(all patients) (%)

12.5

12.5

12.3

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