Recommended Topic Related To:

Femara

"Dec. 6, 2012 -- Women now have one more reason to eat their fruits and veggies.

A new study suggests that women with higher levels of carotenoids (nutrients found in fruits and vegetables) have a lower risk of breast cancer -- especia"...

Femara

CLINICAL PHARMACOLOGY

Mechanism Of Action

The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.

In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor-and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.

Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.

Pharmacodynamics

In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg Femara (letrozole) suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline with maximal suppression achieved within two-three days. Suppression is dose-related, with doses of 0.5 mg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 0.5 mg or higher.

Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of Femara 0.1 mg to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary.

No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of Femara or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg. This indicates that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH levels, T3 uptake, and T4 levels.

Pharmacokinetics

Absorption and Distribution

Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is recovered in urine. Letrozole's terminal elimination half-life is about 2 days and steady-state plasma concentration after daily 2.5 mg dosing is reached in 2-6 weeks. Plasma concentrations at steady state are 1.5 to 2 times higher than predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg).

Metabolism and Excretion

Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole.

In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole strongly inhibited CYP2A6 and moderately inhibited CYP2C19.

Pediatric, Geriatric and Race

In the study populations (adults ranging in age from 35 to > 80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied.

Renal Impairment

In a study of volunteers with varying renal function (24-hour creatinine clearance: 9 to 116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of Femara was found. In addition, in a study of 347 patients with advanced breast cancer, about half of whom received 2.5 mg Femara and half 0.5 mg Femara, renal impairment (calculated creatinine clearance: 20 to 50 mL/min) did not affect steady-state plasma letrozole concentrations.

Hepatic Impairment

In a study of subjects with mild to moderate non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification A and B), the mean AUC values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function.

In a pharmacokinetic study, subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which included bilirubins about 2-11 times ULN with minimal to severe ascites) had twofold increase in exposure (AUC) and 47% reduction in systemic clearance. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients with normal liver function receiving similar doses of this drug. [see DOSAGE AND ADMINISTRATION]

Clinical Studies

Updated Adjuvant Treatment Of Early Breast Cancer

In a multicenter study enrolling over 8,000 postmenopausal women with resected, receptor-positive early breast cancer, one of the following treatments was randomized in a double-blind manner:

Option 1:
  1. tamoxifen for 5 years
  2. Femara for 5 years
  3. tamoxifen for 2 years followed by Femara for 3 years
  4. Femara for 2 years followed by tamoxifen for 3 years
Option 2:
  1. tamoxifen for 5 years
  2. Femara for 5 years

The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether Femara for 5 years was superior to tamoxifen for 5 years (Primary Cor e Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis). Selected baseline characteristics for the study population are shown in Table 5.

The primary endpoint of this trial was disease-free survival (DFS) (i.e., interval between randomization and earliest occurrence of a local, regional, or distant recurrence, or invasive contralateral breast cancer, or death from any cause). The secondary endpoints were overall survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer, time to breast cancer recurrence (TBR) and time to distant metastasis (TDM).

The Primary Core Analysis (PCA) included all patients and all follow-up in the monotherapy arms in both randomization options, but follow-up in the two sequential treatments arms was truncated 30 days after switching treatments. The PCA was conducted at a median treatment duration of 24 months and a median follow-up of 26 months. Femara was superior to tamoxifen in all endpoints except overall survival and contralateral breast cancer [e.g., DFS: hazard ratio, HR 0.79; 95% CI (0.68, 0.92); P=0.002; SDFS: HR 0.83; 95% CI (0.70, 0.97); TDM: HR 0.73; 95% CI (0.60, 0.88); OS: HR 0.86; 95% CI (0.70, 1.06).

In 2005, based on recommendations by the independent Data Monitoring Committee, the tamoxifen arms were unblinded and patients were allowed to complete initial adjuvant therapy with Femara (if they had received tamoxifen for at least 2 years) or to start extended adjuvant treatment with Femara (if they had received tamoxifen for at least 4.5 years) if they remained alive and disease-free. In total, 632 patients crossed to Femara or another aromatase inhibitor. Approximately 70% (448) of these 632 patients crossed to Femara to complete initial adjuvant therapy and most of these crossed in years 3 to 4. All of these patients were in Option 1. A total of 184 patients started extended adjuvant therapy with Femara (172 patients) or with another aromatase inhibitor (12 patients). To explore the impact of this selective crossover, results from analyses censoring follow-up at the date of the selective crossover (in the tamoxifen arm) are presented for the Monotherapy Arms Analysis (MAA).

The PCA allowed the results of Femara for 5 years compared with tamoxifen for 5 years to be reported in 2005 after a median follow-up of only 26 months. The design of the PCA is not optimal to evaluate the effect of Femara after a longer time (because follow-up was truncated in two arms at around 25 months). The Monotherapy Arms Analysis (ignoring the two sequential treatment arms) provided follow-up equally as long in each treatment and did not over-emphasize early recurrences as the PCA did. The MAA thus provides the clinically appropriate updated efficacy results in answer to the first primary question, despite the confounding of the tamoxifen reference arm by the selective crossover to Femara. The updated results for the MAA are summarized in Table 6. Median follow-up for this analysis is 73 months.

The Sequential Treatments Analysis (STA) addresses the second primary question of the study. The primary analysis for the Sequential Treatments Analysis (STA) was from switch (or equivalent time-point in monotherapy arms) + 30 days (STA-S) with a two-sided test applied to each pair-wise comparison at the 2.5% level. Additional analyses wer e conducted from randomization (STA-R) but these comparisons (added in light of changing medical practice) were under-powered for efficacy.

Table 5: Adjuvant Study -Patient and Disease Characteristics (ITT Population)

Characteristic Primary Core Analysis (PCA) Monotherapy Arms Analysis (MAA)
Femara
N=4003
n (%)
tamoxifen
N=4007
n (%)
Femara
N=2463
n (%)
tamoxifen
N=2459
n (%)
Age (median, years) 61 61 61 61
Age range (years) 38-89 39-90 38-88 39-90
Hormone receptor status (%)
  ER+ and/or PgR+ 99.7 99.7 99.7 99.7
  Both unknown 0.3 0.3 0.3 0.3
Nodal status (%)
  Node negative 52 52 50 52
  Node positive 41 41 43 41
  Nodal status unknown 7 7 7 7
Prior adjuvant chemotherapy (%) 24 24 24 24

Table 6: Updated Adjuvant Study Results -Monotherapy Arms Analysis (Median Follow-up 73 Months)

    Femara
N=2463
tamoxifen
N=2459
Hazard ratio
Events (%) 5-year rate Events (%) 5-year rate (95% CI)
Disease-free survival1 ITT 445
(18.1)
87.4 500
(20.3)
84.7 0.87
(0.76, 0.99)
  Censor 445 87.4 483 84.2 0.84
(0.73, 0.95)
  0 positive nodes ITT 165 92.2 189 90.3 0.88
(0.72, 1.09)
  1-3 positive nodes ITT 151 85.6 163 83.0 0.85
(0.68, 1.06)
   > =4 positive nodes ITT 123 71.2 142 62.6 0.81
(0.64, 1.03)
  Adjuvant chemotherapy ITT 119 86.4 150 80.6 0.77
(0.60, 0.98)
  No chemotherapy ITT 326 87.8 350 86.1 0.91
(0.78, 1.06)
Systemic DFS2 ITT 401 88.5 446 86.6 0.88
(0.77,1.01)
Time to distant metastasis3 ITT 257 92.4 298 90.1 0.85
(0.72, 1.00)
  Adjuvant chemotherapy ITT 84 - 109 - 0.75
(0.56-1.00)
  No chemotherapy ITT 173 - 189 - 0.90
(0.73,1.11)
Distant DFS4 ITT 385 89.0 432 87.1 0.87
(0.76,1.00)
Contralateral breast cancer ITT 34 99.2 44 98.6 0.76
(0.49, 1.19)
Overall survival ITT 303 91.8 343 90.9 0.87
(0.75, 1.02)
  Censor 303 91.8 338 90.1 0.82
(0.70, 0.96)
  0 positive nodes ITT 107 95.2 121 94.8 0.90
(0.69.1.16)
  1-3 positive nodes ITT 99 90.8 114 90.6 0.81(0.62,1.06)
   > =4 positive nodes ITT 92 80.2 104 73.6 0.86
(0.65, 1.14)
  Adjuvant chemotherapy ITT 76 91.5 96 88.4 0.79
(0.58, 1.06)
No chemotherapy ITT 227 91.9 247 91.8 0.91
(0.76, 1.08)

Definition of:
1Disease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death without a prior event
2Systemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event
3Time to distant metastasis: Interval from randomization to distant metastasis
4Distant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause
ITT analysis ignores selective crossover in tamoxifen arms
Censored analysis censors follow-up at the date of selective crossover in 632 patients who crossed to Femara or another aromatase inhibitor after the tamoxifen arms were unblinded in 2005

Figure 1 shows the Kaplan-Meier curves for Disease-Free Survival Monotherapy Analysis

Figure 1 : Disease-Free Survival (Median follow-up 73 months, ITT Approach)

Kaplan-Meier curves for Disease-Free Survival Monotherapy Analysis - Illustration

DFS events defined as loco-regional recurrence, distant meta sta sis, inva sive contra latera l brea st cancer, or death from a ny cau se (i.e., definition excludes second non-brea st primary cancers).

The medians of overall survival for both arms were not reached for the Monotherapy Arms Analysis (MAA). There was no statistically significant difference in overall survival. The hazard ratio for survival in the Femara arm compared to the tamoxifen arm was 0.87, with 95% CI (0.75, 1.02) (see Table 6).

There were no significant differences in DFS, OS, SDFS, and Distant DFS from switch in the Sequential Treatments Analysis with respect to either monotherapy (e.g., [Tamoxifen 2 years followed by] Femara 3 years versus tamoxifen beyond 2 years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [Femara 2 years followed by] tamoxifen 3 years versus Femara beyond 2 years, DFS HR 0.93; 97.5% CI 0.71, 1.22).

There were no significant differences in DFS, OS, SDFS, and Distant DFS from randomization in the Sequential Treatments Analyses.

Extended Adjuvant Treatment Of Early Breast Cancer, Median Treatment Duration Of 24 Months

A double-blind, randomized, placebo-controlled trial of Femarawas performed in over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were disease free after 5 years of adjuvant treatment with tamoxifen.

The planned duration of treatment for patients in the study was 5 years, but the trial was terminated early because of an interim analysis showing a favorable Femara effect on time without recurrence or contralateral breast cancer. At the time of unblinding, women had been followed for a median of 28 months, 30% of patients had completed 3 or more years of follow-up and less than 1% of patients had completed 5 years of follow-up.

Selected baseline characteristics for the study population are shown in Table 7.

Table 7: Selected Study Population Demographics (Modified ITT Population)

Baseline Status Femara
N=2582
Placebo
N=2586
Hormone Receptor Status (%)
  ER+ and/or PgR+ 98 98
  Both Unknown 2 2
Nodal Status (%)
  Node Negative 50 50
  Node Positive 46 46
  Nodal Status Unknown 4 4
Chemotherapy 46 46

Table 8 shows the study results. Disease-free survival was measured as the time from randomization to the earliest event of loco-regional or distant recurrence of the primary disease or development of contralateral breast cancer or death. DFS by hormone receptor status, nodal status and adjuvant chemotherapy were similar to the overall results. Data were premature for an analysis of survival.

Table 8: Extended Adjuvant Study Results

  Femara
N = 2582
Placebo
N = 2586
Hazard Ratio (95% CI) P-Value
Disease Free Survival (DFS)1 Events 122 (4.7%) 193 (7.5%) 0.62 (0.49, 0.78)2 0.00003
  Local Breast Recurrence 9 22
  Local Chest Wall Recurrence 2 8    
  Regional Recurrence 7 4    
  Distant Recurrence 55 92 0.61 (0.44 -0.84) 0.003
  Contralateral Breast Cancer 19 29    
  Deaths Without Recurrence or Contralateral Breast Cancer 30 38    
CI = confidence interval for hazard ratio. Hazard ratio of less than 1.0 indicates difference in favor of Femara (lesser risk of recurrence); hazard ratio greater than 1.0 indicates difference in favor of placebo (higher risk of recurrence with Femara).
1First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause
2Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). P-value based on stratified logrank test.

Updated Analyses Of Extended Adjuvant Treatment Of Early Breast Cancer, Median Treatment Duration Of 60 Months

Table 9: Update of Extended Adjuvant Study Results

  Femara
N = 2582
(%)
Placebo
N = 2586
(%)
Hazard Ratio1 (95% CI) P-Value2
Disease Free Survival (DFS) events3 344 (13.3) 402 (15.5) 0.89 (0.77, 1.03) 0.12
Breast cancer recurrence (Protocol definition of DFS events4) 209 286 0.75 (0.63, 0.89) 0.001
  Local Breast Recurrence 15 44    
  Local Chest Wall Recurrence 6 14    
  Regional Recurrence 10 8    
  Distant Recurrence 140 167    
  Distant Recurrence (first or subsequent events) 142 169 0.88 (0.70,1.10) 0.246
  Contralateral Breast Cancer 37 53    
  Deaths Without Recurrence or Contralateral Breast Cancer 135 116    
1Adjusted by receptor status, nodal status and prior chemotherapy
2Stratified logrank test, stratified by receptor status, nodal status and prior chemotherapy
3DFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring switches to Femara in 60% of the placebo arm.
4Protocol definition does not include deaths from any cause

Updated analyses were conducted at a median follow-up of 62 months. In the Femara arm, 71% of the patients were treated for a least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. After the unblinding of the study at a median follow-up of 28 months, approximately 60% of the selected patients in the placebo arm opted to switch to Femara.

In this updated analysis shown in Table 9, Femara significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo (HR 0.75; 95% CI 0.63, 0.89; P=0.001). However, in the updated DFS analysis (interval between randomization and earliest event of loco-regional recurrence, distant metastasis, contralateral breast cancer, or death from any cause) the treatment difference was heavily diluted by 60% of the patients in the placebo arm switching to Femara and accounting for 64% of the total placebo patient-years of follow-up. Ignoring these switches, the risk of DFS event was reduced by a non-significant 11% (HR 0.89; 95% CI 0.77, 1.03). There was no significant difference in distant disease-free survival or overall survival.

First-Line Treatment Of Advanced Breast Cancer

A randomized, double-blind, multinational trial compared Femara 2.5 mg with tamoxifen 20 mg in 916 postmenopausal patients with locally advanced (Stage IIIB or loco-regional recurrence not amenable to treatment with surgery or radiation) or metastatic breast cancer. Time to progression (TTP) was the primary endpoint of the trial. Selected baseline characteristics for this study are shown in Table 10.

Table 10: Selected Study Population Demographics

Baseline Status Femara
N=458
tamoxifen
N=458
Stage of Disease
  IIIB 6% 7%
  IV 93% 92%
Receptor Status
  ER and PgR Positive 38% 41%
  ER or PgR Positive 26% 26%
  Both Unknown 34% 33%
  ER- or PgR-/Other Unknown < 1% 0
Previous Antiestrogen Therapy
  Adjuvant 19% 18%
  None 81% 82%
Dominant Site of Disease
  Soft Tissue 25% 25%
  Bone 32% 29%
  Viscera 43% 46%

Femara was superior to tamoxifen in TTP and rate of objective tumor response (see Table 11).

Table 11 summarizes the results of the trial, with a total median follow-up of approximately 32 months. (All analyses are unadjusted and use 2-sided P-values.)

Table 11: Results of First-Line Treatment of Advanced Breast Cancer

  Femara 2.5 mg N=453 tamoxifen 20 mg
N=454
Hazard or Odds Ratio (95% CI) P-Value (2-Sided)
Median Time to Progression 9.4 months 6.0 months 0.72 (0.62, 0.83)1
P < 0.0001
Objective Response Rate (CR + PR) 145 (32%) 95 (21%) 1.77 (1.31, 2.39)2
P=0.0002
  (CR) 42 (9%) 15 (3%) 2.99 (1.63, 5.47)2
P=0.0004
Duration of Objective Response
  Median 18 months (N=145) 16 months (N=95)  
Overall Survival 35 months (N=458) 32 months (N=458) P=0.51363
1Hazard ratio
2Odds ratio
3Overall logrank test

Figure 2 shows the Kaplan-Meier curves for TTP.

Figure 2 : Kaplan-Meier Estimates of Time to Progression (Tamoxifen Study)

Kaplan-Meier Estimates of Time to Progression (Tamoxifen Study) - Illustration

Table 12 shows results in the subgroup of women who had received prior antiestrogen adjuvant therapy, Table 13, results by disease site and Table 14, the results by receptor status.

Table 12: Efficacy in Patients Who Received Prior Antiestrogen Therapy

Variable Femara 2.5 mg
N=84
tamoxifen 20 mg
N=83
Median Time to Progression (95% CI) 8.9 months (6.2, 12.5) 5.9 months (3.2, 6.2)
  Hazard Ratio for TTP (95% CI) 0.60 (0.43, 0.84)
Objective Response Rate
  (CR + PR) 22 (26%) 7 (8%)
  Odds Ratio for Response (95% CI) 3.85 (1.50, 9.60)

Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.

Table 13: Efficacy by Disease Site

  Femara 2.5 mg tamoxifen 20 mg
Dominant Disease Site
Soft Tissue: N=113 N=115
Median TTP 12.1 months 6.4 months
Objective Response Rate 50% 34%
Bone: N=145 N=131
Median TTP 9.5 months 6.3 months
Objective Response Rate 23% 15%
Viscera: N=195 N=208
Median TTP 8.3 months 4.6 months
Objective Response Rate 28% 17%

Table 14: Efficacy by Receptor Status

Variable Femara 2.5 mg tamoxifen 20 mg
Receptor Positive N=294 N=305
  Median Time to Progression (95% CI) 9.4 months (8.9, 11.8) 6.0 months (5.1, 8.5)
  Hazard Ratio for TTP (95% CI) 0.69 (0.58, 0.83)  
  Objective Response Rate (CR+PR) 97 (33%) 66 (22%)
  Odds Ratio for Response 95% CI) 1.78 (1.20, 2.60)  
Receptor Unknown N=159 N=149
  Median Time to Progression (95% CI) 9.2 months (6.1, 12.3) 6.0 months (4.1, 6.4)
  Hazard Ratio for TTP (95% CI) 0.77 (0.60, 0.99)  
  Objective Response Rate (CR+PR)  48 (30%) 29 (20%)
  Odds Ratio for Response (95% CI) 1.79 (1.10, 3.00)  

Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.

Figure 3 shows the Kaplan-Meier curves for survival.

Figure 3 : Survival by Randomized Treatment Arm

Survival by Randomized Treatment Arm - Illustration

Legend: Randomized Femara: n=458, events 57%, median overall survival 35 months (95% CI 32 to 38 months) Randomized tamoxifen: n=458, events 57%, median overall survival 32 months (95% CI 28 to 37 months) Overall logrank P=0.5136 (i.e., there was no significant difference between treatment arms in overall survival).

The median overall survival was 35 months for the Femara group and 32 months for the tamoxifen group, with a P-value 0.5136. Study design allowed patients to cross over upon progression to the other therapy. Approximately 50% of patients crossed over to the opposite treatment arm and almost all patients who crossed over had done so by 36 months. The median time to crossover was 17 months (Femara to tamoxifen) and 13 months (tamoxifen to Femara). In patients who did not cross over to the opposite treatment arm, median survival was 35 months with Femara (n=219, 95% Cl 29 to 43 months) vs 20 months with tamoxifen (n=229, 95% Cl 16 to 26 months).

Second-Line Treatment Of Advanced Breast Cancer

Femara was initially studied at doses of 0.1 mg to 5.0 mg daily in six non-comparative Phase I/II trials in 181 postmenopausal estrogen/progesterone receptor positive or unknown advanced breast cancer patients previously treated with at least antiestrogen therapy. Patients had received other hormonal therapies and also may have received cytotoxic therapy. Eight (20%) of forty patients treated with Femara 2.5 mg daily in Phase I/II trials achieved an objective tumor response (complete or partial response).

Two large randomized, controlled, multinational (predominantly European) trials were conducted in patients with advanced breast cancer who had progressed despite antiestrogen therapy. Patients were randomized to Femara 0.5 mg daily, Femara 2.5 mg daily, or a comparator (megestrol acetate 160 mg daily in one study; and aminoglutethimide 250 mg b.i.d. with corticosteroid supplementation in the other study). In each study over 60% of the patients had received therapeutic antiestrogens, and about one-fifth of these patients had an objective response. The megestrol acetate controlled study was double-blind; the other study was open label. Selected baseline characteristics for each study are shown in Table 15.

Table 15: Selected Study Population Demographics

Parameter megestrol acetate study aminoglutethimide study
No. of Participants 552 557
Receptor Status
  ER/PR Positive 57% 56%
  ER/PR Unknown 43% 44%
Previous Therapy
  Adjuvant Only 33% 38%
  Therapeutic +/- Adj. 66% 62%
Sites of Disease
  Soft Tissue 56% 50%
  Bone 50% 55%
  Viscera 40% 44%

Confirmed objective tumor response (complete response plus partial response) was the primary endpoint of the trials. Responses were measured according to the Union Internationale Contre le Cancer (UICC) criteria and verified by independent, blinded review. All responses were confirmed by a second evaluation 4 to 12 weeks after the documentation of the initial response.

Table 16 shows the results for the first trial, with a minimum follow-up of 15 months, that compared Femara 0.5 mg, Femara 2.5 mg, and megestrol acetate 160 mg daily. (All analyses are unadjusted.)

Table 16: Megestrol Acetate Study Results

  Femara 0.5 mg
N=188
Femara 2.5 mg
N=174
megestrol acetate
N=190
Objective Response (CR + PR) 22 (11.7%) 41 (23.6%) 31 (16.3%)
Median Duration of Response 552 days (Not reached) 561 days
Median Time to Progression 154 days 170 days 168 days
Median Survival 633 days 730 days 659 days
Odds Ratio for Response Femara 2.5: Femara 0.5=2.33 (95% CI: 1.32, 4.17); P=0.004* Femara 2.5: megestrol=1.58 (95% CI: 0.94, 2.66); P=0.08*
Relative Risk of Progression Femara 2.5: Femara 0.5=0.81 (95% CI: 0.63, 1.03); P=0.09* Femara 2.5: megestrol=0.77 (95% CI: 0.60, 0.98); P=0.03*
* two-sided P-value

The Kaplan-Meier curves for progression for the megestrol acetate study are shown in Figure 4.

Figure 4 : Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study)

Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study) - Illustration

The results for the study comparing Femara to aminoglutethimide, with a minimum follow-up of 9 months, are shown in Table 17. (Unadjusted analyses are used.)

Table 17: Aminoglutethimide Study Results

  Femara 0.5 mg
N=193
Femara 2.5 mg
N=185
aminoglutethimide
N=179
Objective Response (CR + PR) 34 (17.6%) 34 (18.4%) 22 (12.3%)
Median Duration of Response 619 days 706 days 450 days
Median Time to Progression 103 days 123 days 112 days
Median Survival 636 days 792 days 592 days
Odds Ratio for Response Femara 2.5: Femara 0.5=1.05 (95% CI: 0.62, 1.79); P=0.85* Femara 2.5: aminoglutethimide= 1.61 (95% CI: 0.90, 2.87); P=0.11*
Relative Risk of Progression Femara 2.5: Femara 0.5=0.86 (95% CI: 0.68, 1.11); P=0.25* Femara 2.5: aminoglutethimide=0.74 (95% CI: 0.57, 0.94); P=0.02*
*2-sided P-value

The Kaplan-Meier curves for progression for the aminoglutethimide study is shown in Figure 5.

Figure 5 : Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study)

Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study) - Illustration

Last reviewed on RxList: 1/27/2014
This monograph has been modified to include the generic and brand name in many instances.

A A A

Femara - User Reviews

Femara User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Femara sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Breast Cancer

Find support and advances in treatment.