Arimidex

Pharmacotherapeutic group: Aromatase inhibitors, ATC code: L02B G03 Mechanism of action and pharmacodynamic effects Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor.‍‍‍‍‍‍​​​‍​​​​​​ In postmenopausal women, estradiol is produced primarily from the conversion of androstenedione to estrone through the aromatase enzyme complex in peripheral tissues. Estrone is subsequently converted to estradiol. Reducing circulating estradiol levels has been shown to produce a beneficial effect in women with breast cancer. In postmenopausal women, anastrozole at a daily dose of 1 mg produced estradiol suppression of greater than 80% using a highly sensitive assay. Anastrozole does not possess any progestogenic, androgenic, or estrogenic activity. Daily doses of anastrozole up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard adrenocorticotrophic hormone (ACTH) challenge testing. Corticoid supplements are therefore not needed. Clinical efficacy and safety Advanced breast cancer First-line therapy in postmenopausal women with advanced breast cancer Two double-blind, controlled clinical studies of similar design (Study 1033IL/0030 and Study 1033IL/0027) were conducted to assess the efficacy of anastrozole 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 1,021 patients were randomized to receive 1 mg of anastrozole once daily or 20 mg of tamoxifen once daily. The primary endpoints for both trials were time to tumour progression, objective tumour response rate, and safety. For the primary endpoints, Study 1033IL/0030 showed that anastrozole had a statistically significant advantage over tamoxifen for time to tumour progression (Hazard ratio (HR) 1.42, 95% Confidence Interval (CI) [1.11, 1.82], Median time to progression 11.1 and 5.6 months for anastrozole and tamoxifen respectively, p=0.006); objective tumour response rates were similar for anastrozole and tamoxifen. Study 1033IL/0027 showed that anastrozole and tamoxifen had similar objective tumour response rates and time to tumour progression. 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. Second-line therapy in postmenopausal women with advanced breast cancer Anastrozole was studied in two controlled clinical trials (Study 0004 and Study 0005) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. A total of 764 patients were randomized to receive either a single daily dose of 1 mg or 10 mg of anastrozole or megestrol acetate 40 mg four times a day. Time to progression and objective response rates were the primary efficacy variables. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also calculated. In both studies there were no significant differences between treatment arms with respect to any of the efficacy parameters. Adjuvant treatment of early invasive breast cancer for hormone receptor-positive patients In a large phase III study conducted in 9,366 postmenopausal women with operable breast cancer treated for 5 years (see below), anastrozole was shown to be statistically superior to tamoxifen in disease-free survival. A greater magnitude of benefit was observed for disease-free survival in favour of anastrozole versus tamoxifen for the prospectively defined hormone receptor-positive population. Table 4 ATAC endpoint summary: 5-year treatment completion analysis Efficacy endpoints Number of events (frequency) Intention-to-treat population Hormone receptor-positive tumour status Anastrozole (N=3,125) Tamoxifen (N=3,116) Anastrozole (N=2,618) Tamoxifen (N=2,598) Disease-free survival a 575 (18.4) 651 (20.9) 424 (16.2) 497 (19.1) Hazard ratio 0.87 0.83 2-sided 95% CI 0.78 to 0.97 0.73 to 0.94 p-value 0.0127 0.0049 Distant disease-free survival b 500 (16.0) 530 (17.0) 370 (14.1) 394 (15.2) Hazard ratio 0.94 0.93 2-sided 95% CI 0.83 to 1.06 0.80 to 1.07 p-value 0.2850 0.2838 Time to recurrence c 402 (12.9) 498 (16.0) 282 (10.8) 370 (14.2) Hazard ratio 0.79 0.74 2-sided 95% CI 0.70 to 0.90 0.64 to 0.87 p-value 0.0005 0.0002 Time to distant recurrence d 324 (10.4) 375 (12.0) 226 (8.6) 265 (10.2) Hazard ratio 0.86 0.84 2-sided 95% CI 0.74 to 0.99 0.70 to 1.00 p-value 0.0427 0.0559 Contralateral breast primary 35 (1.1) 59 (1.9) 26 (1.0) 54 (2.1) Odds ratio 0.59 0.47 2-sided 95% CI 0.39 to 0.89 0.30 to 0.76 p-value 0.0131 0.0018 Overall survival e 411 (13.2) 420 (13.5) 296 (11.3) 301 (11.6) Hazard ratio 0.97 0.97 2-sided 95% CI 0.85 to 1.12 0.83 to 1.14 p-value 0.7142 0.7339 a Disease-free survival includes all recurrence events and is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death (for any reason). b Distant disease-free survival is defined as the first occurrence of distant recurrence or death (for any reason). c Time to recurrence is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death due to breast cancer. d Time to distant recurrence is defined as the first occurrence of distant recurrence or death due to breast cancer. e Number (%) of patients who had died. The combination of anastrozole and tamoxifen did not demonstrate any efficacy benefits in comparison with tamoxifen in all patients as well as in the hormone receptor-positive population. This treatment arm was discontinued from the study. With an updated follow-up at a median of 10 years, long-term comparison of the treatment effects of anastrozole relative to tamoxifen were shown to be consistent with previous analyses. Adjuvant treatment of early invasive breast cancer for hormone receptor-positive patients being treated with adjuvant tamoxifen In a phase III trial (Austrian Breast and Colorectal Cancer Study Group [ABCSG] 8) conducted in 2,579 postmenopausal women with hormone receptor-positive early breast cancer who had received surgery with or without radiotherapy and no chemotherapy (see below), switching to anastrozole after 2 years adjuvant treatment with tamoxifen was statistically superior in disease-free survival when compared to remaining on tamoxifen, after a median follow-up of 24 months. Table 5 ABCSG 8 trial endpoint and results summary Efficacy endpoints Number of events (frequency) Anastrozole (N=1,297) Tamoxifen (N=1,282) Disease-free survival 65 (5.0) 93 (7.3) Hazard ratio 0.67 2-sided 95% CI 0.49 to 0.92 p-value 0.014 Time to any recurrence 36 (2.8) 66 (5.1) Hazard ratio 0.53 2-sided 95% CI 0.35 to 0.79 p-value 0.002 Time to distant recurrence 22 (1.7) 41 (3.2) Hazard ratio 0.52 2-sided 95% CI 0.31 to 0.88 p-value 0.015 New contralateral breast cancer 7 (0.5) 15 (1.2) Odds ratio 0.46 2-sided 95% CI 0.19 to 1.13 p-value 0.090 Overall survival 43 (3.3) 45 (3.5) Hazard ratio 0.96 2-sided 95% CI 0.63 to 1.46 p-value 0.840 Two further similar trials (GABG/ARNO 95 and ITA), in one of which patients had received surgery and chemotherapy, as well as a combined analysis of ABCSG 8 and GABG/ARNO 95, supported these results. The anastrozole safety profile in these 3 studies was consistent with the known safety profile established in postmenopausal women with hormone receptor-positive early breast cancer. Primary reduction of breast cancer risk Anastrozole reduces, but does not eliminate the risk of breast cancer. The International Breast Cancer Intervention Study, IBIS-II, was a large international, multicentre, double-blind, randomised, placebo-controlled trial which investigated the efficacy and safety of chemoprevention with daily anastrozole over 5 years in postmenopausal women aged 40–70 years who were at an increased risk of breast cancer. The inclusion criteria defined an increased risk of breast cancer based on various family and personal history criteria that corresponded to a relative risk compared to the general population. Key exclusion criteria included: premenopausal status; any previous diagnosis of breast cancer (except for ER+ ductal carcinoma in situ diagnosed less than 6 months previously and treated by mastectomy); any invasive cancer in the previous 5 years (except for non-melanoma skin cancer or cervical cancer); present or previous use of selective oestrogen receptor modulators for more than 6 months (unless as part of IBIS-I and treatment was completed at least 5 years before study entry); intention to continue hormone replacement therapy; prophylactic mastectomy; evidence of severe osteoporosis (T score <–4.0 or more than two vertebral fractures). 19,399 women-years of follow-up were available (9727 in the anastrozole group and 9672 in the placebo group), with a median follow-up period of 5.0 years (IQR 3.0–7.1). At this time point, 51% (979 women) in the anastrozole group and 50% (975) in the placebo group had completed the full 5 years of treatment. The primary study endpoint was histologically confirmed breast cancer (defined as invasive cancer or non-invasive ductal carcinoma in situ), which demonstrated significantly fewer breast cancer cases in the anastrozole group (40, 2%) in comparison to the placebo group (85, 4%; HR 0.47, 95% CI 0.32–0.68, p<0.0001) at this time point. Additional long-term follow-up (12 years) was undertaken in the post-treatment period. This analysis included 3864 women (1920 assigned to the anastrozole group and 1944 were assigned to placebo group). Mean follow-up for this analysis was 131 months, which consisted of a total of 41,295 women-years of follow-up (20,803 women-years for anastrozole and 20,491 women-years for placebo), of this 22,367 women-years came after the 5-year treatment period. For the primary study endpoint, there was a significant reduction in breast cancer cases in the anastrozole group (85, 4.4%) compared to placebo (165, 8.5%, p<0.0001). This corresponds to a 49% reduction for all breast cancer cases with anastrozole (HR 0.51, 95% CI 0.39–0.66, p<0.0001). A Kaplan-Meier survival curve (figure 1) was constructed which allowed the calculation of an estimated risk of breast cancer during the 12-year follow-up period. These figures were calculated to be 5.3% in the anastrozole group versus 8.8% in placebo group. Based on these results, anastrozole had a number needed to treat of 29 in order to prevent one breast cancer case (over 12 years). Figure 1: risk from start of treatment (0 years) and risk after the end of active treatment (5 years) to show comparison of risk reduction over 0–5 years period and post–5 years period. These results show that the reduction in breast cancer incidence with anastrozole over placebo was greatest during the 5 years of treatment, with a smaller (but still significant) reduction seen over the subsequent follow-up period. Bone mineral density (BMD) In the phase III/IV study (Study of Anastrozole with the Bisphosphonate Risedronate [SABRE]), 234 postmenopausal women with hormone receptor-positive early breast cancer scheduled for treatment with anastrozole 1 mg/day were stratified to low, moderate and high risk groups according to their existing risk of fragility fracture. The primary efficacy parameter was the analysis of lumbar spine bone mass density using DEXA scanning. All patients received treatment with vitamin D and calcium. Patients in the low risk group received anastrozole alone (N=42), those in the moderate group were randomised to anastrozole plus risedronate 35 mg once a week (N=77) or anastrozole plus placebo (N=77) and those in the high risk group received anastrozole plus risedronate 35 mg once a week (N=38). The primary endpoint was change from baseline in lumbar spine bone mass density at 12 months. The 12-month main analysis has shown that patients already at moderate to high risk of fragility fracture showed no decrease in their bone mass density (assessed by lumbar spine bone mineral density using DEXA scanning) when managed by using anastrozole 1 mg/day in combination with risedronate 35 mg once a week. In addition, a decrease in BMD which was not statistically significant was seen in the low risk group treated with anastrozole 1 mg/day alone. These findings were mirrored in the secondary efficacy variable of change from baseline in total hip BMD at 12 months. This study provides evidence that the use of bisphosphonates could be considered in the management of possible bone mineral loss in postmenopausal women with early breast cancer scheduled to be treated with anastrozole. IBIS-II Bone Health Study A total of 1410 women were enrolled from the main IBIS-II study into three stratified groups depending on baseline T score: Stratum I, women with healthy T score (at least –1·0); Stratum II, women who were osteopenic (T score at least –2·5 but less than –1·0); and Stratum III, osteoporotic women with a T score of less than –2·5 but greater than –4·0 or those with one to two low trauma fragility fractures (as assessed by spinal radiographs from up to 2 years before randomisation). The primary objective of the bone substudy was to compare the effect of risedronate versus placebo on bone density in women taking anastrozole (Stratum II). Within Stratum II, patients receiving anastrozole showed a linear bone mineral density loss at both the lumber spine and hip, that was significantly reduced by co-administration of risedronate. These conclusions were strengthened through analysis of patients in the other strata. Paediatric population Anastrozole is not indicated for use in children and adolescents. Efficacy has not been established in the paediatric populations studied (see below). The number of children treated was too limited to draw any reliable conclusions on safety. No data on the potential long-term effects of anastrozole treatment in children and adolescents are available (see section 5.3). The licensing authority has waived the obligation to submit the results of studies with anastrozole in one or several subsets of the paediatric population in short stature due to growth hormone deficiency (GHD), testotoxicosis, gynaecomastia, and McCune-Albright syndrome (see section 4.2). Short stature due to Growth Hormone Deficiency A randomised, double-blind, multi-centre study evaluated 52 pubertal boys (aged 11 to 16 years inclusive) with GHD treated for 12 to 36 months with anastrozole 1 mg/day or placebo in combination with growth hormone. Only 14 subjects on anastrozole completed 36 months. No statistically significant difference from placebo was observed for the growth related parameters of predicted adult height, height, height SDS (standard deviation score), and height velocity. Final height data were not available. While the number of children treated was too limited to draw any reliable conclusions on safety, there was an increased fracture rate and a trend towards reduced bone mineral density in the anastrozole arm compared to placebo. Testotoxicosis An open-label, non-comparative, multi-centre study evaluated 14 male patients (aged 2 to 9 years) with familial male-limited precocious puberty, also known as testotoxicosis, treated with combination of anastrozole and bicalutamide. The primary objective was to assess the efficacy and safety of this combination regimen over 12 months. Thirteen out of the 14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). There was no significant difference in growth rate after 12 months of treatment, relative to the growth rate during the 6 months prior to entering the study. Gynaecomastia studies Trial 0006 was a randomised, double-blind, multi-centre study of 82 pubertal boys (aged 11-18 years inclusive) with gynaecomastia of greater than 12 months duration treated with anastrozole 1 mg/day or placebo daily for up to 6 months. No significant difference in the number of patients who had a 50% or greater reduction in total breast volume after 6 months of treatment was observed between the anastrozole 1 mg treated group and the placebo group. Trial 0001 was an open-label, multiple-dose pharmacokinetic study of anastrozole 1 mg/day in 36 pubertal boys with gynaecomastia of less than 12 months duration. The secondary objectives were to evaluate the proportion of patients with reductions from baseline in the calculated volume of gynaecomastia of both breasts combined of at least 50% between day 1 and after 6 months of study treatment, and patient tolerability and safety. A decrease in 50% or more of total breast volume was seen in 56% (20/36) of the boys after 6 months. McCune-Albright Syndrome study Trial 0046 was an international, multi-centre, open-label exploratory trial of anastrozole in 28 girls (aged 2 to ≤10 years) with McCune-Albright Syndrome (MAS). The primary objective was to evaluate the safety and efficacy of anastrozole 1 mg/day in patients with MAS. The efficacy of study treatment was based on the proportion of patients fulfilling defined criteria relating to vaginal bleeding, bone age, and growth velocity. No statistically significant change in the frequency of vaginal bleeding days on treatment was observed. There were no clinically significant changes in Tanner staging, mean ovarian volume, or mean uterine volume. No statistically significant change in the rate of increase in bone age on treatment compared to the rate during baseline was observed. Growth rate (in cm/year) was significantly reduced (p<0.05) from pre-treatment through month 0 to month 12, and from pre-treatment to the second 6 months (month 7 to month 12).