Recommended Topic Related To:

Aromasin

"Nov. 21, 2012 -- Women over age 40 are often urged to get yearly mammograms with the promise that early detection is their best hope for beating breast cancer.

But a new study published in The New England Journal of Medicine su"...

Aromasin

Aromasin

CLINICAL PHARMACOLOGY

Mechanism of Action

Breast cancer cell growth may be estrogen-dependent. Aromatase is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer.

Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme, causing its inactivation, an effect also known as “suicide inhibition.” Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.

Pharmacodynamics

Effect on Estrogens

Multiple doses of exemestane ranging from 0.5 to 600 mg/day were administered to postmenopausal women with advanced breast cancer. Plasma estrogen (estradiol, estrone, and estrone sulfate) suppression was seen starting at a 5-mg daily dose of exemestane, with a maximum suppression of at least 85% to 95% achieved at a 25-mg dose. Exemestane 25 mg daily reduced whole body aromatization (as measured by injecting radiolabeled androstenedione) by 98% in postmenopausal women with breast cancer. After a single dose of exemestane 25 mg, the maximal suppression of circulating estrogens occurred 2 to 3 days after dosing and persisted for 4 to 5 days.

Effect on Corticosteroids

In multiple-dose trials of doses up to 200 mg daily, exemestane selectivity was assessed by examining its effect on adrenal steroids. Exemestane did not affect cortisol or aldosterone secretion at baseline or in response to ACTH at any dose. Thus, no glucocorticoid or mineralocorticoid replacement therapy is necessary with exemestane treatment.

Other Endocrine Effects

Exemestane does not bind significantly to steroidal receptors, except for a slight affinity for the androgen receptor (0.28% relative to dihydrotestosterone). The binding affinity of its 17-dihydrometabolite for the androgen receptor, however, is 100 times that of the parent compound. Daily doses of exemestane up to 25 mg had no significant effect on circulating levels of androstenedione, dehydroepiandrosterone sulfate, or 17-hydroxyprogesterone, and were associated with small decreases in circulating levels of testosterone. Increases in testosterone and androstenedione levels have been observed at daily doses of 200 mg or more. A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with daily exemestane doses of 2.5 mg or higher. Slight, nondose-dependent increases in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels have been observed even at low doses as a consequence of feedback at the pituitary level. Exemestane 25 mg daily had no significant effect on thyroid function [free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH)].

Coagulation and Lipid Effects

In study 027 of postmenopausal women with early breast cancer treated with exemestane (N=73) or placebo (N=73), there was no change in the coagulation parameters activated partial thromboplastin time [APTT], prothrombin time [PT], and fibrinogen. Plasma HDL cholesterol was decreased 6–9% in exemestane treated patients; total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-A1, apolipoprotein-B, and lipoprotein-a were unchanged. An 18% increase in homocysteine levels was also observed in exemestane treated patients compared with a 12% increase seen with placebo.

Pharmacokinetics

Following oral administration to healthy postmenopausal women, exemestane is rapidly absorbed. After maximum plasma concentration is reached, levels decline polyexponentially with a mean terminal half-life of about 24 hours. Exemestane is extensively distributed and is cleared from the systemic circulation primarily by metabolism. The pharmacokinetics of exemestane are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50 mg). Following repeated daily doses of exemestane 25 mg, plasma concentrations of unchanged drug are similar to levels measured after a single dose.

Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following single or repeated doses have been compared with those in healthy, postmenopausal women. Exemestane appeared to be more rapidly absorbed in the women with breast cancer than in the healthy women, with a mean -tmax of 1.2 hours in the women with breast cancer and 2.9 hours in the healthy women. After repeated dosing, the average oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 ng·h/mL) were about twice those in healthy women (41.4 ng·h/mL).

Absorption

Following oral administration of radiolabeled exemestane, at least 42% of radioactivity was absorbed from the gastrointestinal tract. Exemestane plasma levels increased by approximately 40% after a high-fat breakfast.

Distribution

Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and α11-acid glycoprotein both contribute to the binding. The distribution of exemestane and its metabolites into blood cells is negligible.

Metabolism/Elimination

Following administration of radiolabeled exemestane to healthy postmenopausal women, the cumulative amounts of radioactivity excreted in urine and feces were similar (42 ± 3% in urine and 42 ± 6% in feces over a 1-week collection period). The amount of drug excreted unchanged in urine was less than 1% of the dose. Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity (see). Studies using human liver preparations indicate that cytochrome P 450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane.

Exemestane is metabolized by cytochrome P 450 3A4 (CYP 3A4) and aldoketoreductases. It does not inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1, and 3A4.

Special Populations

Geriatric: Healthy postmenopausal women aged 43 to 68 years were studied in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range.

Gender: The pharmacokinetics of exemestane following administration of a single, 25-mg tablet to fasted healthy males (mean age 32 years) were similar to the pharmacokinetics of exemestane in fasted healthy postmenopausal women (mean age 55 years).

Race: The influence of race on exemestane pharmacokinetics has not been evaluated.

Hepatic Insufficiency: The pharmacokinetics of exemestane have been investigated in subjects with moderate or severe hepatic insufficiency (Childs-Pugh B or C). Following a single 25-mg oral dose, the AUC of exemestane was approximately 3 times higher than that observed in healthy volunteers.

Renal Insufficiency: The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with moderate or severe renal insufficiency (creatinine clearance < 35 mL/min/1.73 m²) compared with the AUC in healthy volunteers.

Pediatric: The pharmacokinetics of exemestane have not been studied in pediatric patients.

Clinical Studies

Adjuvant Treatment in Early Breast Cancer

The Intergroup Exemestane Study 031 (IES) was a randomized, double-blind, multicenter, multinational study comparing exemestane (25 mg/day) vs. tamoxifen (20 or 30 mg/day) in postmenopausal women with early breast cancer. Patients who remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomized to receive an additional 3 or 2 years of AROMASIN or tamoxifen to complete a total of 5 years of hormonal therapy.

The primary objective of the study was to determine whether, in terms of disease-free survival, it was more effective to switch to AROMASIN rather than continuing tamoxifen therapy for the remainder of five years. Disease-free survival was defined as the time from randomization to time of local or distant recurrence of breast cancer, contralateral invasive breast cancer, or death from any cause.

The secondary objectives were to compare the two regimens in terms of overall survival and long-term tolerability. Time to contralateral invasive breast cancer and distant recurrence-free survival were also evaluated.

A total of 4724 patients in the intent-to-treat (ITT) analysis were randomized to AROMASIN (exemestane tablets) 25 mg once daily (N = 2352) or to continue to receive tamoxifen once daily at the same dose received before randomization (N = 2372). Demographics and baseline tumor characteristics are presented in Table 5. Prior breast cancer therapy is summarized in Table 6.

Table 5: Demographic and Baseline Tumor Characteristics from the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)

Parameter Exemestane
(N = 2352)
Tamoxifen
(N = 2372)
Age (years):
Median age (range) 63.0 (38.0 - 96.0) 63.0 (31.0 - 90.0)
Race, n (%): Caucasian 2315(98.4) 2333(98.4)
Hispanic 13(0.6) 13(0.5)
Asian 10(0.4) 9(0.4)
Black 7(0.3) 10(0.4)
Other/not reported 7(0.3) 7(0.3)
Nodal status, n (%):
Negative 1217(51.7) 1228(51.8)
Positive 1051(44.7) 1044(44.0)
  1-3 Positive nodes 721(30.7) 708(29.8)
  4-9 Positive nodes 239(10.2) 244(10.3)
   > 9 Positive nodes 88(3.7) 86(3.6)
  Not reported 3(0.1) 6(0.3)
Unknown or missing 84(3.6) 100(4.2)
Histologic type, n (%):
Infiltrating ductal 1777(75.6) 1830(77.2)
Infiltrating lobular 341(14.5) 321(13.5)
Other 231(9.8) 213(9.0)
Unknown or missing 3(0.1) 8(0.3)
Receptor status*, n (%):
ER and PgR Positive 1331(56.6) 1319(55.6)
ER Positive and PgR Negative/Unknown 677(28.8) 692(29.2)
ER Unknown and PgR Positive**/Unknown 288(12.2) 291(12.3)
ER Negative and PgR Positive 6(0.3) 7(0.3)
ER Negative and PgR Negative/Unknown (none positive) 48(2.0) 58(2.4)
Missing 2(0.1) 5(0.2)
Tumor Size, n (%):
< 0.5 cm 58(2.5) 46(1.9)
> 0.5 - 1.0 cm 315(13.4) 302(12.7)
> 1.0 - 2 cm 1031(43.8) 1033(43.5)
> 2.0 - 5.0 cm 833(35.4) 883(37.2)
> 5.0 cm 62(2.6) 59(2.5)
Not reported 53(2.3) 49(2.1)
Tumor Grade, n (%):
G1 397(16.9) 393(16.6)
G2 977(41.5) 1007(42.5)
G3 454(19.3) 428(18.0)
G4 23(1.0) 19(0.8)
Unknown/Not Assessed/Not reported 501(21.3) 525(22.1)
* Results for receptor status include the results of the post-randomization testing of specimens from subjects for whom receptor status was unknown at randomization.
**Only one subject in the exemestane group had unknown ER status and positive PgR status.

Table 6: Prior Breast Cancer Therapy of Patients in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)

Parameter Exemestane
(N = 2352)
Tamoxifen
(N = 2372)
Type of surgery, n (%):
Mastectomy 1232 (52.4) 1242(52.4)
Breast-conserving 1116 (47.4) 1123(47.3)
Unknown or missing 4 (0.2) 7(0.3)
Radiotherapy to the breast, n (%):
Yes 1524 (64.8) 1523(64.2)
No 824 (35.5) 843(35.5)
Not reported 4 (0.2) 6(0.3)
Prior therapy, n (%):
Chemotherapy 774 (32.9) 769(32.4)
Hormone replacement therapy 567 (24.1) 561(23.7)
Bisphosphonates 43 (1.8) 34(1.4)
Duration of tamoxifen therapy at randomization (months):
Median (range) 28.5 (15.8 - 52.2) 28.4 (15.6 - 63.0)
Tamoxifen dose, n (%):
20 mg 2270 (96.5) 2287(96.4)
30 mg* 78 (3.3) 75(3.2)
Not reported 4 (0.2) 10(0.4)
*The 30 mg dose was used only in Denmark, where this dose was the standard of care.

After a median duration of therapy of 27 months and with a median follow-up of 34.5 months, 520 events were reported, 213 in the AROMASIN group and 307 in the tamoxifen group (Table 7).

Table 7: Primary Endpoint Events (ITT Population)

Event First Events N (%)
Exemestane
(N = 2352)
Tamoxifen
(N = 2372)
Loco-regional recurrence 34 (1.45) 45 (1.90)
Distant recurrence 126 (5.36) 183 (7.72)
Second primary -contralateral breast cancer 7 (0.30) 25 (1.05)
Death - breast cancer 1 (0.04) 6 (0.25)
Death - other reason 41 (1.74) 43 (1.81)
Death - missing/unknown 3 (0.13) 5 (0.21)
Ipsilateral breast cancer 1 (0.04) 0
Total number of events 213 (9.06) 307 (12.94)

Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.69, 95% CI: 0.58, 0.82, P = 0.00003, Table 8, Figure 1] in the AROMASIN arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 85% of the trial patients, disease-free survival was also statistically significantly improved (HR = 0.65, 95% CI: 0.53, 0.79, P = 0.00001) in the AROMASIN arm compared to the tamoxifen arm. Consistent results were observed in the subgroups of patients with node negative or positive disease, and patients who had or had not received prior chemotherapy. Overall survival was not significantly different in the two groups, with 116 deaths occurring in the AROMASIN group and 137 in the tamoxifen group.

Table 8: Efficacy Results from the IES Study in Postmenopausal Women with Early Breast Cancer

ITT Population Hazard Ratio (95% CI) p-value (log-rank test)
Disease-free survival 0.69 (0.58-0.82) 0.00003
Time to contralateral breast cancer 0.32 (0.15-0.72) 0.00340
Distant recurrence-free survival 0.74 (0.62-0.90) 0.00207
Overall survival 0.86 (0.67-1.10) 0.22962
ER and/or PgR positive
Disease-free survival 0.65 (0.53-0.79) 0.00001
Time to contralateral breast cancer 0.22 (0.08-0.57) 0.00069
Distant recurrence-free survival 0.73 (0.59-0.90) 0.00367
Overall survival 0.88 (0.67-1.17) 0.37460

Figure 1: Disease-Free Survival in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)

Disease-Free Survival in the IES Study - Illustration

Treatment of Advanced Breast Cancer

Exemestane 25 mg administered once daily was evaluated in a randomized double-blind, multicenter, multinational comparative study and in two multicenter single-arm studies of postmenopausal women with advanced breast cancer who had disease progression after treatment with tamoxifen for metastatic disease or as adjuvant therapy. Some patients also have received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease.

The primary purpose of the three studies was evaluation of objective response rate (complete response [CR] and partial response [PR]). Time to tumor progression and overall survival were also assessed in the comparative trial. Response rates were assessed based on World Health Organization (WHO) criteria, and in the comparative study, were submitted to an external review committee that was blinded to patient treatment. In the comparative study, 769 patients were randomized to receive AROMASIN (exemestane tablets) 25 mg once daily (N = 366) or megestrol acetate 40 mg four times daily (N = 403). Demographics and baseline characteristics are presented in Table 9.

Table 9: Demographics and Baseline Characteristics from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy

Parameter AROMASIN
(N = 366)
Megestrol Acetate
(N = 403)
Median Age (range) 65 (35-89) 65 (30-91)
ECOG Performance Status
  0 167 (46%) 187 (46%)
  1   162 (44%) 172 (43%)
  2 34 (9%) 42 (10%)
Receptor Status
  ER and/or PgR + 246 (67%) 274 (68%)
  ER and PgR unknown 116 (32%) 128 (32%)
    Responders to prior tamoxifen 68 (19%) 85 (21%)
    NE for response to prior tamoxifen 46 (13%) 41 (10%)
Site of Metastasis
  Visceral ± other sites 207 (57%) 239 (59%)
  Bone only 61 (17%) 73 (18%)
  Soft tissue only 54 (15%) 51 (13%)
  Bone & soft tissue 43 (12%) 38 (9%)
Measurable Disease 287 (78%) 314 (78%)
Prior Tamoxifen Therapy
  Adjuvant or Neoadjuvant 145 (40%) 152 (38%)
  Advanced Disease, Outcome
    CR, PR, or SD ≥ 6 months 179 (49%) 210 (52%)
    SD < 6 months, PD or NE 42 (12%) 41 (10%)
Prior Chemotherapy
  For advanced disease ± adjuvant 58 (16%) 67 (17%)
  Adjuvant only 104 (28%) 108 (27%)
  No chemotherapy 203 (56%) 226 (56%)

The efficacy results from the comparative study are shown in Table 10. The objective response rates observed in the two treatment arms showed that AROMASIN was not different from megestrol acetate. Response rates for AROMASIN from the two single-arm trials were 23.4% and 28.1%.

Table 10: Efficacy Results from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy

Response Characteristics AROMASIN
(N=366)
Megestrol Acetate
(N=403)
Objective Response Rate = CR + PR (%) 15.0 12.4
  Difference in Response Rate (AR-MA) 2.6
  95% C.I. 7.5, -2.3
CR (%) 2.2 1.2
PR (%) 12.8 11.2
  SD ≥ 24 Weeks (%) 21.3 21.1
Median Duration of Response (weeks) 76.1 71.0
Median TTP (weeks) 20.3 16.6
     Hazard Ratio (AR-MA) 0.84
Abbreviations: CR = complete response, PR = partial response, SD = stable disease (no change), TTP = time to tumor progression, C.I. = confidence interval, MA = megestrol acetate, AR = AROMASIN

There were too few deaths occurring across treatment groups to draw conclusions on overall survival differences. The Kaplan-Meier curve for time to tumor progression in the comparative study is shown in Figure 2.

Figure 2: Time to Tumor Progression in the Comparative Study of Postmenopausal Women With Advanced Breast Cancer Whose Disease Had Progressed After Tamoxifen Therapy

Time to Tumor Progression in the Comparative Study - Illustration

Last reviewed on RxList: 3/5/2013
This monograph has been modified to include the generic and brand name in many instances.

A A A

Aromasin - User Reviews

Aromasin 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 Aromasin 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.

advertisement
advertisement
Use Pill Finder Find it Now See Interactions

Pill Identifier on RxList

  • quick, easy,
    pill identification

Find a Local Pharmacy

  • including 24 hour, pharmacies

Interaction Checker

  • Check potential drug interactions
Search the Medical Dictionary for Health Definitions & Medical Abbreviations