Drugs 2009; 69 (7): 889-918

ADIS DRUG EVALUATION 0012-6667/09/0007-0889/$55.55/0

ª 2009 Adis Data Information BV. All rights reserved.

Exemestane
A Review of its Use in Postmenopausal Women with
Breast Cancer
Emma D. Deeks and Lesley J. Scott
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer
Health, Philadelphia, Pennsylvania, USA

Various sections of the manuscript reviewed by:

A.U. Buzdar, Department of Breast Medical Oncology, M. D. Anderson Cancer Center, University of Texas,
Houston, Texas, USA; P. Carlini, Department of Medical Oncology, Regina Elena National Cancer Institute,
Rome, Italy; S. Gonnelli, Department of Internal Medicine, University of Siena, Siena, Italy; P.E. Lønning,
Institute of Medicine, University of Bergen, and Department of Oncology, Haukeland University Hospital,
Bergen, Norway.

Data Selection
Sources: Medical literature published in any language since 1980 on ‘exemestane’, identified using MEDLINE and EMBASE,
supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the
reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the
company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘exemestane’ and (‘early breast cancer’ or ‘early-stage breast
cancer’ or ‘advanced breast cancer’). Searches were last updated 21 April 2009.
Selection: Studies in patients with breast cancer who received exemestane. Inclusion of studies was based mainly on the methods
section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant
pharmacodynamic and pharmacokinetic data are also included.
Index terms: Exemestane, aromatase inhibitors, breast cancer, postmenopausal, pharmacodynamics, pharmacokinetics, therapeutic
use, tolerability, pharmacoeconomics.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 890
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893
2. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893
3. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 896
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898
4.1 Early-Stage Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898
4.1.1 Adjuvant Treatment After 2–3 Years of Tamoxifen Treatment . . . . . . . . . . . . . . . . . . . . . . . . 899
4.1.2 Primary Adjuvant Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 901
4.2 Advanced Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 901
4.2.1 Disease Refractory to One or More Antiestrogen Therapies . . . . . . . . . . . . . . . . . . . . . . . . . 901
4.2.2 First-Line Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 904
5.1 General Tolerability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 904
5.1.1 Versus Tamoxifen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 905
5.1.2 Versus Other Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906
5.2 Osteoporosis and Bone Fractures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
6. Pharmacoeconomic Analyses in Early-Stage Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
890 Deeks & Scott

7. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910

8. Place of Exemestane in the Management of Breast Cancer in Postmenopausal Women . . . . . . . . . 910

Summary
Abstract Exemestane (Aromasin) is an orally active steroidal irreversible inactivator of
the aromatase enzyme indicated as an adjuvant treatment in postmenopausal
women with estrogen receptor-positive early-stage breast cancer following
2–3 years of adjuvant treatment with tamoxifen, and for the treatment of ad-
vanced breast cancer in postmenopausal women whose disease has progressed
following tamoxifen or other antiestrogen therapy.
Exemestane is effective for the treatment of postmenopausal women with
early-stage or advanced breast cancer. In early-stage disease, switching to ex-
emestane for 2–3 years after 2–3 years of adjuvant tamoxifen treatment was
more effective in prolonging disease-free survival than continuing tamoxifen
therapy, although it was not associated with an overall survival benefit, except
in those with estrogen receptor-positive or unknown receptor status disease
when nodal status, hormone replacement therapy (HRT) and chemotherapy
use were adjusted for. Moreover, preliminary data suggest that the efficacy
of exemestane is generally no different to that of tamoxifen in the primary
adjuvant treatment of early-stage breast cancer, although exemestane may
be better in prolonging the time to distant recurrence. In advanced disease,
exemestane showed equivalent efficacy to megestrol in patients with disease
refractory to tamoxifen and an efficacy not significantly different from that
of fulvestrant in those refractory to a nonsteroidal aromatase inhibitor. Avail-
able data, some of which are limited, suggest exemestane is also effective in
the first-line hormonal treatment of advanced breast cancer in postmenopausal
women. Exemestane is generally well tolerated, although the potential bone
fracture risk of the drug requires further investigation. Results from directly
comparative trials indicating the efficacy, tolerability and bone fracture risk
of exemestane relative to third-generation aromatase inhibitors and other
agents in both early-stage and advanced disease, as well as the optimal
sequence of endocrine therapies, are awaited with interest. In the mean-
time, switching to exemestane should be considered in postmenopausal
women who have received 2–3 years of adjuvant tamoxifen treatment for
early-stage breast cancer, and is an emerging treatment option for post-
menopausal women with advanced breast cancer refractory to one or more
antiestrogen therapies.
Pharmacological Exemestane acts by irreversibly binding to the aromatase active site, resulting in
Properties potent suppression of whole body aromatization and estrogen synthesis, without
any marked or clinically relevant effect on levels of other steroid hormones. The
drug may affect lipid levels and increase levels of homocysteine, but does not
appear to have long-term effects on coagulation parameters. A switch from ta-
moxifen to exemestane may also reverse the endometrial thickening associated
with tamoxifen. Exemestane is generally associated with a loss of bone mineral
density and increases in serum or urinary levels of markers of bone turnover in
postmenopausal women.

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (7)
Exemestane: A Review
Therapeutic Efficacy
ª 2009 Adis Data Information BV. All rights reserved.
891
The absorption of exemestane is rapid after oral administration, with
maximum plasma concentrations reached within 2 hours of a single 25 mg
dose. The drug is 90% plasma protein bound and is extensively distributed
into tissues. Exemestane undergoes extensive metabolism, primarily via cyto-
chrome P450 3A4, as well as via aldoketoreductases, to metabolites that are
inactive or have less activity than the parent drug. Exemestane is excreted
mainly via urine and faeces and has a mean terminal elimination half-life of
»24 hours.
Oral exemestane 25 mg/day for 2–3 years after 2–3 years of adjuvant tamoxi-
fen was generally more effective than 5 years of continuous adjuvant tamoxi-
fen in the treatment of postmenopausal women with early-stage estrogen
receptor-positive/unknown receptor status breast cancer in a large well de-
signed trial (IES). Switching from tamoxifen to exemestane was consistently
associated with a significantly lower risk of experiencing one of the events
(recurrence, contralateral breast cancer or death without recurrence) in the
primary combined endpoint of disease-free survival than continued tamoxifen
at median follow-ups of 30.6 and 55.7 months. The exemestane regimen was
also more effective with regard to other endpoints, including the risk of con-
tralateral breast cancer and breast cancer-free survival. There was generally no
overall survival benefit in switching to exemestane, except in patients with
estrogen receptor-positive or unknown receptor status disease at the median
55.7-month follow-up, when nodal status, HRT and chemotherapy use were
adjusted for.
Moreover, preliminary data from the large, randomized, open-label, phase III,
TEAM trial comparing exemestane with tamoxifen indicate that exemestane
25 mg/day is also effective in the primary adjuvant treatment of early-stage
breast cancer in postmenopausal women. Disease-free survival (primary
endpoint) did not significantly differ between exemestane and tamoxifen re-
cipients. There was also no difference between the treatments in terms of re-
lapse-free survival; however, exemestane was more effective in terms of the
risk of distant metastases.
Exemestane 25 mg/day has also demonstrated efficacy in the treatment of
postmenopausal women with advanced breast cancer refractory to one or
more antiestrogen therapies in two large, well designed, phase III studies. In
one of these studies, exemestane provided similar efficacy to megestrol in
terms of objective response rate (primary endpoint) in postmenopausal wo-
men with advanced breast cancer refractory to tamoxifen. Although there
was also no significant difference between the treatments in the median
duration of objective response or the rate of overall success, exemestane re-
cipients had a significantly longer median duration of overall success, time to
disease progression and time to treatment failure than megestrol recipients. In
the other trial, exemestane demonstrated efficacy not significantly different
from that of intramuscular fulvestrant in patients with advanced breast
cancer refractory to a nonsteroidal aromatase inhibitor, with no significant
between-group difference in the time to disease progression (primary end-
point) or other endpoints, including objective response rate, clinical benefit
rate or overall survival.
Data, some of which are limited, from randomized, open-label, phase II or III
studies comparing exemestane with anastrozole or tamoxifen, respectively, suggest
that exemestane is an effective first-line hormonal treatment in postmenopau-
sal women with advanced breast cancer. There were generally no differences
Drugs 2009; 69 (7)
892 Deeks & Scott

between exemestane and these agents in terms of efficacy, although a significantly

higher objective response rate was seen with exemestane than with tamoxifen in the
largest phase III study.
Tolerability Exemestane was generally well tolerated in postmenopausal women with early-
stage or advanced breast cancer, with adverse events generally being mild to
moderate in severity and of a similar nature irrespective of the stage of disease.
Overall, hot flashes were the most common adverse event considered to be drug-
related or of indeterminate cause experienced by exemestane recipients in active
comparator-controlled trials.
In the large IES, at a median 55.7-month follow-up, patients with early-stage
breast cancer switched to exemestane had significantly fewer serious gynaeco-
logical events, endometrial hyperplasia, uterine polyps/fibroids, venous throm-
bolytic events and muscle cramp than those who continued tamoxifen treatment.
In contrast, exemestane was associated with a significantly higher incidence of
musculoskeletal pain, arthralgia, diarrhoea, carpal tunnel syndrome, paraesthesia
and joint stiffness than tamoxifen. There were no between-group differences in
the incidences of the most common adverse events: menopausal symptoms (e.g.
hot flashes), hypertension and fatigue. Moreover, a switch to exemestane was
associated with a significantly lower incidence of abnormal endometrial thick-
ening than continued tamoxifen. Preliminary data from the TEAM study after
2.75 years’ treatment indicated that the tolerability profile of exemestane versus
tamoxifen in the primary adjuvant treatment of early-stage breast cancer was
generally consistent with the findings of the IES. The incidence of fractures did
not significantly differ between exemestane and tamoxifen recipients in the
TEAM trial or in an on-treatment analysis of the IES, although it was sig-
nificantly greater in exemestane than tamoxifen recipients in the IES when post-
treatment adverse events were included.
Exemestane also had a generally similar tolerability profile to that of ta-
moxifen when used as a first-line hormonal treatment in postmenopausal
women with advanced breast cancer, although it appeared to be more fa-
vourable than tamoxifen in terms of anaemia, thrombocytopenia and vaginal
discharge, and less favourable in terms of weight gain, arthralgias, hyperten-
sion and diarrhoea (all between-group differences in incidence ‡5%). Post-
menopausal women with advanced breast cancer who received exemestane
were less likely to experience dyspnoea or moderate to severe gains in body-
weight than those who received megestrol, although they were more likely to
experience hot flashes, nausea and vomiting. The tolerability profile of ex-
emestane was broadly similar to that of fulvestrant in postmenopausal women
with advanced breast cancer.
Pharmacoeconomic In modelled cost-utility analyses that incorporated data from the IES and direct
Analyses medical costs, switching to exemestane after 2–3 years of tamoxifen was generally
predicted to be cost effective with regard to the cost per quality-adjusted life-year
(QALY) gained relative to continuing tamoxifen treatment in postmenopausal
women with early-stage breast cancer in a number of countries over 10-year,
20-year and/or lifetime time horizons. Using data from trials that did not directly
compare the regimens, analyses in Canada and Belgium suggested that switching
from tamoxifen to exemestane was cost saving in terms of the cost per QALY
gained relative to primary adjuvant anastrozole or extended adjuvant therapy
with tamoxifen followed by letrozole in postmenopausal women with early-stage
breast cancer over a time horizon of 20 years.

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (7)
Exemestane: A Review
1. Introduction
Worldwide, breast cancer is the leading cause
of death from cancer among women, with more
than 464 000 women estimated to have died from
the disease in 2007.[1] Although the global in-
cidence of breast cancer is increasing, mortality
from the disease has stabilized or declined in
some countries in recent years as a result of early
detection and better treatments.[1]
Established risk factors for breast cancer in-
clude low parity, late age at first pregnancy,
obesity and high alcohol consumption.[2] The
mechanisms by which such risk factors relate to
breast cancer are unclear at present, although
may involve alterations in exposure to estrogens.
In postmenopausal women, production of estro-
gens occurs primarily via the aromatization of
androgens in the periphery in contrast to the
predominantly ovarian production seen in pre-
menopausal women.[3] Increased levels of estro-
gens have been associated with an increased risk
of developing breast cancer in postmenopausal
women.[2] Indeed, a large proportion of breast
cancers in postmenopausal women express es-
trogen receptors and are stimulated by estrogens
to proliferate.[4] Consequently, estrogen depriva-
tion has proven to be effective in the treatment of
breast cancer.[4,5]
Aromatase inactivators/inhibitors are now an
established alternative treatment option to tamoxi-
fen for use in postmenopausal women, reducing
estrogen production by inhibiting the activity of
aromatase, a key enzyme involved in the synthesis
of the majority of non-ovarian estrogen.[4,6]
Exemestane (Aromasin) is a third-generation
steroidal aromatase inactivator (often referred to
as an aromatase inhibitor) approved in the UK,[7]
US[8] and several other countries worldwide as an
adjuvant treatment in postmenopausal women
with estrogen receptor-positive early-stage breast
cancer following 2–3 years of adjuvant tamoxifen
treatment, as well as for the treatment of ad-
vanced breast cancer in postmenopausal women
whose disease has progressed following tamoxi-
fen or other antiestrogen therapy. This article
focuses on the clinical efficacy and tolerability
data relevant to the use of oral exemestane in the
ª 2009 Adis Data Information BV. All rights reserved.
893
treatment of breast cancer and discusses the key
pharmacological properties of the drug.
2. Pharmacodynamic Profile
The pharmacodynamic properties of exeme-
stane have been reviewed in detail previously.[9,10]
Therefore, this section provides an overview of
key pharmacodynamic data, focusing on more
recent data related to the approved dosage of
exemestane 25 mg/day (section 7). Further data
from some clinical trials[11-13] are discussed in
section 4. Some data are available only as
abstracts[14-19] and posters.[14,19]
Exemestane is an irreversible steroidal in-
activator of the aromatase enzyme.[7,8] Being
structurally related to the aromatase substrate
androstenedione,[7,8] exemestane competes with
the androgen for binding to the aromatase active
site.[8] Upon catalysis, an exemestane inter-
mediate is produced that binds irreversibly to the
aromatase active site, thus inactivating the en-
zyme.[8] In vitro data suggest that exemestane,
unlike the aromatase inhibitors anastrozole and
letrozole, may destabilize the aromatase protein,
leading to its degradation.[20]
Exemestane 25 mg/day for 6–8 weeks almost
completely suppressed (»98%) whole body aro-
matization in postmenopausal women with ad-
vanced breast cancer.[28] Consistent with this
finding, exemestane is associated with potent
suppression of estrogen levels (table I),[21,27,28]
with levels of circulating estrogens maximally
suppressed 2–3 days after a single exemestane
25-mg dose.[8,31]
In general, exemestane appears to be selective
in the suppression of aromatase, generally having
no marked affect on plasma levels of steroid
hormones other than estrogen (table I).[21,27,29,31]
However, studies have produced mixed results
with regard to the effect of exemestane 25 mg
on levels of sex hormone binding globulin
(SHBG) [table I],[27,29] the synthesis of which
is stimulated by estrogens and suppressed by
androgens. Nevertheless, dose-dependent suppres-
sion of plasma SHBG levels was seen with ex-
emestane 5–200 mg/day, possibly due to intrinsic
Drugs 2009; 69 (7)
894 Deeks & Scott

Table I. Overview of the general pharmacodynamic properties of exemestane (EXE). Results in postmenopausal women with early-
stage[19,21-23] (operable[24] or resected[21-23,25]), invasive[18] or advanced[13,26,27] (locally advanced[28,29] or metastatic[28-30]) breast cancer,
healthy postmenopausal women[31,32] (n = 10–340 evaluable) and animal models.[10] The effects of EXE on bone are discussed in table II.
Data in postmenopausal women relate to EXE 25 mg/day, unless otherwise noted; the EXE dosage was not specified in one study[18]
Effects on estrogen and other steroid hormones
EXE suppressed plasma[28] or serum[27] levels of estrone, estradiol and/or estrone sulfate from baseline by 50–95% after 6–8 wk[27,28]
and fl serum levels of the estrogens by 83–93% vs PL after 12–24 mo[21]
EXE suppressed estrone, estradiol and estrone sulfate levels from baseline by 80–92% vs 49–83% with MEG after 8–48 wk[13]
EXE had no marked or clinically relevant effect on plasma levels of cortisol, aldosterone,[29,31] 17-hydroxycorticosteroids[27]
(e.g. 17-hydroxyprogesterone[29,31]), DHEAS,[27,29,31] androstenedione or testosterone[21,29] at most dosages of 2.5–200 mg/day
FSH and LH levels were generally not markedly affected by EXE,[29,31] except in one study[27] where levels ›
Effects on SHBG
Dose-dependent suppression with EXE 5–200 mg/day, with fl vs baseline with dosages ‡25 mg/day[29]
Suppression was not statistically significant at dosages of EXE 2.5–25 mg/day in another study[27]
Antitumour effects
EXE induced regression of dimethylbenzanthracene-induced mammary tumours in rat models of postmenopausal breast cancer[10]
Effects on lipids and fat mass
EXE fl HDL-C and fl Apo A1 levels vs PL; no significant between-group difference in TC, LDL-C, TG, Apo B or lipoprotein A levels[21]
In some instances, EXE[30] or TAM-EXE[22,24,25] fl HDL-C levels vs baseline in some,[22,25] but not all,[24,30] studies, › cholesterol levels
vs baseline in some,[24] but not all,[25,30] studies, and › LDL-C[22,24,25] and fl TG[22,24,25,30] levels vs baseline
With TAM-EXE, where reported, LDL-C levels were significantly (p < 0.05) higher than[25] or › relative to[22] continued TAM at 12[22,25]
or 24[22] mo; TAM-EXE fl HDL-C and TG levels vs continued TAM at these timepoints in some,[22] but not all,[25] studies
Changes in lipid parameters did not significantly differ between TAM-EXE and observation alone in a 1-y study[24]
Vs TAM, primary adjuvant EXE › LDL-C levels at 3 and 6 mo, produced a lesser (p < 0.05) reduction in cholesterol at 12 mo and fl TG levels at
6 and 9 mo, but generally did not differ in terms of cholesterol or HDL-C levels[23]
EXE did not differ significantly from ANA or LET with regard to changes from baseline in TC, TG or non-HDL-C levels after 24 wk, although
fl HDL-C levels and › LDL : HDL ratio and Apo B : Apo A-I ratios vs ANA or LET[32]
TAM-EXE fl fat mass and › fat-free mass : fat mass ratio vs baseline and vs continued TAM at 12[22,25] and/or 24[22] mo
Effects on coagulation parameters
EXE had no significant affect on fibrinogen, prothrombin time or activated partial thromboplastin time vs PL over 24 mo[21]
EXE fl ATIII and › free protein S levels from baseline and fl protein C levels relative to ANA or LET in a 16-wk study[18]
Effects on homocysteine
EXE › plasma homocysteine levels vs PL over 24 mo (18% vs 12%)[21]
EXE had no marked affect on total plasma homocysteine levels in a 5-mo study[26]
Endometrial effects
TAM-EXE vs continued TAM fl both endometrial thickness (mean change from baseline -1.9 to -2.9 vs -0.1 to -0.6 mm) and uterine volume
(-15.3 to -22.6 vs -0.4 to -1.8 cm3) after 6–24 mo[19]
ANA = anastrozole; Apo = apolipoprotein; ATIII = antithrombin III; DHEAS = dehydroepiandrosterone sulfate; FSH = follicle-stimulating
hormone; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; LET = letrozole; LH = leutenizing
hormone; MEG = megestrol; PL = placebo; SHBG = sex hormone binding globulin; TAM = tamoxifen; TAM-EXE; a switch from TAM to
EXE (except in one study evaluating EXE after 5–7 y of TAM[24]); TC = total cholesterol; TG = triglyceride; › indicates significantly increased
(p < 0.05; p-value not reported in one study[18]); fl indicates significantly decreased (p < 0.05; p-values not reported in some instances in some
studies[18,29]).

androgenic activity of the exemestane metabolite
17-hydro-exemestane.[29]
Antitumour effects of the drug were initially
demonstrated in rat models of postmenopausal
breast cancer (table I).[10]
Data concerning the effect of exemestane
on lipid levels are variable (table I). Exemestane
was generally not associated with any detrimen-
tal effects on lipid parameters compared
with placebo in postmenopausal women with

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (7)
Exemestane: A Review
early-stage breast cancer during 24 months of
treatment.[21] Although high-density lipoprotein
(HDL) cholesterol and apolipoprotein A1 levels
were significantly reduced relative to placebo
during exemestane therapy,[21] levels returned
to near those at baseline 3 months after drug
discontinuation.[33]
The effects of exemestane on several lipid
parameters were generally not markedly different
from those of tamoxifen,[23,25] anastrozole[32]
or letrozole[32] in most studies. However, ex-
emestane had less favourable effects on certain
lipids, most notably low-density lipoprotein
(LDL) cholesterol, than tamoxifen in some in-
stances in postmenopausal women with breast
cancer who switched to exemestane after receiv-
ing adjuvant tamoxifen[22,25] or who received
exemestane in a primary adjuvant setting[23]
(table I). By contrast, exemestane had beneficial
effects on triglyceride levels versus tamoxifen in
two of these studies[22,23] (table I). In healthy
postmenopausal women, exemestane signifi-
cantly reduced HDL cholesterol levels and in-
creased both LDL : HDL and apolipoprotein
B : apolipoprotein A-I ratios relative to anastro-
zole or letrozole at 24 weeks (table I).[32]
Exemestane recipients had beneficial changes
in body fat mass[22,25] and, although the drug had
variable effects on coagulation parameters in a
short-term study,[18] it did not appear to have
long-term effects on such parameters[21] (table I).
However, relative to placebo, long-term treat-
ment with exemestane was associated with
significant, albeit modest, elevations in plasma
levels of total homocysteine,[21] a potential
marker of increased vascular disease risk[34,35]
(table I), although the between-group difference
was not significant 6–12 months after drug
discontinuation.[33] Shorter term, exemestane for
5 months had no marked affect on plasma levels
of total homocysteine (table I).[26]
With regard to endometrial effects, a switch
from tamoxifen to exemestane reduced endo-
metrial thickness and uterine volume relative to
continued tamoxifen in postmenopausal women
with early-stage breast cancer, according to data
from a substudy (n = 183)[19] of the IES (Inter-
group Exemestane Study)[11,12] in patients with
ª 2009 Adis Data Information BV. All rights reserved.
895
no prior uterine malignancy, such as endometrial
cancer, or undiagnosed vaginal bleeding in the
year prior to the trial (table I). The incidence of
abnormal endometrial thickness are discussed in
section 5.1.1.[19]
Exemestane, as with other aromatase in-
hibitors, is generally associated with a loss of
bone mineral density (BMD).[8] Indeed, the drug
significantly increased the mean annual rate of
BMD loss at some sites compared with placebo
after 2 years in postmenopausal women with
early-stage breast cancer (table II),[21] although
between-group differences were not significant
1 year after drug discontinuation.[33] A switch to
exemestane after 2–3 years of tamoxifen was also
associated with significant reductions from base-
line in BMD at several sites in postmenopausal
women with early-stage or resected breast cancer
(table II).[36,37] For example, in a substudy
(n = 206)[36] of the IES,[11,12] lumbar spine and
total hip BMD were significantly reduced
between 12 and 24 months after switching to
exemestane, although reductions from baseline
predominantly occurred in the first 6 months,
perhaps partly due to a loss of the bone protective
effects of tamoxifen. Switching to exemestane
significantly reduced lumbar spine and total hip
BMD relative to continuing tamoxifen ther-
apy,[36] with the changes in BMD at these sites
significantly (p < 0.005) differing by 2.8% and
1.4% between treatments at the end of the trial.[17]
However, there were no significant between-
group differences in BMD 2 years after treatment
cessation.[17]
The effect of exemestane on BMD has also
been compared with that of tamoxifen[14,15,38,40]
or anastrozole[14] in a primary adjuvant setting in
postmenopausal women with early-stage breast
cancer in substudies (n = 51–167 evaluable) of
larger clinical trials (some preliminary data
available only as abstracts and/or posters[14,15])
[table II]. Where statistical analyses were re-
ported, exemestane generally reduced spine and
hip BMD in comparison with tamoxifen after
6–24 months of treatment,[38,40] although no sig-
nificant difference in BMD was evident among
exemestane, tamoxifen or anastrozole recipients
after 12 months’ therapy in one study.[14]
Drugs 2009; 69 (7)
896 Deeks & Scott

Table II. Effects of exemestane (EXE) 25 mg/day on bone in postmenopausal women. Summary of results in studies in postmenopausal
women with early-stage,[14,15,21,33,36,38-40] resected[21,33,36,37] or invasive[16] breast cancer,[14-16,21,33,36-40] and in healthy postmenopausal
women[32] (n = 51–206 evaluable); the EXE dosage was not reported in one study[16]
Effects on BMD
EXE › mean annual rate of BMD loss vs PL at the femoral neck (2.72% vs 1.48%) but not the lumbar spine (2.17% vs 1.84%) after 2 y[21]

TAM-EXE fl BMD at the lumbar spine and total hip vs baseline after 6 mo (-2.7% and -1.4%) and from 12 to 24 mo (-1.0% and -0.8%)[36]

In another study,[37] TAM-EXE fl lumbar spine (-3%), total hip (-2.0%) and femoral neck (-1.9%) BMD vs baseline after 24 mo ( fl from 12
or 18 mo onwards); no significant changes in whole body BMD were observed

Where reported, lumbar spine, total hip and femoral neck BMD were fl with TAM-EXE vs continued TAM at most timepoints;[37] continued
TAM produced no significant changes in BMD[36,37]

EXE changed spine BMD from baseline by -2.0% to -3.0% vs -0.4% to +2% with TAM after 6–24 mo,[15,38,40] femoral neck BMD by -1.4%
and +0.3% vs +0.1% and -1.8% with TAM after 6 and 12 mo[38] and hip BMD by -2.5% to +2.4% vs -0.7% to +3.8% with TAM after
6–24 mo[15,38,40]

Where specified, EXE fl hip BMD vs TAM at 6 mo (-1.8% vs +1.5%)[38] and at 12 mo in some (-2.2% vs +0.4%),[38] but not all,[40] trials, and
fl spine BMD vs TAM at 6 (-2.6% vs +0.5%),[38] 12 (-2.8%[38,40] vs +0.5%[38] or +1.2%[40]) and 24 (-3.0% vs -0.4%)[40] mo

BMD did not significantly differ between EXE, TAM or ANA after 1 y (BMD 87%, 89% and 81% of young adult BMD, respectively)[14]

Effects on bone markers

EXE › levels of urinary CTX and NTX and serum CTX, ALP, P1NP and osteocalcin vs PL after 24 mo;[21] no significant between-group
difference in levels of most resorption markers 6 mo after cessation of treatment, although serum CTX and formation marker levels remained
› vs PL[33]

TAM-EXE › levels of urinary NTX[36] and deoxypyridinoline[36] and serum CTX,[36,37] ALP,[36,37] osteocalcin[36] and P1CP[36] vs baseline at
all or most timepoints[37] and/or vs TAM at all[36] or most[37] timepoints in 24-mo studies

In postmenopausal women with early-stage breast cancer, EXE › serum levels of P1NP, ALP, ICTP and osteocalcin vs TAM after 3–12 mo[39]
and appeared to have less favourable effects on serum ALP and urinary NTX levels than TAM after 12 mo;[14] EXE had no effect on serum
CTX or P1NP levels after 2 years in this patient population, whereas levels of both were fl with TAM[15]

› in serum CTX, P1NP and ALP levels vs baseline with EXE were not significantly different from those seen with ANA or LET in
postmenopausal women with invasive breast cancer[16] or in healthy postmenopausal women after 24 wk[32]
ALP = bone alkaline phosphatase; ANA = anastrozole; BMD = bone mineral density; CTX = C-telopeptide; ICTP = carboxyterminal cross-linked
telopeptide of type I collagen; LET = letrozole; NTX = N-telopeptide; P1CP = C-terminal procollagen peptide fragment; P1NP = procollagen
type 1 N-terminal propeptide; PL = placebo; TAM = tamoxifen; TAM-EXE; a switch from TAM to EXE; › indicates significantly increased
(p < 0.05; some p-values were not reported in some studies[16,32]); fl indicates significantly decreased (p < 0.05).

Consistent with its effects on BMD, exe- 3. Pharmacokinetic Profile

mestane generally increased serum or urinary
levels of bone resorption and bone formation
markers relative to baseline, placebo or tamoxi-
fen in postmenopausal women with early-
stage,[21,33,36,39] invasive[16] or resected[21,33,36,37]
breast cancer and in healthy postmenopausal
women,[32] although its effects did not signi-
ficantly differ from those seen with anastrozole or
letrozole[16,32] (table II). Data concerning the in-
cidence of fractures and osteoporosis during ex-
emestane treatment are discussed in section 5.2.
This section provides an overview of the
pharmacokinetic profile of exemestane, which
has been reviewed previously.[9,10] Pharmaco-
kinetic data for exemestane in postmenopausal
women with breast cancer are limited, thus
data in this section are mostly from studies in
healthy postmenopausal volunteers.[31,41-43]
Data from studies evaluating the effect of
moderate or severe hepatic (Child-Pugh grade B
or C) or renal (creatinine clearance [CLCR] of

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (7)
Exemestane: A Review
30–60 mL/min/1.73 m2 [1.8–3.6 L/h/1.73 m2] or
10–29 mL/min/1.73 m2 [0.6–1.7 L/h/1.73 m2]) im-
pairment on the pharmacokinetics of a single
exemestane 25-mg dose are also discussed.[44]
Some data are available only as abstracts,[41-43]
with additional data obtained from the manu-
facturer’s prescribing information.[7,8]
The absorption of exemestane is rapid after
oral administration,[31] with ‡42% of the dose
being absorbed from the gastrointestinal tract.[8]
The average maximum plasma concentration
(Cmax) of exemestane (17 ng/mL) was reached
2 hours after a single oral 25-mg dose in healthy
postmenopausal volunteers.[41] Absorption of
exemestane occurred more than twice as rapidly
in postmenopausal women with advanced breast
cancer than in healthy postmenopausal women
(mean time to Cmax 1.2 vs 2.9 hours), with mean
area under the plasma concentration-time curve


(AUC) values also 82% higher in the women with
breast cancer (75.4 vs 41.4 ng h/mL).[8]
Plasma levels of the drug were generally simi-
lar following administration of single or repeated
doses of 25 mg in healthy postmenopausal
women,[41] with no unexpected accumulation
after repeated administration.[7] Oral exemestane
displays dose-proportional pharmacokinetics
after administration of single and repeated doses
over the range of 10–200 mg and 0.5–50 mg,
respectively.[8]
Systemic exposure to exemestane is greater in
the fed than the fasted state.[42] The AUC was
significantly higher in the presence of food than
under fasting conditions after administration of a


single dose of exemestane 25 mg in healthy post-
menopausal volunteers (41.3 vs 29.7 ng h/mL;
p < 0.05); corresponding Cmax values were 17.7
versus 11.1 ng/mL.[42] Exemestane should, there-
fore, be taken after a meal (section 7).[7,8]
Exemestane is 90% plasma protein bound in-
dependent of concentration,[7,8] with both a1-acid
glycoprotein and albumin contributing to bind-
ing.[8] The drug is extensively distributed into
tissues,[8] and has a volume of distribution of
»20 000 L (not corrected for oral bioavailability).[7]
Exemestane undergoes extensive metabolism,
with <10% of the dose circulating in plasma un-
changed.[8] Metabolism of the drug occurs via
ª 2009 Adis Data Information BV. All rights reserved.
897
oxidation (primarily by the cytochrome P450
[CYP] enzyme CYP3A4) and reduction (by
aldoketoreductases), producing metabolites that
are inactive or less active than the parent drug.[7,8]
The major metabolite, 17-hydro-exemestane, has
been shown to reach plasma levels <10% of those
of the parent drug.[31]
Elimination of exemestane was mainly via
the faeces (42%) and urine (42%) after admini-
stration of a radiolabelled dose in healthy
postmenopausal volunteers, with <1% of the
administered dose excreted via the urine un-
changed.[8] The manufacturer’s prescribing
information reports a mean terminal half-life for
exemestane of »24 hours.[7,8] The mean oral
plasma clearance of the drug was 517 L/h after a
single 25-mg dose and 715 L/h after repeated
doses in healthy postmenopausal women.[41]
Notably, average exemestane oral clearance
was 45% lower in postmenopausal women with
advanced breast cancer than in healthy post-
menopausal volunteers.[8]
Postmenopausal women with moderate or
severe hepatic impairment had a 2- to 3-fold in-
crease in AUC from time zero to infinity (AUC¥)
and a 2-fold increase in Cmax relative to women
with normal hepatic function.[44] A 2- to 3-fold
increase in exemestane AUC¥ was also evident in
postmenopausal women with moderate or severe
renal impairment relative to women with normal
renal function, with a positive correlation de-
monstrated between CLCR and the apparent oral
clearance of the drug.[44] However, exemestane
dosage adjustments are not considered necessary
in these patient populations (section 7),[7,8] al-
though caution is advised in the UK.[7] The
pharmacokinetics of exemestane do not appear
to be affected by age.[8]
Coadministration of exemestane and potent
CYP3A4 inducers, such as rifampicin (rifampin),
may reduce exemestane exposure.[8] In healthy
postmenopausal volunteers, mean exemestane
Cmax and AUC¥ values were reduced by 41% and
54% after coadministration of exemestane 25 mg
and rifampicin 600 mg/day.[8] An increased ex-
emestane dosage of 50 mg/day is recommended in
patients receiving potent CYP3A4 inducing
agents in the US (section 7).[8]
Drugs 2009; 69 (7)
898
The clearance of exemestane is not anticipated
to be significantly affected by concomitant ad-
ministration of CYP inhibitors. The pharmaco-
kinetic profile of exemestane 10 mg was not
affected when coadministered with the CYP3A4
inhibitor ketoconazole 200 mg/day,[43] although
no additional drug interaction studies have been
performed.[8] Exemestane does not inhibit the
activity of key CYP enzymes, such as CYP1A2,
CYP2C9, CYP2D6, CYP2E1 or CYP3A4.[8]
4. Therapeutic Efficacy
The efficacy of exemestane in the treatment of
breast cancer in postmenopausal women has
been evaluated in numerous clinical studies. This
section focuses on data from several randomized,
phase II[45] or III[12,13,46-49] trials that compared
the efficacy of exemestane with that of a number
of active comparators in postmenopausal women
with early-stage (section 4.1)[12,46] or advanced
(section 4.2)[13,45,47-49] breast cancer. Exemestane
was administered orally at a dosage of 25 mg/day
in all studies, and patient characteristics at base-
line were generally similar between treatment
groups. Efficacy assessments were performed in
the intent-to-treat (ITT)[12,13,47,48] or modified
ITT (exclusive of nine patients who withdrew
consent)[46] population, where specified.
4.1 Early-Stage Breast Cancer
The clinical efficacy of switching to oral ex-
emestane for 2–3 years after receiving 2–3 years
of tamoxifen (to complete a total of 5 years of
adjuvant therapy) has been compared with that
of 5 years of continuous tamoxifen therapy in
postmenopausal women with early-stage breast
cancer in the large, randomized, double-blind,
multicentre, phase III IES (section 4.1.1; see
table III for dosage and design details).[12] The
efficacy of exemestane has also been compared
with that of tamoxifen in the primary adjuvant
treatment of early-stage breast cancer in
postmenopausal women in the randomized,
open-label, multinational, phase III, TEAM
ª 2009 Adis Data Information BV. All rights reserved.
Deeks & Scott
(Tamoxifen Exemestane Adjuvant Multinational)
trial (section 4.1.2; see figure 1 for dosage and
design details).[46]
Other studies include the National Surgical
Adjuvant Breast and Bowel Project B-33
study,[50] a randomized, double-blind trial that
compared the efficacy of 5 years of exemestane
with that of placebo following 5 years of adjuvant
tamoxifen. However, as the study was statisti-
cally underpowered for the primary endpoint
analysis because of early termination of patient
accrual (in light of efficacy data from another
trial), it is not discussed further within this
review.
As the preliminary findings of IES have been
reviewed previously,[9] this section reviews data
from the IES at median follow-up periods of
30.6[12] and 55.7[11] months that are now fully
published. Data from the first planned analysis of
the TEAM trial at 2.75 years are available as a
conference presentation.[46]
Postmenopausal women eligible for inclu-
sion in these studies were aged ‡55 years[12]
with histologically[12,46] and/or cytologically[46]
confirmed, resected,[12,46] invasive[12,46] breast
cancer (unilateral where specified[12]) that was
estrogen receptor-[12,46] and/or progesterone
receptor-positive[46] or of unknown receptor
status.[12]
The primary efficacy variable in both the
IES[12] and TEAM study[46] was disease-free sur-
vival, which was based on analysis of the com-
bined occurrence of the following events: local
recurrence,[12,46] distant recurrence[12] or meta-
stases,[46] primary contralateral breast cancer,[12]
new primary breast cancer without metastasis[46]
and intercurrent death[12,46] (without recur-
rence[12]). Among other endpoints were individ-
ual events,[46] overall survival,[12] relapse-free
survival[46] and breast cancer-free survival (sub-
sidiary endpoint in one study[12]).
Both the IES[51,52] and TEAM study[53] eval-
uated health-related quality of life (HR-QOL)
and the burden of endocrine symptoms in a sub-
group of patients (n = 582[51,52] and 543[53]), using
a variety of disease-specific questionnaires. Data
are available in a separate publication[51] or as an
abstract[52,53] and/or a poster.[52]
Drugs 2009; 69 (7)
Exemestane: A Review 899

Table III. Efficacy of exemestane (EXE) in postmenopausal women with early-stage breast cancer. Summary of results at median follow-up
of 30.6[12] and 55.7[11] mo in patients (pts) who were switched to EXE 25 mg once daily for 2–3 years after 2–3 years of tamoxifen (TAM) 20 mg
once daily or continued treatment with TAMa in the randomized, double-blind, multicentre, phase III, IES (total of 5 years of adjuvant endocrine
therapy)
Endpoint Median No. of events in analysis (% of ITT pts)b Hazard ratio (95% CI) [EXE vs TAM]
follow-up EXE TAM ITT population ER+/unknown
(mo)
Disease-free survivalc 30.6[12] 183 (7.7) 266 (11.1) 0.68 (0.56, 0.82)***
55.7 [11]
354 (15.1) 455 (19.2) 0.76 (0.66, 0.88)*** 0.75 (0.65, 0.87)***
Contralateral breast cancer 30.6[12] 9 (0.4) 20 (0.8) 0.44 (0.20, 0.98)*
55.7[11] 18 (0.8) 35 (1.5) 0.57 (0.33, 0.98)* 0.56 (0.33, 0.98)*
Overall survivald 30.6[12] 93 (3.9) 106 (4.5) 0.88 (0.67, 1.16)
55.7[11] 222 (9.4) 261 (11.0) 0.85 (0.71, 1.02) 0.83 (0.69, 1.00)
Breast cancer-free survival e
30.6[12] 144 (6.1) 227 (9.5) 0.63 (0.51, 0.77)***
55.7[11] 0.76 (0.65, 0.89)** 0.75 (0.64, 0.88)**
a Approximately 3% of all pts were known to be receiving TAM 30 mg/day at baseline and remained receiving this dosage if assigned to
continue TAM treatment.
b Included 2362 EXE recipients and 2380 TAM recipients at the median 30.6-month follow-up,[12] and 2352 evaluable EXE and 2372
evaluable TAM recipients at the median 55.7-month follow-up (difference is due to the exclusion of data with unconfirmed validity from one
centre).[11]
c Primary endpoint. Events included in the analysis were local recurrence, distant recurrence, primary contralateral breast cancer and
intercurrent death without breast-cancer recurrence.
d Events included in the analysis were deaths from any cause (i.e. related or not related to breast cancer).
e Pt deaths without recurrence or contralateral breast cancer were censored.
ER = estrogen receptor; ITT = intent-to-treat; * p < 0.05, ** p < 0.001, *** p £ 0.0001 vs TAM.

4.1.1 Adjuvant Treatment After 2–3 Years of
Tamoxifen Treatment
Only patients who had received ‡2 years and
£3 years and 1 month of adjuvant tamoxifen were
eligible to participate in the IES.[12] The trial ex-
cluded patients who had an estrogen receptor-
negative breast tumour, evidence of a distant
metastasis or local relapse since diagnosis, a car-
diac, skeletal or endocrine disorder of clinical
significance or had received hormone replace-
ment therapy (HRT) <4 weeks prior to rando-
mization. At randomization, participants had
been treated with tamoxifen for a median of
2.4 years.[12]
In addition to ITT analyses, outcomes for
patients whose breast cancer was estrogen
receptor-positive (»86% of patients) or of un-
known receptor status (»12%) were analyzed at
the 55.7-month follow-up;[11] this population ex-
cluded patients whose estrogen receptor status
was unknown at randomization but subsequently
identified as being estrogen receptor-negative.
At median follow-ups of 30.6 and 55.7 months,
patients with early-stage breast cancer who
switched to exemestane consistently had a sig-
nificantly lower risk of experiencing one of the
events in the combined endpoint of recurrence,
contralateral breast cancer or death without re-
currence than patients who continued treatment
with tamoxifen, as indicated by the hazard ratio
(HR) for disease-free survival (primary endpoint)
[table III].[11,12] This finding was observed in the
ITT population[11,12] and in patients whose breast
cancer was estrogen receptor-positive or of un-
known receptor status.[11] The incidence of disease-
free survival 3 years after randomization was
91.5% (95% CI 90.0, 92.7) in recipients of ex-
emestane compared with 86.8% (95% CI 85.1,
88.3) in patients who continued tamoxifen,
yielding an absolute difference of 4.7% in the ITT
population.[12]
Subgroup analyses for disease-free survival
demonstrated that the HRs for this endpoint
were not markedly affected by adjusting for

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (7)
900 Deeks & Scott

9 EXE 25 mg/day
8 TAM 20 mg/day
Incidence (% of pts)

7
6
5
4
3
2
1
0
Combined events Local recurrence Distant metastases New primary breast Intercurrent death
cancer (without
metastases)

Individual events

Fig. 1. Comparative efficacy of exemestane (EXE) versus tamoxifen (TAM) as primary adjuvant treatment for early-stage breast cancer in
postmenopausal women. Incidence of combined and individual endpoint events at 2.75 years in the modified intent-to-treat population in the
randomized, open-label, multinational, phase III, TEAM study[46] in which patients (pts) received EXE 25 mg/day (n = 4898) or TAM 20 mg/day
(n = 4868). The hazard ratio (HR) for the primary endpoint of disease-free survival (based on the combined endpoint events) was 0.89 (95% CI
0.77, 1.03). HRs for individual endpoint events (other than distant metastases; HR 0.81 [95% CI 0.67, 0.98; p < 0.03]) were not reported.

prognostic factors, such as estrogen receptor status,
nodal status and use of HRT or chemother-
apy.[11,12] Moreover, the HRs were generally con-
sistent across subgroups defined by these factors.
A switch to exemestane was also more effec-
tive than continued tamoxifen with regard to the
risk of contralateral breast cancer in both the ITT
population[11,12] and in patients with estrogen
receptor-positive or unknown receptor status
disease[11] (table III).
There was generally no overall survival benefit
in switching to exemestane compared with con-
tinuing treatment with tamoxifen (table III).[11,12]
However, at the median follow-up of 55.7
months,[11] the risk of death was significantly
lower with exemestane than with tamoxifen in
patients whose breast cancer was estrogen
receptor-positive or of unknown receptor status
when adjusted for nodal status and HRT and
chemotherapy use (HR 0.83 [95% CI 0.69, 0.99];
p = 0.04). Moreover, exemestane recipients had a
significantly lower risk of experiencing death
from breast cancer than patients who continued
to receive tamoxifen, both in the ITT popula-
tion and among patients whose disease was
estrogen receptor-positive or of unknown status,
according to the subsidiary endpoint of breast
cancer-free survival (table III).[11,12]
The HR-QOL of patients switched to ex-
emestane generally did not significantly differ
from that of patients who continued treatment
with tamoxifen, according to data reported in a
substudy[51] of the IES.[12] There were generally
no significant between-group differences in the
primary HR-QOL endpoint of mean change
from baseline in FACT-B (Functional Assess-
ment of Cancer Therapy – Breast) Trial Outcome
Index score from 3–60 months post-randomiza-
tion,[51,52] except at the 6-month timepoint
(-2.10 with exemestane vs -0.01 with tamoxifen;
p = 0.009), although this difference was not con-
sidered to be clinically relevant.[51]
The burden of endocrine symptoms was lower
at 9, 12, 18, 24[51] and 60[52] months than at
baseline in both exemestane and tamoxifen
recipients, as indicated by significant (p £ 0.01)
mean increases in endocrine subscale (ES) scores;
no significant between-group differences were
evident at any timepoint. In addition, exemestane
and tamoxifen recipients did not significantly
differ in terms of overall HR-QOL, as measured
by combined FACT-B and ES scores, at any
timepoint from 3–24 months, despite a significant
(p = 0.007) mean reduction from baseline of 3.12
at 6 months in exemestane recipients that was not
considered to be clinically relevant.[51]

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (7)
Exemestane: A Review
4.1.2 Primary Adjuvant Treatment
In the TEAM trial,[46] eligible patients were
required to receive adjuvant hormonal therapy
within 10 weeks of undergoing surgery and/or
receiving chemotherapy; exclusion criteria were
not reported.
As a primary adjuvant treatment in post-
menopausal women with early-stage breast
cancer, the efficacy of exemestane was not sig-
nificantly different to that of tamoxifen in terms
of the risk of experiencing one of the events
(i.e. local recurrence, distant metastases, new
primary breast cancer without metastases or
intercurrent death) in the primary combined
endpoint of disease-free survival at a follow-up
of 2.75 years (HR 0.89 [95% CI 0.77, 1.03])
[figure 1].[46] However, data from an analysis that
excluded 96 patients who did not receive either
treatment indicated that exemestane (n = 4853)
was associated with a significantly (p = 0.02)
lower risk of experiencing disease-free survival
events than tamoxifen (n = 4817) at this timepoint
(HR 0.83; 95% CI 0.71, 0.97).
Moreover, exemestane was more effective
than tamoxifen with regard to the risk of distant
metastases (HR 0.81 [95% CI 0.67, 0.98]; p < 0.03)
[figure 1], although there was no significant
between-group difference in terms of relapse-free
survival (HR 0.85 [95% CI 0.72, 1.00]).[46]
The HR-QOL of postmenopausal women
with early-stage breast cancer who received ex-
emestane therapy generally did not differ from
that of those who received tamoxifen, as mea-
sured using several questionnaires, including the
FACT-ES, European Organisation for Research
and Treatment of Cancer (EORTC) Quality of
Life Questionnaire (QLQ)-C30, and the EORTC-
Breast Cancer-Specific QLQ-BR23.[53] After 1
and 2 years of therapy, there were no significant
between-group differences with regard to physi-
cal, role, cognitive or emotional functioning,
breast, arm or endocrine symptoms, or body
image. However, exemestane was associated with
significantly (p £ 0.005) more insomnia and less
sexual enjoyment than tamoxifen after 1 year of
treatment, and significantly (p < 0.05) more in-
somnia and worse sexual functioning after 2 years
of treatment, although there was no significant
ª 2009 Adis Data Information BV. All rights reserved.
901
between-group difference in sexual enjoyment at
the 2-year timepoint.
4.2 Advanced Breast Cancer
4.2.1 Disease Refractory to One or More
Antiestrogen Therapies
The results of several noncomparative[54-59] or
crossover[45] phase II trials and an exploratory
trial[60] (n = 60–241) have demonstrated the
clinical efficacy of oral exemestane 25 mg once
daily in postmenopausal women with advanced
breast cancer[45,54-60] (locally advanced,[54] meta-
static[54,57-60] or inoperable,[60] where specified)
refractory to tamoxifen,[58] tamoxifen and me-
gestrol[57] or aromatase inhibitors as the most
recent hormonal therapy.[45,54-56,59,60] Conse-
quently, the efficacy of exemestane in postmeno-
pausal women with advanced breast cancer
refractory to tamoxifen[13] or nonsteroidal aro-
matase inhibitors[48] has been compared with that
of megestrol[13] and fulvestrant[48] in two large,
randomized, double-blind, placebo-controlled,
multicentre, phase III studies (n = 769[13] and
693[48]) [see table IV for dosage and design
details]. Some of these studies[13,55,57-59] have
been reviewed previously in Drugs,[10] with dis-
cussion in this section focused on the findings
of the larger phase III trials.[13,48] Some data are
available from the manufacturer’s prescribing
information.[8]
In addition, the efficacy of exemestane has
been compared with that of anastrozole in post-
menopausal women with tamoxifen-refractory
advanced breast cancer in a randomized, open-
label, multicentre study.[61] However, as the study
was prematurely closed because of accrual delays
and, therefore, not powered to demonstrate dif-
ferences between treatment groups, data from the
study are not discussed further.
Postmenopausal women included in the
phase III trials had advanced breast cancer[13,48]
(locally advanced or metastatic, where speci-
fied[48]) that had progressed[13,48] or relapsed[13]
during tamoxifen[13] or nonsteroidal aromatase
inhibitor[48] treatment. Also included in one of
the studies[48] were postmenopausal women with
locally advanced or metastatic breast cancer
Drugs 2009; 69 (7)
902 Deeks & Scott

Table IV. Efficacy of exemestane (EXE) in postmenopausal women with advanced breast cancer. Summary of two randomized, double-
blind, multicentre, phase III studies of oral EXE versus oral megestrol (MEG)[13] or intramuscular fulvestrant (FUL)[48] in patients (pts) with
advanced breast cancer whose disease had progressed or recurred during tamoxifen[13] or nonsteroidal aromatase inhibitor[48] therapy.
Values for times are medians; intent-to-treat analyses are presented
Study Treatment (mg) Response rate Duration of Duration of TTP TTF Survival
[no. of pts] (% of pts) OR OS
OR OS
Chia et al.[48] EXE 25 od [342]a 6.7 31.5 9.8 mob 3.7 moc 23.1 mod
FUL 250 q4we [351]a 7.4 32.2 13.5 mo 3.7 moc 24.3 mod
* * *
Kaufmann et al. [13]
EXE 25 od [366] 15.0 c,f
37.4 76.1 wk 60.1 wk 20.3 wk 16.3 wk NR*
c
MEG 40 qid [403] 12.4 34.6 71.0 wk 49.1 wk 16.6 wk 15.7 wk 123.4 wk
a For OR and clinical benefit (OS) endpoints, 270 EXE and 270 FUL recipients were evaluable.
b Between-group statistical analyses were not reported.
c Primary endpoint.
d Reported in an updated analysis available as an abstract.[62]
e Final dosage; intramuscular FUL was initiated with a loading dose of 500 mg at randomization and 250 mg on days 14 and 28.
f The predefined criterion for equivalence between EXE and MEG for OR (upper limit of two-sided 95% CI <25% of the OR for MEG) was
met; 95% CI -7.5, 2.3.
NR = not reached; od = once daily; OR = objective response (included pts with complete or partial responses); OS = overall success (referred to
as clinical benefit in one study,[48] included pts with complete or partial responses or stable disease for ‡24 wk); q4w = once every 4 weeks;
qid = four times daily; TTF = time to treatment failure; TTP = time to disease progression (time from randomization to objective disease
progression, as assessed by Response Evaluation Criteria in Solid Tumours, where specified[48]); * p < 0.05 vs MEG.

who had experienced a disease relapse during, or
within 6 months of discontinuing, adjuvant non-
steroidal aromatase inhibitor therapy (»12% of
patients). Patients had to have estrogen and/or
progesterone receptor-positive disease[13,48] or
disease of unknown receptor status with a pre-
vious response to tamoxifen.[13] Other inclusion
criteria included a WHO[48] or Eastern Co-
operative Oncology Group (ECOG)[13] perfor-
mance status of 0–2, one or more measurable
or evaluable lesions[13,48] and a life expectancy
of ‡3 months.[48]
Patients previously treated with up to one
chemotherapy regimen for advanced disease were
eligible for participation in the trials.[13,48] How-
ever, those previously treated with stron-
tium89,[13] high-dose chemotherapy,[13] hormonal
agents other than tamoxifen,[13] or extensive cy-
totoxic or radiation therapy within the 4 weeks
prior to the study[48] were excluded. Also ex-
cluded were patients with brain metastases,[13,48]
leptomeningeal disease[13] or metastases,[48] or
massive[13] or life-threatening metastatic[48] visc-
eral disease.
Primary endpoints were objective response
rate (defined as the proportion of patients who
achieved a complete or partial response, based on
modified WHO criteria)[13] and time to disease
progression.[48] A number of secondary end-
points related to clinical efficacy (table IV),[13,48]
pain,[13] tumour-related signs and symptoms,[13]
and HR-QOL[13] were also assessed.
Where reported,[13] the median duration of
treatment was »17 weeks. The median duration
of follow-up was 48.9 weeks[13] and »13 months,[48]
with an updated analysis of one study[48] at a
median follow-up of 20.9 months available as an
abstract.[62]
Versus Megestrol
Exemestane provided similar efficacy to me-
gestrol in postmenopausal women with advanced
breast cancer refractory to tamoxifen, as de-
termined by prespecified equivalence criteria for
the objective response rate (primary endpoint)
[table IV].[13] However, although there was also
no significant difference between the treatments
in the median duration of objective response or
the rate of overall success, exemestane recipients
had a significantly longer median duration of
overall success, time to disease progression
and time to treatment failure than megestrol

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (7)
Exemestane: A Review
recipients (table IV). In addition, exemestane
appeared to be associated with a statistical sur-
vival advantage over megestrol (table IV),[13] al-
though there were too few patient deaths during
the study to firmly establish between-group dif-
ferences in overall survival.[8]
At two or more consecutive assessments,
24.7% of exemestane versus 24.2% of megestrol
recipients reported an improvement from base-
line of >20% in overall pain score (pain severity
graded on a 5-point scale from 0 [none] to 5 [in-
tolerable]). Moreover, improvements in overall
pain scores were reported in 51.4% and 46.2% of
exemestane and megestrol recipients who experi-
enced complete or partial responses.[13] The pro-
portion of patients reporting an improvement in
tumour-related signs and symptoms other than
pain (graded via the National Cancer Institute
Common Toxicity Criteria [CTC]) did not sig-
nificantly differ between exemestane (12.1%) and
megestrol (7.5%) recipients.[13]
Several aspects of HR-QOL were different
between exemestane and megestrol recipients.[13]
Exemestane significantly (p < 0.01) improved
certain scores on the EORTC QLQ-C30 relative
to megestrol, including global health, both phy-
sical and role functioning, fatigue, dyspnoea
and constipation. However, between-group dif-
ferences were significant in favour of megestrol
for improvements in emotional functioning, pain
and appetite loss scores (quantitative data and
some statistical analyses not reported).
Versus Fulvestrant
Oral exemestane demonstrated clinical effi-
cacy not significantly different from that of intra-
muscular fulvestrant in postmenopausal women
with advanced breast cancer whose disease pro-
gressed or recurred during treatment with a
nonsteroidal aromatase inhibitor (table IV).[48]
There was no significant between-group differ-
ence in the median time to disease progression
(primary endpoint), the objective response rate or
the clinical benefit (i.e. overall success) rate at a
median follow-up of »13 months (table IV).
Moreover, the exemestane and fulvestrant groups
did not significantly differ in terms of overall
survival in an updated (median 20.9-month
ª 2009 Adis Data Information BV. All rights reserved.
903
follow-up)[62] analysis (available as an abstract)
[table IV].
4.2.2 First-Line Treatment
The efficacy of exemestane in the first-line
hormonal treatment of postmenopausal women
with advanced breast cancer (i.e. metastatic or
locally recurrent inoperable disease) was initially
demonstrated in a randomized, open-label, mul-
ticentre, phase II study,[63] in which patients
received exemestane 25 mg (n = 61) or tamoxifen
20 mg (n = 59) orally once daily. However, as the
study was not powered to detect differences
between treatment groups, data from the study
are not discussed further. Subsequently, two
randomized, open-label, multicentre, phase III
studies[47,49] were conducted to compare the effi-
cacy of exemestane and tamoxifen in this setting.
Results of a randomized, open-label, multicentre,
phase II, crossover study comparing the efficacy
of exemestane with that of anastrozole in the
first-line hormonal treatment of advanced breast
cancer in postmenopausal women are also dis-
cussed.[45] One study is fully published,[47] whilst
other data are available only as abstracts;[45,49]
additional data for one study[45] are available
from other sources.[64]
Eligible patients had metastatic[47,49,64] or
locally advanced[64] or recurrent[47,49] inoperable
breast cancer that was hormone receptor-
positive[47,49] (estrogen receptor and/or proges-
terone receptor-positive, where specified[64]) or
of unknown receptor status with a disease-free
interval of ‡2 years.[47] Other eligibility criteria
included measurable disease,[64] one or more
measurable lesions[47,49] and an ECOG perfor-
mance status of 0–2.[64] Where stated, patients
who had received prior hormone therapy for
metastatic disease were excluded;[47,64] however,
patients previously treated with adjuvant ta-
moxifen with a recurrence-free interval of
‡6 months[47] or with disease progression ‡2 years
since such adjuvant treatment[64] were eligible,
as were patients previously treated with one che-
motherapy regimen for advanced[64] or meta-
static[47] disease.
Patients were randomized to receive oral exe-
mestane 25 mg/day,[45,47,49] tamoxifen 20 mg/day[47,49]
Drugs 2009; 69 (7)
904
or anastrozole 1 mg/day[45] until disease progres-
sion[45,47,49] or unacceptable toxicity.[47,49] Where
stated,[47] the median follow-up was 29 months,
with overall survival data available from an up-
dated 49-month analysis.
Primary efficacy measures included progression-
free survival[47] and objective response rate.[49,64]
A number of secondary endpoints were also re-
ported. In one study,[47] the ITT analysis included
all randomized patients with the exception of
11 patients from two sites that were excluded
because of inadequate documentation.
Versus Tamoxifen
In the largest phase III trial, the efficacy of
exemestane (n = 182) did not significantly differ
from that of tamoxifen (n = 189) as first-line
hormonal treatment in postmenopausal women
with advanced breast cancer, with a median
progression-free survival of 9.9 and 5.8 months
(primary endpoint) after a median follow-up
of 29 months.[47] However, exemestane was
associated with a significantly higher objective
response rate than tamoxifen at this timepoint
(46% vs 31% of patients; odds ratio [OR] 1.85
[95% CI 1.21, 2.82]; p = 0.005), although there
was no significant between-group difference with
regard to overall survival at 49 months’ follow-up
(45% vs 43% of patients had died; HR 1.13; 95%
CI 0.85, 1.50).
These data are supported by a smaller study in
167 postmenopausal women with advanced
breast cancer.[49] Objective response rates in the
exemestane (n = 83) and tamoxifen (n = 84)
groups were 37.4% and 29.8% (primary end-
point), median durations of objective response
were 59 and 39 weeks, clinical benefit rates were
79.5% and 78.6% and median times to disease
progression were 52 and 36 weeks (no statistical
analyses reported).
Versus Anastrozole
Exemestane demonstrated efficacy not sig-
nificantly different from that of anastrozole in
the first-line hormonal treatment of 103 post-
menopausal women with advanced breast
cancer.[45] There were no significant differences
between exemestane and anastrozole recipients in
the objective response rate (primary endpoint)
ª 2009 Adis Data Information BV. All rights reserved.
Deeks & Scott
[37% vs 52% of patients], clinical benefit rate
(47% vs 60%) or mean time to disease progression
(8.1 vs 12.1 months).
5. Tolerability
The tolerability profile of exemestane in post-
menopausal women with early-stage[9] or ad-
vanced[10] breast cancer has been previously
reviewed. This section provides key tolerability
data related to administration of exemestane
25 mg once daily in patients with early-stage[11,46]
or advanced[13,47,48] breast cancer available from
large phase III clinical studies discussed in sec-
tions 4.1 and 4.2, with additional data obtained
from a substudy (n = 1614)[65] of the TEAM
trial[46] and substudies (n = 183[19] and 206[36]) of
the IES.[11] Given that provisional data from the
IES at a median 30.6-month follow-up compar-
ing a switch to exemestane versus continued
tamoxifen treatment in patients with early-stage
breast cancer[12] have been discussed in detail
previously,[9] this section reviews the longer-term
tolerability data from a median 55.7-month
follow-up,[11] focusing mainly on the on-treatment
adverse events (i.e. those occurring between
randomization and 30 days after treatment dis-
continuation). Adverse events were graded ac-
cording to the National Cancer Institute CTC,
where specified.[11] Some data are available only
as a conference presentation[46] or as an abstract
plus poster.[19]
5.1 General Tolerability
Exemestane 25 mg once daily was generally well
tolerated in postmenopausal women with early-
stage[11,46] or advanced[13,47,48] breast cancer, with
adverse events being mostly of mild or moderate
severity, where specified.[11,47] The nature of ad-
verse events associated with exemestane treatment
was generally similar irrespective of whether the
drug was being administered for early-stage or
advanced disease. Hot flashes were the most
common adverse event considered to be treatment-
related[13,48] or of indeterminate cause[13] in ex-
emestane recipients with advanced breast cancer
(occurred in 12.6%[13] and 11.5%[48] of patients),
Drugs 2009; 69 (7)
Exemestane: A Review 905

50 EXE
45 TAM
40
Incidence (% of pts)

35
30
25
20
*
15
*
10
5
0
om al

es

ue

in

ia

T)

S)

is

a
he

es
io

ni

tin

se
rit
pt s

pa

lg

M
sh

tig
s
m au

ns

ra

th

in
ea

au
ot
fla

da

ng
Fa

so

z
sy op

te

Ar
th

Sw

(n

N
M

iz
er

In

ea

di
Ar
ot
en

D
ts

lu
yp
H

H
M

en

xc
H

ev

(e
in
V

Pa
C
Fig. 2. Comparative tolerability of exemestane (EXE) and tamoxifen (TAM) in postmenopausal women with early-stage breast cancer.
Adverse events (graded by the Common Toxicity Criteria of the National Cancer Institute) that occurred on-treatment with an incidence
of ‡10% in either treatment group in the randomized, double-blind, multicentre, phase III, IES (median follow-up 55.7 months).[11] Patients
(pts) who had already received 2–3 years of oral TAM 20 mg/day were randomized to receive oral EXE 25 mg/day (n = 2320 modified intent-to-
treat pts) or to continue receiving TAM 20 mg/day (n = 2338) for 2–3 years, thus completing a total of 5 years of adjuvant endocrine therapy.
The prespecified level for statistical significance was p < 0.01. Menopausal symptoms included hot flashes. CV = cardiovascular;
MS = musculoskeletal; VT = venous thromboembolism. * p < 0.0001 vs EXE.

with menopausal symptoms (46.3% of patients[11]),
such as hot flashes (41.3%[11] and 28.5%[46]), the
most commonly reported treatment-emergent ad-
verse events associated with exemestane in patients
with early-stage breast cancer.
5.1.1 Versus Tamoxifen
The vast majority of postmenopausal women
with early-stage breast cancer who switched to
exemestane or continued tamoxifen in the IES
experienced a treatment-emergent adverse event
of any grade (93% in both groups).[11] Serious
treatment-emergent adverse events (grade 3 or 4
in severity) occurred in 18.4% of patients in the
exemestane group and 17.6% of patients in the
tamoxifen group. The most common treatment-
emergent adverse events (i.e. incidence ‡10% in
either group) are summarized in figure 2, with
menopausal symptoms, such as hot flashes,
and hypertension being the most frequent. No-
tably, there was a significantly (p < 0.01) lower
incidence of serious gynaecological events (5.9%
vs 9.0% of patients), such as vaginal bleeding
(4.6% vs 6.5%) and uterine dilation and curet-
tage (0.6% vs 1.4%), as well as endometrial hy-
perplasia (0.1% vs 1.0%), uterine polyps/fibroids
(1.2% vs 3.2%), venous thromboembolytic events
(1.2% vs 2.3%) and muscle cramp (2.3% vs 4.2%)
in the exemestane than in the tamoxifen group,
whereas musculoskeletal pain (figure 2), ar-
thralgia (figure 2), diarrhoea (4.2% vs 2.2% of
patients), carpal tunnel syndrome (2.8% vs 0.3%),
paraesthesia (2.8% vs 1.0%) and joint stiffness
(1.9% vs 1.0%) occurred with a significantly
higher frequency with exemestane therapy. There
was no significant between-group difference in
the incidence of cardiovascular events (excluding
venous thromboembolism) [figure 2], ischaemic
cardiovascular disease (8.0% of exemestane vs
6.9% of tamoxifen recipients) or myocardial in-
farction (1.3% vs 0.8%).
In a substudy[19] of the IES in patients with no
prior uterine malignancy, such as endometrial
cancer, or undiagnosed vaginal bleeding in the
year prior to the trial, significantly fewer ex-
emestane recipients than continued tamoxifen
recipients had abnormal endometrial thickness
(‡5 mm) after 24 months of treatment (35.5% vs
61.8%; p = 0.004), with significant between-group
differences in favour of exemestane also seen
after 6 (43.5% vs 65.2%; p = 0.01) and 12 (31.2%
vs 57.4%; p = 0.004) months (see also section 2).

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (7)
906
The tolerability profile of exemestane when
used as a primary adjuvant treatment in post-
menopausal women with early-stage breast can-
cer was generally consistent with that seen in the
IES switching trial. In the TEAM study,[46] sev-
eral selected treatment-emergent adverse events
occurred in significantly (p £ 0.001) fewer ex-
emestane than tamoxifen recipients, including
hot flashes (28.5% vs 33.3% of patients), throm-
bolytic events (0.9% vs 2.3%), vaginal discharge
(2.3% vs 6.8%), vaginal haemorrhage (1.6% vs
3.1%), vaginal infection (0.7% vs 2.2%), uterine
polyps (0.1% vs 0.5%) and endometrial hyper-
plasia (0% vs 2.0%), whereas the incidence of
arthralgia (17.9% vs 9.2%), arthritis (3.0% vs
1.7%) and hypertension (3.3% vs 2.1%) was sig-
nificantly (p £ 0.001) higher with exemestane.[46]
The incidence of cardiac events, such as myo-
cardial ischaemia/infarction (0.8% of exemestane
vs 0.6% of tamoxifen recipients) and cardiac
death (0.4% vs 0.2%), was low and did not sig-
nificantly differ between the treatment groups.
In an analysis of ten common menopausal
symptoms (assessed by self-report questionnaire)
during the first 12 months’ treatment in the TEAM
study,[65] significantly (p < 0.05) more exemestane
than tamoxifen recipients had bone/muscle aches
(77% vs 70% of patients), difficulty sleeping (59%
vs 56%; estimated from a graph), decreased libido
(58% vs 54%) and vaginal dryness (50% vs 42%),
whereas tamoxifen was associated with a sig-
nificantly (p < 0.0001) higher incidence of vaginal
discharge (32% vs 12% of exemestane recipients)
and a significantly (p = 0.03) higher mean hot flash
score (3.6 vs 2.9). However, there was no sig-
nificant between-group difference in terms of
vaginal bleeding, mood alteration, impaired word
finding or low energy.
In postmenopausal women with advanced breast
cancer, the most common treatment-emergent
adverse events (of those with an incidence >30%)
in exemestane or tamoxifen recipients included
fatigue/malaise/lethargy (37% vs 37% of patients),
hot flashes (35% vs 38%), pain other than in bone
(35% vs 31%), bone pain (33% vs 35%) and anaemia
(29% vs 36%).[47] Changes (all grades) in levels
of ALT (64% of exemestane vs 50% of tamoxifen
recipients) and AST (54% vs 56%) were also
ª 2009 Adis Data Information BV. All rights reserved.
Deeks & Scott
commonly reported in each of the treatment groups.
Serious nonhaematological adverse events (41 vs 61
events) and laboratory parameter changes (30 vs 21
events) of grade 3 or 4 severity were documented
in both exemestane and tamoxifen recipients.[47]
Notably, weight gain (19% vs 13% of patients),
arthralgias (12% vs 5%), hypertension (12% vs 6%)
and diarrhoea (9% vs 3%) occurred in ‡5% more
exemestane than tamoxifen recipients, whereas
anaemia (36% vs 29%), thrombocytopenia (12% vs
6%) and vaginal discharge (7% vs 2%) occurred in
‡5% more tamoxifen than exemestane recipients
(descriptive analyses only).[47]
5.1.2 Versus Other Agents
The nature of selected adverse events considered
to be drug-related or of indeterminate cause was
similar in the exemestane and megestrol groups,
with 39.1% and 45.8% of patients experiencing
such events.[13] However, fewer exemestane than
megestrol recipients withdrew from treatment be-
cause of adverse events (1.7% vs 5.0%; p = 0.011).
The most commonly reported (i.e. an incidence
>10% in either treatment group) adverse events
were hot flashes (12.6% vs 5.0% of patients) and
fatigue (7.5% vs 10.3%). Exemestane treatment
was associated with a greater risk of hot flashes
(OR 2.73 [95% CI 1.58, 4.72]), nausea (9.2% vs
5.0% of megestrol recipients; OR 1.93 [95% CI
1.09, 3.43]) and vomiting (2.8% vs 0.8%; OR 3.80
[95% CI 1.04, 13.93]), but a lower risk of dyspnoea
(0.3% vs 3.0%; OR 0.09 [95% CI 0.01, 0.70]) than
megestrol. In addition, moderate to severe (grade 3
or 4) gains in bodyweight occurred in significantly
(p = 0.001) fewer exemestane than megestrol
recipients (7.6% vs 17.1%), with bodyweight in-
creases of ‡10% reported in 4% and 21.3% of
patients in the respective treatment groups who
were overweight at baseline.
Exemestane demonstrated a tolerability pro-
file broadly similar to that of fulvestrant in post-
menopausal women with advanced breast cancer
(figure 3).[48] The most common treatment-
related adverse events that occurred in >5%
of patients in either treatment group (other
than injection-site pain) were hot flashes, fa-
tigue, nausea and arthralgia. Few exemestane
or fulvestrant recipients experienced venous
Drugs 2009; 69 (7)
Exemestane: A Review 907

20 EXE
18 FUL
16
Incidence (% of pts)

14
12
10
8
6
4
2
0

ia
es

ue

pa ite

ia

he

m in

ia

ia

ia

tio e

ia
se

oe

ac sit
lg
lg

en

ps

ex

ec
sh

tre in
tig

c
in

ity

n
ya
n-

ra

re on-
au

da
rrh

ex Pa

pe

or

op
th
fla

Fa

M
io

th
N

ea

As

An
ia

ys

Al
i
ct

ct
Ar
ot

D
je

je
H

In

In
Fig. 3. Comparative tolerability of exemestane (EXE) and fulvestrant (FUL) in postmenopausal women with advanced breast cancer.
Descriptive incidence of drug-related adverse events that occurred in >2% of patients (pts) who received oral EXE 25 mg/day (n = 340
evaluable patients) or intramuscular FUL 250 mg every 4 weeks (n = 351) in a randomized, double-blind, multicentre, phase III study (median
follow-up of 13 months) conducted in postmenopausal women with advanced breast cancer whose disease had progressed or recurred during
nonsteroidal aromatase inhibitor therapy.[48]

thrombolytic events (0.9% vs 1.1%), serious drug- exemestane who had a healthy BMD at baseline
related adverse events occurred in 0.6% and 1.1% and no patients treated with tamoxifen had de-
of recipients, and 2.6% and 2% of patients with- veloped osteoporosis at this timepoint.
drew from therapy because of an adverse event. The incidence of fractures was not signifi-
cantly different between exemestane and tamoxifen
5.2 Osteoporosis and Bone Fractures recipients in the TEAM trial (2.7% vs 2.3% of pa-
tients)[46] or in the on-treatment analysis of the IES
As with other aromatase inhibitors, exeme- (4.3% vs 3.1%).[11] However, significantly more
stane is associated with loss of BMD (section 2), a exemestane than tamoxifen recipients had experi-
risk factor for osteoporosis and fractures. Indeed, enced fractures in the IES when analyses included
when used as a primary adjuvant treatment in both on-treatment and post-treatment adverse
postmenopausal women with early-stage breast events (7.0% vs 4.9%; OR 1.45 [95% CI 1.13, 1.87];
cancer, exemestane was associated with a signifi- p = 0.003),[11,36] although most fractures occurred at
cantly (p £ 0.001) greater incidence of osteopo- sites other than the hip, spine or wrist.[11]
rosis than tamoxifen after 2.75 years of treatment
in the TEAM trial (4.7% vs 2.1%).[46] However, 6. Pharmacoeconomic Analyses in
switching to exemestane was not (based on a Early-Stage Breast Cancer
prespecified p-value of <0.01 being significant)
associated with a higher incidence of osteoporosis This section reviews recent fully published
than continued treatment with tam- pharmacoeconomic analyses that used efficacy
oxifen in the on-treatment analysis of the IES at a data from the IES (discussed in section 4.1) to es-
median 55.7-month follow-up (7.3% vs 5.5% of timate the cost utility of switching to exemestane
patients) or the corresponding on-treatment plus after 2–3 years of adjuvant tamoxifen relative to
post-treatment analysis (9.2% vs 7.2%).[11] 5 years of continued tamoxifen,[66-70] 5 years of
Moreover, in a substudy[36] of the IES in patients anastrozole[68,69] or extended therapy with tamoxi-
who were not osteoporotic at randomization, 5% fen for 5 years then letrozole for 3 years,[69] in
of exemestane recipients developed osteoporosis postmenopausal women with early-stage[67-70] or
over a 24-month period, although all had been operable[66] breast cancer in an adjuvant treatment
osteopenic at baseline. No patients treated with setting in a number of countries (table V).

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (7)
908 Deeks & Scott

Table V. Cost effectiveness of exemestane (EXE) in the treatment of early-stage[67-70] or operable[66] breast cancer in postmenopausal
women. Summary of cost-utility analyses of a switch to EXE after 2–3 years of adjuvant tamoxifen (TAM) relative to 5 years of continued
treatment with TAM, 5 years of primary adjuvant treatment with anastrozole (ANA) or extended adjuvant treatment with TAM for 5 years then
letrozole (LET) for 3 years. Patients (pts) had hormone receptor-positive,[68,69] estrogen receptor-positive (ER+)[66,70] or unknown ER[70] status
breast cancer and were aged 60,[68,69] 63[66] or 64[67,70] years, where specified. All analyses used Markov models (5[66,68-70] or 6[67] major
health states; 3-,[67] 6-[70] or 12-month[66] cycles, where specified) and incorporated efficacy data from the IES; annual discounts (costs and
benefits) were 3%[67-70] or 3.5%[66]
Study Country Time Treatment regimen Incremental Incremental Incremental cost per
(y of costing) horizon cost/pt QALY/pt QALY gaineda
(y)
Gil et al.[66] Spain (2004) 10 TAM-EXE vs TAMb h14 380 0.230 h62 522
20 h20 020 0.566 h35 371
10 ANAc vs TAM h11 887 0.114 h104 272
20 h17 806 0.285 h62 477
10 TAM-LETd vs PL h16 053 0.176 h91 210
20 h23 444 0.474 h49 460

Lundkvist et al. [67]

Sweden (2005) Lifetime TAM-EXE vs TAM b
h3156 0.16 h20 358

Skedgel et al.[68] Canada (2005) 10 TAM-EXE vs TAMb $Can1889 0.076 $Can24 752
20 $Can1872 0.244 $Can7683
10 ANAc vs TAM-EXEb $Can4280 0.016 $Can272 100
20 $Can4401 -0.017 TAM-EXE dominant

Skedgel et al.[69] Belgium (2005) 20 TAM-EXE vs TAMb h1251 0.251 h4976

TAM-EXEb vs -h324 0.102 TAM-EXE dominant
TAM-LETd
ANAc vs TAM-EXEb h3366 -0.02 TAM-EXE dominant

Thompson et al.[70]e US (2004) Lifetime TAM-EXE vs TAMb $US4400 (all pts) 0.22 (all pts) $US20 100 (all pts)
$US4299 (ER+ 0.26 (ER+ pts) $US16 600 (ER+ pts)
pts)
a Where stated, analyses assumed cost-effectiveness thresholds of h30 000,[66,69] $Can50 000[68] or $US25 000 or $US50 000[70] per QALY
gained.
b Efficacy data from the IES at a median 30.6-mo[12] follow-up were used in several studies,[66-69] with 37.4-mo data[71] also used in some
analyses.[66,68,69] One study[70] used unpublished 48-mo IES data.
c Efficacy data for ANA were sourced from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after a median 68-mo follow-up[72]
in some studies,[68,69] and at a median follow-up of 33.3 mo[73] in one study[66] and 47 mo[74] in another study.[69]
d Efficacy data for TAM-LET were sourced from the MA17 trial at a median follow-up of 2.4 y[75] in one study[66] and 2.5 y[76] in another
study.[69]
e This study was reported to be from a societal perspective, although it did not directly include loss-of-productivity costs. Only direct costs
were included; utility weights were assumed to reflect losses in productivity, thus such costs were excluded.
PL = placebo; QALY = quality adjusted life-year; TAM-EXE = switch from TAM to EXE; TAM-LET = extended adjuvant treatment with TAM
(5 y) then LET (3 y).

The studies used Markov models to estimate
the long-term cost utility of a switch to ex-
emestane relative to other adjuvant therapies.
Analyses were stated[66,68,69] or assumed[67,70] to
be from a healthcare payer perspective as they
included only direct medical costs (drug and
other resource costs, including those related to
adverse events or complications, such as recur-
rence or relapse); although the US analysis[70]
stated it was from a societal perspective, it did not
directly include loss-of-productivity costs. Costs
were based on a variety of sources, including
healthcare databases,[66,70] expert opinion[67] and
literature.[67-70] Utility values were based on

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (7)
Exemestane: A Review
literature, and transition values were from the
IES and other trials, literature and other sources.
Switching to exemestane after 2–3 years of
tamoxifen generally appeared to be cost effective
with regard to the cost per quality-adjusted life-
years (QALYs) gained compared with continuing
tamoxifen in postmenopausal women with early-
stage breast cancer in several countries.[67-70] Re-
lative to continued treatment with tamoxifen,
switching to exemestane increased costs, but
also increased QALYs, resulting in incremental
costs per QALY gained that were below widely
accepted cost-effectiveness thresholds (e.g.
$US50 000 or h30 000 per QALY gained),[67-70]
with the exception of 10- and 20-year horizon
results in postmenopausal women with operable
breast cancer in a Spanish analysis[66] (table V).
As might be predicted, the incremental costs per
QALY gained appeared to be greater (i.e. less
favourable) when shorter time horizons were
modelled (table V).[66,68]
In a US analysis,[70] the cost effectiveness of the
exemestane regimen relative to 5 years of continued
tamoxifen appeared to be marginally greater in
patients with known estrogen receptor-positive
disease than in patients whose disease was estrogen
receptor-positive or of unknown receptor status.
A cost-effectiveness acceptability curve demonstrated
that the probability of a switch from tamoxifen to
exemestane being cost effective relative to con-
tinued tamoxifen was 70.5% and 96.4% at accept-
ability thresholds of $US25 000 and $US50 000 per
QALY gained in postmenopausal women with
early-stage estrogen receptor-positive or unknown
receptor status breast cancer.[70]
When consequences of coronary heart disease
were included in a Swedish analysis,[67] a switch
to exemestane still appeared to be cost effective
relative to continued tamoxifen, with an incre-
mental cost per QALY gained of h31 434 (year
of costing 2005). Tamoxifen was assumed to be
associated with a reduced risk of coronary heart
disease relative to exemestane for a total of
11 years post-treatment initiation in this analysis.
The incremental cost per QALY gained for the
exemestane regimen versus tamoxifen remained
below h50 000 when the period of reduced
risk associated with tamoxifen was increased to
ª 2009 Adis Data Information BV. All rights reserved.
909
14 and 18 years, but not when increased to
24 years.[67]
Analyses from Belgian[69] and Canadian[68]
healthpayer perspectives over 20-year time hor-
izons predicted that a switch to exemestane after
2.5 years of adjuvant tamoxifen was dominant
(i.e. less costly and more effective) over both first-
line treatment with adjuvant anastrozole
(5 years)[68,69] and extended adjuvant therapy
with tamoxifen (5 years) followed by letrozole
(3 years)[69] with regard to the cost per QALY
gained (table V). Furthermore, estimates over a
10-year horizon in Canada suggested that
first-line treatment with anastrozole was not a
cost-effective option relative to a switch from
tamoxifen to exemestane, as the incremental
costs per QALY gained were well in excess of
the accepted cost-effectiveness threshold of
$Can50 000.[68] Moreover, data from a Spanish
analysis[66] suggested that switching to ex-
emestane after 2–3 years of tamoxifen instead of
continuing tamoxifen was associated with incre-
mental costs per QALY gained that were lower
than those associated with comparisons of other
regimens (table V). These data should be inter-
preted with caution owing to the marked differ-
ences in the regimens compared and the indirect
nature of the comparisons.
Sensitivity analyses conducted in the studies
demonstrated that overall findings were generally
robust to plausible variations in most key as-
sumptions and input parameters.[66-70]
However, as with all pharmacoeconomic stu-
dies, pharmacoeconomic analyses of exemestane
are subject to several inherent limitations. Phar-
macoeconomic analyses based on clinical trials
extrapolate the results of such trials to the general
population; however, patient populations, rates
of compliance and major outcomes in clinical
trials may differ from those observed in real-life
practice. Modelled analyses, such as those pre-
sented in this section,[66-70] rely on a number of
assumptions and use data from a variety of sour-
ces. The studies were generally well designed,
although some analyses[66,68,69] incorporated data
from trials that did not directly compare the
various regimens owing to a lack of relevant
head-to-head clinical trial data. Results of
Drugs 2009; 69 (7)
910
pharmacoeconomic analyses may not be applic-
able to other geographical regions because of dif-
ferences in healthcare systems, medical practice
and unit costs.
7. Dosage and Administration
Exemestane is approved in the UK,[7] US[8] and
several other countries worldwide as an adjuvant
treatment in postmenopausal women with estro-
gen receptor-positive early-stage (invasive[7]) breast
cancer following 2–3 years of adjuvant tamoxifen
treatment, as well as for the treatment of advanced
breast cancer in postmenopausal women whose
disease has progressed following tamoxifen or
other antiestrogen therapy.
The recommended dosage is exemestane 25 mg
administered orally once daily after a meal.[7,8] In
patients with early-stage disease who have received
2–3 years of tamoxifen treatment, exemestane
should be administered until a total of 5 years of
adjuvant endocrine therapy has been received, or
until tumour relapse[7]/recurrence[8] or contra-
lateral breast cancer[8] occurs. In patients with
advanced disease, exemestane treatment should con-
tinue until there is evidence of tumour progression.
Dosage adjustments are not required in patients
with hepatic or renal impairment (section 3).[7,8]
However, in patients receiving drugs that are potent
inducers of CYP3A4 enzymes, such as phenytoin
or rifampicin, an increased exemestane dosage of
50 mg/day is recommended in the US.[8] Local pre-
scribing information should be consulted for fur-
ther information regarding contraindications,
warnings, drug interactions and other precautions.
8. Place of Exemestane in the
Management of Breast Cancer in
Postmenopausal Women
The benefits of endocrine therapy in the
treatment of breast cancer have been known for
over 100 years, and is today the cornerstone
therapy in management of the disease.[77] The
selective estrogen receptor modulator tamoxifen,
which blocks estrogen activity at the receptor
level, was the gold standard endocrine therapy
for the treatment of both early-stage and
ª 2009 Adis Data Information BV. All rights reserved.
Deeks & Scott
advanced hormone receptor-positive breast can-
cer for many years. However, safety concerns
relating to certain estrogenic effects, including an
increased risk of endometrial cancer and throm-
boembolytic disease, as well as the problem of
developing resistance to the drug, prompted de-
velopment of alternative antiestrogen agents.[78]
The aromatase inactivators/inhibitors are one
such group of agents, inhibiting the peripheral
production of estrogens and thus lacking any
estrogenic activity. Currently available third-
generation aromatase inactivators/inhibitors include
the steroidal aromatase inactivator exemestane
and the nonsteroidal inhibitors anastrozole and
letrozole.[79] Fadrozole, an earlier second-
generation nonsteroidal aromatase inhibitor, is
available only in Japan. Other endocrine agents,
available for the treatment of advanced breast
cancer, include progestins (e.g. megestrol), an-
drogens and high-dose estrogen,[79] although
their mechanisms of action are not clearly un-
derstood. More recently, the estrogen receptor
down-regulator fulvestrant has become available
for use in this patient population.[79]
In early-stage breast cancer, the overall aim of
treatment is to increase the time to tumour pro-
gression and improve overall patient survival.[80]
The mainstay endocrine treatment for post-
menopausal women with early-stage hormone
receptor-positive breast cancer has historically
been 5 years of adjuvant tamoxifen.[81,82] How-
ever, data from recent clinical trials using third-
generation aromatase inactivators/inhibitors
instead of, or in sequence with, tamoxifen indicated
that these agents were more effective in preventing
disease recurrence than tamoxifen in this
patient population.[81,82] As a result, aromatase
inactivators/inhibitors presently challenge tam-
oxifen as the standard of care for the treatment of
early-stage hormone receptor-positive breast
cancer in postmenopausal women.[82]
According to current treatment guidelines[79,83]
and the 10th St Gallen expert consensus meeting
on the primary therapy of early breast cancer,[84]
postmenopausal women with hormone receptor-
positive disease can be given aromatase in-
activator/inhibitor therapy upfront for 5 years or
following 2–3 or 5 years of tamoxifen therapy.
Drugs 2009; 69 (7)
Exemestane: A Review
The treatment guidelines[79,83] recommend that aro-
matase inactivators/inhibitors are used at some
stage during the treatment of all postmenopausal
women for whom endocrine therapy is appro-
priate. However, in the St Gallen consensus
meeting,[84] a switch to an aromatase inactivator/
inhibitor after 2–3 years of tamoxifen was the
preferred aromatase inactivator/inhibitor treat-
ment strategy, with the majority of the panel
considering 5 years of tamoxifen to be a viable
treatment option in some patients.
Exemestane was approved in the UK,[7] the
US[8] and several other countries for use as an ad-
juvant treatment in postmenopausal women with
estrogen receptor-positive early-stage breast cancer
after 2–3 years of adjuvant tamoxifen treatment
based on the results of the large well designed IES
(section 4.1.1). According to data from this study,
exemestane for 2–3 years after 2–3 years of ad-
juvant tamoxifen is generally more effective than
5 years of continuous adjuvant tamoxifen in the
treatment of postmenopausal women with early-
stage breast cancer (section 4.1.1). Switching from
tamoxifen to exemestane was consistently asso-
ciated with a significantly lower risk of experien-
cing one of the events (recurrence, contralateral
breast cancer or death without recurrence) in the
primary combined endpoint of disease-free survi-
val than continued tamoxifen at median follow-
ups of 30.6 and 55.7 months. The exemestane
regimen was also more effective with regard to
other endpoints, including the risk of contralateral
breast cancer and breast cancer-free survival.
There was generally no overall survival benefit in
switching to exemestane, except in patients with
estrogen receptor-positive or unknown receptor
status disease at the median 55.7-month follow-up,
when nodal status, HRT and chemotherapy use
were adjusted for. Whether switching from ta-
moxifen to an aromatase inhibitor/inactivator
provides an overall survival benefit over continued
tamoxifen in postmenopausal women with early-
stage breast cancer is unclear at present, with
variable results reported in the analyses of three
large clinical studies that compared a switch to
anastrozole with continued tamoxifen therapy.[85]
Anastrozole is the only third-generation aro-
matase inhibitor to have been approved for use in
ª 2009 Adis Data Information BV. All rights reserved.
911
this indication (in the UK[86] and a number of
other countries), based on the findings of several
studies.[81,85] However, the efficacy of letrozole in
sequence with tamoxifen (2 years of tamoxifen
followed by 3 years of letrozole; 2 years of le-
trozole followed by 3 years of tamoxifen) in the
adjuvant setting was not significantly different
from that of primary adjuvant treatment with
letrozole, according to limited data from a trial
available as an abstract.[87]
Although, at present, exemestane is not ap-
proved for use as a primary adjuvant treatment in
postmenopausal women with hormone receptor-
positive early-stage breast cancer, preliminary data
from the large, randomized, open-label, phase III,
TEAM trial comparing exemestane with tamoxi-
fen indicate that exemestane 25 mg/day is effective in
this setting (section 4.1.2). After 2.75 years, disease-
free (primary endpoint) or relapse-free survival
did not significantly differ between exemestane
and tamoxifen recipients, although exemestane
was more effective with regard to the risk of dis-
tant metastases. However, the TEAM trial has
since been revised to compare the efficacy of
5 years of exemestane therapy with that of se-
quential treatment with tamoxifen for 2–3 years
followed by exemestane for 2–3 years based on
the findings of the IES.[12] In contrast to ex-
emestane, both anastrozole and letrozole are
approved for use as primary adjuvant treatments
in this patient population in the UK,[86,88] the
US[89,90] and other countries worldwide on the
basis of the findings of clinical studies.[81]
For women who have received 5 years of hor-
monal therapy there remains a persistent risk
of relapse.[82] Benefits of extending adjuvant
treatment with an aromatase inhibitor following
standard adjuvant treatment with tamoxifen
have been demonstrated for both letrozole and
anastrozole in postmenopausal women with
early-stage breast cancer.[81] Currently, only le-
trozole is approved for such an indication
(in several countries worldwide, including the
UK[88] and US[90]).
Several questions still surround the use of ex-
emestane and the aromatase inhibitors in post-
menopausal women with early-stage breast cancer.
For instance, because of the lack of comparative
Drugs 2009; 69 (7)
912
trials, it is not clear whether there are differences in
efficacy between the agents. It is also not yet clear
what the optimal duration of therapy is, whether it
is beneficial to include a period of tamoxifen
treatment before treatment with an aromatase
inactivator/inhibitor and which patients may benefit
the most from therapy. However, data from on-
going head-to-head trials[64] and other studies may
help to provide answers to some of these questions.
Advanced breast cancer is incurable, with
most patients dying due to progression of the
disease.[78] As treatment in this patient popula-
tion is predominantly palliative, factors affecting
HR-QOL, such as toxicity, are important. Thus,
endocrine therapy is generally preferred over
chemotherapy in patients with advanced hor-
mone receptor-positive breast cancer, unless the
disease is rapidly progressive in nature.[78]
Current treatment guidelines commonly re-
commend third-generation aromatase inactivators/
inhibitors as first-line treatment options for
postmenopausal women with advanced hormone
receptor-positive breast cancer,[79,91,92] with ta-
moxifen also considered an acceptable first-line
agent in certain instances in some guidelines[79,91]
(e.g. in patients naive to antiestrogen therapy or
who received antiestrogen treatment >1 year
previously[79]).
For patients who experience progression during
treatment with an antiestrogen, such as tamoxifen,
the previous standard of care was treatment with
the progestin megestrol or the non-selective first-
generation aromatase inhibitor aminoglutethi-
mide.[93] However, these agents tend to be poorly
tolerated, with adverse effects commonly leading
to discontinuation of therapy.[93] For instance,
progestins are associated with shortness of breath,
gains in bodyweight and thromboembolytic dis-
ease, whereas aminoglutethimide is associated with
drowsiness, vertigo, skin rashes and blood dyscra-
sias and requires concomitant corticosteroid re-
placement therapy.[94] Important advances over
these agents have been seen with third-generation
aromatase inactivators/inhibitors, which are now
generally the preferred second-line endocrine ther-
apy option for the treatment of advanced hormone
receptor-positive breast cancer in postmenopausal
women.[95]
ª 2009 Adis Data Information BV. All rights reserved.
Deeks & Scott
Exemestane is approved for the treatment
of advanced breast cancer in postmenopausal
women whose disease has progressed following
tamoxifen or other antiestrogen therapy in sev-
eral countries, including the UK[7] and the US;[8]
anastrozole and letrozole are also approved for
similar indications.[88-90]
In a large, well designed, phase III study, ex-
emestane provided similar efficacy to megestrol
in terms of objective response rate (primary end-
point) in postmenopausal women with advanced
breast cancer refractory to tamoxifen (section
4.2.1). Although there was also no significant
difference between the treatments in the median
duration of objective response or the rate of
overall success, exemestane recipients had a sig-
nificantly longer median duration of overall
success, time to disease progression and time to
treatment failure than megestrol recipients.
In light of the increasing use of aromatase
inactivators/inhibitors in the adjuvant treatment of
breast cancer, it is ever more likely that patients
presenting with advanced disease will already have
been treated with such agents, and some patients
will have progressed after receiving aromatase
inactivator/inhibitor therapy for advanced disease.
Results from a large, well designed, phase III study
indicate that the efficacy of exemestane is not sig-
nificantly different from that of intramuscular ful-
vestrant in patients with advanced breast cancer
refractory to a nonsteroidal aromatase inhibitor,
with regard to time to disease progression (primary
endpoint) and other endpoints, including objective
response rate, clinical benefit rate or overall survi-
val (section 4.2.1).
Unlike exemestane and the third-generation
aromatase inhibitors, which are administered
orally daily, fulvestrant is administered intramus-
cularly once monthly, which some patients may
find inconvenient. Fulvestrant has recently been
approved for the treatment of postmenopausal
women with hormone receptor-positive locally
advanced[96] or metastatic[96,97] breast cancer
with disease progression on (EU)[96] or following
(US)[97] antiestrogen therapy and for relapse on/
after adjuvant antiestrogen treatment (EU).[96]
Although exemestane is not currently approved
for use in this setting, data, some of which are
Drugs 2009; 69 (7)
Exemestane: A Review
preliminary, suggest that exemestane is an effective
first-line hormonal treatment in postmenopausal
women with hormone receptor-positive advanced
breast cancer (section 4.2.2). There were generally
no differences between exemestane and tamoxifen
or anastrozole in terms of efficacy, although a sig-
nificantly higher objective response rate was seen
with exemestane than with tamoxifen in the largest
phase III study. However, the widely available
third-generation aromatase inhibitors, anastrozole
and letrozole, have also demonstrated efficacy
relative to tamoxifen in the first-line treatment of
such patients in large well designed studies,[6] and
are approved for use as first-line treatment
options in postmenopausal women with locally
advanced or metastatic breast cancer that is hor-
mone receptor-positive or of unknown receptor
status in the US[89,90] and for similar indications in
other countries, including the UK.[88]
As yet, there are no direct comparisons of ex-
emestane and the aromatase inhibitors in patients
refractory to antiestrogen therapy, and additional
robust head-to-head clinical trials are required to
evaluate the efficacy of these agents relative to ful-
vestrant in this setting. Further head-to-head trials
are also warranted to evaluate the efficacy of ex-
emestane with respect to the aromatase inhibitors
in the first-line treatment setting and to establish the
optimal sequence of endocrine therapies.
Exemestane is generally well tolerated in
postmenopausal women with early-stage or ad-
vanced breast cancer, with most adverse events
being mild to moderate in severity and of a simi-
lar nature irrespective of the stage of disease
(section 5). As with tamoxifen and the aromatase
inhibitors,[98] exemestane is commonly associated
with adverse events typical of the menopause,
such as hot flashes (section 5). The tolerability
profile of exemestane is similar to that of fulves-
trant in women with advanced breast cancer
(section 5.1.2). However, the tolerability profiles
of the aromatase inactivators/inhibitors are dif-
ferent to, and for some tolerability issues better
than, those of traditional endocrine therapies.
Tamoxifen has estrogenic effects on some tis-
sues and is consequently associated with gynae-
cological symptoms, such as vaginal bleeding, an
increased risk of endometrial cancer, as well as
ª 2009 Adis Data Information BV. All rights reserved.
913
thromboembolic events, including deep vein
thrombosis, stroke and pulmonary embolism.[99]
Some of these tolerability issues, such as in-
creased endometrial cancer risk, are of particular
relevance to patients with early-stage breast can-
cer who may receive tamoxifen therapy for longer
than those with advanced disease. Relative to
tamoxifen, exemestane was associated with a
significantly lower incidence of certain gynaeco-
logical and thrombolytic events in the IES and
TEAM studies (section 5.1.1). Moreover, sub-
study data from the IES suggest that endometrial
abnormalities associated with tamoxifen may be
reversed after switching to exemestane in the
adjuvant setting (sections 2 and 5.1.1).
Exemestane also has some tolerability advant-
ages over megestrol in postmenopausal women
with advanced breast cancer, with exemestane re-
cipients less likely to experience dyspnoea or
moderate to severe gains in bodyweight; however,
exemestane recipients are more likely to experience
hot flashes, nausea and vomiting (section 5.1.2).
As is typical of the aromatase inhibitors,
exemestane is more commonly associated with
musculoskeletal adverse events, such as arthral-
gias, than tamoxifen (section 5), although de-
termining the precise origin of arthralgia can be
difficult because of the joint pain often associated
with the degenerative changes that typically
occur in menopausal women.[80] However, ar-
thralgias can often be managed with lifestyle
modifications (e.g. weight-bearing exercise),
physiotherapy and analgesics, such as para-
cetamol (acetaminophen) or NSAIDs.[80]
The main concern with aromatase inactivator/
inhibitor treatment, particularly in the adjuvant
setting, is the risk of skeletal events, such as os-
teoporosis and fractures, due to estrogen deple-
tion and bone demineralization (section 2).[99]
Tamoxifen has estrogenic effects on bone that
help to protect against menopause-associated
bone loss,[99] and was associated with a sig-
nificantly lower incidence of osteoporosis or
fractures than exemestane in some, but not all,
trials or substudies (section 5.2). The UK pre-
scribing information for exemestane recommend
that BMD is monitored when commencing ad-
juvant treatment in patients with, or at risk of,
Drugs 2009; 69 (7)
914
osteoporosis, and that treatment for osteoporosis
is given to patients at risk of the disease.[7] Similar
recommendations apply to both anastrozole and
letrozole.[86,88] It may be possible to minimize
bone loss during aromatase inactivator/inhibitor
therapy with the use of bisphosphonates.[100]
Anastrozole and letrozole regimens have been
associated with an increased incidence of fractures
relative to tamoxifen in some studies,[99] with more
letrozole than placebo recipients reporting osteo-
porosis in an extended adjuvant trial.[99] The effect
of exemestane on biochemical bone marker levels
did not significantly differ from those seen with
anastrozole or letrozole in healthy postmenopausal
women (section 2); however, the agents have yet to
be directly compared in terms of osteoporosis and
fracture risk in robust clinical trials in patients with
breast cancer.
Unlike tamoxifen, which may improve lipid
parameters, there is some concern regarding the
effect that aromatase inactivators/inhibitors may
have on the lipid profile, and thus, a patient’s
cardiovascular risk.[99] At present, the effect of
exemestane (section 2) and the aromatase in-
hibitors on lipid levels are not clear, with the
findings of some adjuvant studies comparing
these agents with tamoxifen considered possibly
misleading because of the potentially beneficial
effects of tamoxifen.[99] However, the incidence
of various cardiovascular adverse events was not
significantly different between exemestane and
tamoxifen recipients in the IES and TEAM stu-
dies (section 5.1.1). The effect of agents such as
exemestane on bone and lipid parameters has
not been as intensively studied in patients with
advanced breast cancer, as data interpretation is
limited by the bone metastases and metabolic
disturbances often present in such patients.[101]
Given that breast cancer is the leading cause of
death from cancer among women worldwide,[1] it
follows that treatment choices may be determined
in part by pharmacoeconomic factors. Fully
published pharmacoeconomic model analyses that
included direct medical costs have indicated that
switching to exemestane after 2–3 years of tamoxi-
fen is generally cost effective with regard to the cost
per QALY gained relative to continuing tamoxifen
treatment in postmenopausal women with early-
ª 2009 Adis Data Information BV. All rights reserved.
Deeks & Scott
stage breast cancer (section 6). Using data from
trials that did not directly compare therapeutic
regimens, some analyses predicted that switch-
ing from tamoxifen to exemestane was generally
cost saving relative to primary adjuvant treatment
with anastrozole or extended adjuvant therapy
with tamoxifen followed by letrozole with regard
to the cost per QALY gained in postmenopausal
women with early-stage breast cancer when
costs and benefits were modelled over a 20-year
time horizon (section 6). However, the findings
of such indirect analyses should be interpreted
with caution. Pharmacoeconomic studies evalua-
ting whether there are any pharmacoeconomic
differences between primary adjuvant treatment
with exemestane and sequential treatment with
tamoxifen and exemestane would be of interest, as
would pharmacoeconomic studies in advanced
breast cancer.
In conclusion, exemestane is effective for the
treatment of postmenopausal women with early-
stage or advanced breast cancer. In early-stage
disease, switching to exemestane for 2–3 years
after 2–3 years of adjuvant tamoxifen treatment
was more effective in prolonging disease-free
survival than continuing tamoxifen therapy,
although it was not associated with an overall
survival benefit, except in those with estrogen
receptor-positive or unknown receptor status
disease when nodal status, HRT and chemother-
apy use were adjusted for. Moreover, preliminary
data suggest that the efficacy of exemestane is
generally no different to that of tamoxifen in the
primary adjuvant treatment of early-stage breast
cancer, although exemestane may be better in
prolonging the time to distant metastases. In ad-
vanced disease, exemestane showed equivalent
efficacy to megestrol in patients with disease
refractory to tamoxifen and an efficacy not sig-
nificantly different from that of fulvestrant in
those refractory to a nonsteroidal aromatase in-
hibitor. Available data, some of which are limi-
ted, suggest exemestane is also effective in the
first-line hormonal treatment of advanced breast
cancer in postmenopausal women. Exemestane is
generally well tolerated, although the potential
bone fracture risk of the drug requires further
investigation and comparison with that of other
Drugs 2009; 69 (7)
Exemestane: A Review
aromatase inhibitors. Additional comparative data
are required to definitively position exemestane
with respect to other agents, in both early-stage
and advanced disease, and to determine the opti-
mal sequence of endocrine therapies. Data from
ongoing trials in patients with early-stage breast
cancer directly comparing exemestane with the
third-generation aromatase inhibitors may provide
an indication as to the relative efficacy and toler-
ability of these agents, at least in the adjuvant set-
ting. In the meantime, switching to exemestane
should be considered in postmenopausal women
who have received 2–3 years of adjuvant tamoxifen
treatment for early-stage breast cancer and is an
emerging treatment option for postmenopausal
women with advanced breast cancer refractory to
one or more antiestrogen therapies.
Disclosure
The preparation of this review was not supported by any
external funding. During the peer review process, the manu-
facturer of the agent under review was offered an opportunity to
comment on this article. Changes resulting from comments re-
ceived were made on the basis of scientific and editorial merit.
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