Download ARIMIDEX® (anastrozole) in the Treatment of Early Breast Cancer

ARIMIDEX® (anastrozole)
in the Treatment of
Early Breast Cancer
US Breast Cancer Statistics
 ~211,240 women will develop invasive breast cancer
in 20051
 ~40,410 women will die of breast cancer in 20051
 Five-year survival rate by stage2:
–
–
–
–
–
In situ
Stage I
Stage II
Stage III
Stage IV
95% to 99%
90% to 94%
68% to 86%
42% to 55%
15% to 18%
1. American Cancer Society. Cancer Facts and Figures 2005; 2. Morrow M et al. Oncology. 1997;11:
877-886. With permission of ONCOLOGY, Melville, NY.
Treatment Options for Early
Breast Cancer
Surgery to remove tumor
Radiation therapy
Adjuvant therapy
Hormonal therapy
Chemotherapy
National Cancer Institute. Breast Cancer (PDQ®): Treatment 2004.
www.nci.nih.gov/cancertopics/pdq/treatment/breast/healthprofessional.
Estrogen Production in Premenopausal
and Postmenopausal Patients
Hypothalamus
Premenopausal
Premenopausal and
Postmenopausal
Gonadotropins
(FSH + LH)
Adrenocorticotropic
hormone (ACTH)
Ovary
Pituitary gland
Prolactin
Growth Hormone
Adrenal gland
Corticosteroids
Estrogens
Progesterone
FSH=follicle-stimulating hormone; LH=luteinizing hormone.
Progesterone
Androgens
Estrogens
Hormone Receptor Status:
Relationship to Menopausal Status
Menopausal
Status
Receptor Status (%)
ER+/PgR+ ER+/PgR-
ER-/PgR+
ER-/PgR-
Pre
(n=488)
45
12
15
28
Post
(n=826)
63
15
5
17
ER=estrogen receptor; PgR=progesterone receptor.
Bland KI et al. Surg Forum. 1981;32:410-412.
Hormonal Therapies for Postmenopausal
Women With Hormone Receptor-Positive
Early Breast Cancer
Therapy
Mechanism of Action
Antiestrogens
(eg, tamoxifen)
Compete with endogenous
estrogen for binding sites
on estrogen receptors
Aromatase inhibitors
(eg, ARIMIDEX®
[anastrozole])
Inhibit conversion of
androgens to estrogens
EBCTCG. Lancet. 1992;339:1-15;71-85; ARIMIDEX® (anastrozole) full Prescribing Information;
AstraZeneca Pharmaceuticals LP, Wilmington, DE.
Aromatase Inhibition
 The aromatase enzyme selectively catalyzes
only the production of estrogens (not other
steroid hormones)
 Types of aromatase inhibitors
– Selective vs nonselective
– Competitive vs noncompetitive (irreversible)
Selective vs Nonselective
Aromatase Inhibition
Cholesterol
Multiple steps involving cytochrome P450 enzymes
and production of steroid intermediates
Selective inhibitors
Nonselective inhibitors
Aldosterone
Cortisol
Androstenedione
Testosterone
Aromatase
Estrone
Aromatase
Estradiol
Federman DD. The Adrenal. In: Dale DC, Federman DD, eds. Scientific American Medicine.
New York, NY: Scientific American Inc.; 1997.
Noncompetitive vs Competitive
Aromatase Inhibitors
Noncompetitive (“suicide”)
Competitive
 Steroidal
 Nonsteroidal or steroidal
 Daily administration
 Daily administration
 Covalent bond irreversibly
inactivates enzyme
 Reversibly binds to the active
enzyme binding site
 Enzyme activity is restored by
new enzyme synthesis
 Enzyme binding depends on
relative concentrations and
affinities of inhibitor and
substrate
 Partial lack of crossresistance with nonsteroidal
inhibitors
Brodie AMH. Pharmacol Ther. 1993;60:501-515; Geisler J et al. Eur J Cancer. 1996;32A:789-792;
Murray R, Pitt P. Breast Cancer Res Treat. 1995;35:249-253; Lønning PE et al. J Clin Oncol.
2000;18:2234-2244.
Aromatase Inhibitors*: Characteristics
and Approved Indications
EBC
Agent
Primary
Adjuvant
Extended
Adjuvant
Competitive
Steroidal
Anastrozole
(ARIMIDEX)
Yes
No

–

Letrozole
(Femara)
Yes
No
–


Exemestane
(Aromasin)
No
Yes
–
–

Aminoglutethimide
(Cytadren)
Yes
No
–
–

=indicated ; – =not indicated.
*Available in the United States.
EBC=early breast cancer; ABC=advanced breast cancer.
ABC
ARIMIDEX® (anastrozole)
 Potent nonsteroidal inhibitor of
aromatase
N
 Achiral triazole derivative
N
 Selective and competitive
N
 Orally active
 Half-life = 50 hours
 Steady state in 7 days
 Hepatic metabolism (85%)
CH3
CH3
CH3
CN
CN
CH3
 Available in United States since 1996
 Approved dosage = 1 mg/day
Anastrozole
(C17H19N5)
ARIMIDEX® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE.
Effect of ARIMIDEX® (anastrozole) on
Aromatase and Plasma Estrogens
% Reduction (Mean)
ARIMIDEX
1 mg (n=12)
ARIMIDEX
10 mg (n=12)
Aromatase
96.7
98.1
Estradiol
84.0
83.5
Estrone
86.8
86.5
Estrone sulfate
93.5
95.7
The clinical relevance of these findings has not been fully evaluated.
Geisler J et al. Br J Cancer. 1996;74:1286-1291.
Current Indications for ARIMIDEX®
(anastrozole)
 Primary adjuvant treatment of postmenopausal women with
hormone receptor-positive early breast cancer based on an analysis
of disease-free survival in patients treated for a median of 31
months. Further follow-up of study patients is required to determine
long-term outcomes
 First-line treatment of postmenopausal women with hormone
receptor-positive or hormone receptor-unknown locally advanced or
metastatic breast cancer
 Second-line treatment of advanced breast cancer in
postmenopausal women with disease progression following
tamoxifen therapy. Patients with ER-negative disease and patients
who did not respond to previous tamoxifen therapy rarely responded
to ARIMIDEX
ARIMIDEX® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE.
The ATAC Trial
 ATAC – ARIMIDEX, Tamoxifen Alone or in Combination
– One of the largest breast cancer treatment trials ever conducted
(N=9366) involving 881 centers in 21 countries
– First trial of adjuvant treatment of early operable breast cancer
in postmenopausal women using a selective aromatase
inhibitor
– Indication in early breast cancer based on median of 31 months
of treatment; median follow-up now extends to 68 months
 Designed to determine:
1. ARIMIDEX® (anastrozole) at least as effective or more effective
than tamoxifen
2. Safety for ARIMIDEX compared with tamoxifen
3. Safety and efficacy of the combination compared with tamoxifen
ATAC Trial: Design
Postmenopausal women with operable invasive
breast cancer (N=9366)
Surgery ± radiotherapy ± chemotherapy
randomization 1:1:1 for 5 years
ARIMIDEX® (anastrozole)
1 mg qd
+
Tamoxifen placebo
ARIMIDEX placebo
+
Tamoxifen 20 mg qd
ARIMIDEX 1 mg qd
+
Tamoxifen 20 mg qd
Regular follow-up
Primary trial endpoints
 Disease-free survival
 Safety/tolerability
Secondary trial endpoints
 Incidence of contralateral breast cancer
 Time to distant recurrence
 Survival
ATAC Trial: Combination Arm
 Discontinued after initial analysis (median followup of 33 months)
 Rationale for discontinuation
– No significant difference between tamoxifen and
combination arm in efficacy or tolerability
ATAC Trial: Efficacy Endpoints
Primary Endpoint
Disease-free survival
(Locoregional or distant recurrence, new primary breast
cancer, or death from any cause [as a first event])
Secondary Endpoints
Overall survival
Distant disease-free survival
Incidence of new (contralateral) breast cancers
Hormone receptor-positive population was a protocol-defined subgroup.
ARIMIDEX® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE.
ATAC Trial: Patient Characteristics
ARIMIDEX®
(anastrozole)
(n=3125)
Tamoxifen
(n=3116)
Combination
(n=3125)
Mean age (years)
64.1
64.1
64.3
Mean weight (kg)
70.8
71.1
71.3
Positive*
83.5
83.1
83.8
Negative†
7.4
8.0
7.0
Other‡
8.8
8.6
9.1
Receptor status (%)
*Includes patients who were ER-positive or PgR-positive, or both positive; †includes patients with both
ER-negative and PgR-negative receptor status; ‡includes all other combinations of ER and PgR receptor
status unknown.
ARIMIDEX® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE.
ATAC Trial: Patient Characteristics
(cont’d)
ARIMIDEX®
(anastrozole)
(n=3125)
Tamoxifen
(n=3116)
Combination
(n=3125)
Mastectomy
47.8
47.3
48.1
Breast conservation*
52.3
52.8
52
Axillary surgery
95.5
95.7
95.2
Radiotherapy
63.3
62.5
62
Chemotherapy
22.3
20.8
20.8
Prior tamoxifen
1.6
1.6
1.7
Primary Treatment (%)
*Among patients with breast conservation, radiotherapy was administered to 95% of patients in the
ARIMIDEX arm, 94.1% in the tamoxifen arm, and 94.5% in the tamoxifen + ARIMIDEX combination arm.
ARIMIDEX® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE.
ATAC Trial: Table of First Events in ITT
Population (Median Follow-up of 33 Months)
ARIMIDEX®
(anastrozole)
(n=3125)
Tamoxifen
(n=3116)
Total first events
318
379
Locoregional*
67
83
Distant
157
181
New contralateral primaries
14
33
Contralateral (invasive)
9
30
Contralateral (DCIS)
5
3
Deaths from breast cancer†
4
1
Deaths for other reason‡
76
81
DCIS=ductal carcinoma in situ.
*Including new primary ipsilateral breast cancer (including DCIS), and recurrences at the chest wall, axillary, and other
regional lymph nodes; †includes deaths due to breast cancer that were reported as first events without evidence of prior
recurrence. Subsequent evaluation for 47-month follow-up identified documentation for recurrence prior to death or death
from cause other than breast cancer in these patients; ‡includes only deaths that were first events.
ARIMIDEX® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE.
ATAC Trial: All Recurrence and Death Events in
HR+ Population (Median Follow-up of 68 Months)
ARIMIDEX®
(anastrozole)
(n=2618)
Tamoxifen
(n=2598)
Locoregional recurrence*
76
101
Distant recurrence*
226
265
Contralateral breast cancer
26
54
Death from any cause
296
301
*Distant
recurrence is defined as the time between randomization and the earliest occurrence of distant recurrence or
death following a locoregional occurrence.
ATAC Trial: Disease-Free Survival in HR-Positive
Subpopulation (Median Follow-up of 68 Months)
Proportion with first event (%)
Probability of a first event (HR-positive subgroup)
25
Number of events:
ARIMIDEX vs tamoxifen
Hazard ratio
95% CI
P
424 vs 497
575 vs 651
0.83
0.87
0.73-0.94
0.78-0.97
.005
.01
HR+
ITT
20
15
10
ARIMIDEX®
Tamoxifen
5
Absolute
difference:
1.6%
0
0
1
2
At risk:
ARIMIDEX
2618
2540
2448
2355
Tamoxifen
2598
2516
2398
2304
2.6%
3
4
Follow-up time (years)
2.5%
3.3%
5
6
2268
2014
830
2189
1932
774
Howell A et al. Presentation at the 27th Annual San Antonio Breast Cancer Symposium; December 8-11, 2004;
San Antonio, Tex.
ATAC Trial: Increased Incidence of Prespecified Adverse
Events With ARIMIDEX® (anastrozole) Compared With
Tamoxifen (Median Treatment of 60 Months)
ARIMIDEX
% (n=3092)
Tamoxifen
% (n=3094)
Odds Ratio
(A vs T)
95% CI
P
11.0
7.7
1.49
1.25-1.77
<.0001
Hip†
1.2
1.0
1.20
0.74-1.93
.5
Spine
1.5
0.9
1.68
1.04-2.71
.03
Wrist/ Colles
2.3
2.0
1.15
0.81-1.61
.4
All other sites‡
7.1
4.6
1.59
1.28-1.98
<.0001
35.6
29.4
1.32
1.19-1.47
<.0001
All fractures*
Fractures of
Musculoskeletaldisorders: Arthralgia
*Patients 1 fracture occurring before recurrence, including patients no longer on treatment; †the
incidence of hip fracture was low and similar for ARIMIDEX and tamoxifen; ‡patients may have had 1
fractures at different sites.
ATAC Trialists’ Group. Lancet. 2005:365:60-62.
ATAC Trial: Decreased Incidence of Prespecified Adverse
Events With ARIMIDEX® (anastrozole) Compared With
Tamoxifen (Median Treatment of 60 Months)
ARIMIDEX
% (n=3092)
Tamoxifen
% (n=3094)
Odds Ratio
(A vs T)
95% CI
P
Hot flashes
35.7
40.9
0.80
0.73- 0.89
<00001
Vaginal bleeding
5.4
10.2
0.50
0.41-0.61
<.0001
Vaginal discharge
3.5
13.2
0.24
0.19-0.30
<.0001
Venous thromboembolic events
2.8
4.5
0.61
0.47-0.80
.0004
Deep venous thromboembolic
events
1.6
2.4
0.64
0.45-0.93
.02
Ischemic cerebrovascular
events
2.0
2.8
0.70
0.50-0.97
.03
Endometrial cancer*
0.2
0.8
0.29
0.11-0.80
.02
*n=2229 for ARIMIDEX, n=2236 for tamoxifen, excluding patients with hysterectomy at baseline,
recorded at any time.
ATAC Trialists’ Group. Lancet. 2005:365:60-62.
ATAC Trial: Comparable Incidence of Prespecified Adverse
Events With ARIMIDEX® (anastrozole) Compared With
Tamoxifen (Median Treatment of 60 Months)
ARIMIDEX
% (n=3092)
Tamoxifen
% (n=3094)
Odds Ratio
(A vs T)
95% CI
P
Ischemic
cardiovascular
disease
4.1
3.4
1.23
0.95-1.60
.1
Mood disturbances
19.3
17.9
1.10
0.97-1.25
.2
Nausea and vomiting
12.7
12.4
1.03
0.88-1.19
.7
Fatigue/tiredness
18.6
17.6
1.07
0.94-1.22
.3
Cataracts
5.9
6.9
0.85
0.69-1.04
.1
*Angina pectoris was reported more frequently in the ARIMIDEX-treated patients (2.3%) than in the
tamoxifen-treated patients (1.6%). Comparable number of incidences of myocardial infarction (ARIMIDEX
[1.2%]; tamoxifen, [1.1%]) and of cardiac-related mortality (ARIMIDEX [1.4%]; tamoxifen, [1.4%]) were
reported.
ATAC Trialists’ Group. Lancet. 2005:365:60-62; Data on File, DA-ARI-06, AstraZeneca Pharmaceuticals, LP.
Important Safety Information About
ARIMIDEX® (anastrozole)
 Analysis performed at a median treatment of 60 months
 Patients receiving ARIMIDEX had a mean decrease in
both lumbar spine and total hip bone mineral density
(BMD) compared with baseline. Patients receiving
tamoxifen had a mean increase in both lumbar spine and
total hip BMD compared with baseline
 More patients receiving ARIMIDEX were reported to
have an elevated serum cholesterol compared with
patients receiving tamoxifen
(9% vs 3.5%, respectively)
Other Important Safety Information
 Women must be postmenopausal to take ARIMIDEX®
(anastrozole). ARIMIDEX can cause fetal harm when
administered to a pregnant woman
 Estrogen-containing therapies should not be used with
ARIMIDEX as they may diminish its pharmacologic
action
 Tamoxifen should not be co-administered with
ARIMIDEX
Other Important Safety Information
(cont’d)
 At a median treatment of 60 months, the most common
side effects seen with ARIMIDEX® (anastrozole) vs
tamoxifen in the ATAC Trial include
– Hot flashes (36% vs 41%)
– Joint disorders (including arthritis, arthrosis, and arthralgia)
(36% vs 29%)
– Fatigue/asthenia (19% vs 18%)
– Mood disturbances (19% vs 18%)
– Pain (17% vs 16%)
– Nausea and vomiting (13% vs 12%)
– Pharyngitis (14% vs 14%)
– Depression (13% vs 12%)
– Fractures, including fractures of the spine, hip, and wrist
(10% vs 7%)
Current Indications for NOLVADEX®
(tamoxifen citrate)
 Treatment of node-positive breast cancer in
postmenopausal women following total mastectomy or
segmental mastectomy, axillary dissection, and breast
irradiation
 Treatment of axillary node-negative breast cancer in
women following total mastectomy or segmental
mastectomy, axillary dissection, and breast irradiation
 NOLVADEX reduces the occurrence of contralateral
breast cancer in patients receiving adjuvant therapy with
NOLVADEX for breast cancer
NOLVADEX® (tamoxifen citrate) full Prescribing information, AstraZeneca Pharmaceuticals LP,
Wilmington, DE
Important Safety Information
About Tamoxifen
 Serious and life-threatening events associated with NOLVADEX
(tamoxifen citrate) include uterine malignancies, stroke, and pulmonary
emboli, some of which have been fatal. In clinical trials, uterine
malignancies, including endometrial cancer and uterine sarcomas (see
WARNINGS, Effects on the Uterus—Endometrial Cancer and Uterine
Sarcoma, in full Prescribing Information), and venous thrombotic events,
including pulmonary emboli, occurred 2 to 4 times more often with
NOLVADEX than placebo, but each in less then 1% of women. Stroke,
cataracts, and cataract surgery also occurred more often with
NOLVADEX. The most frequently reported adverse reactions were hot
flashes and vaginal discharge
 Women who are pregnant or plan to become pregnant should not take
NOLVADEX. Women who have a history of deep vein thrombosis or
pulmonary embolism or who currently use anticoagulants should not take
NOLVADEX to reduce their risk of breast cancer (see
CONTRAINDICATIONS section of full Prescribing Information)
Dosage and Duration of ARIMIDEX®
(anastrozole) Therapy
 Dosage: 1-mg tablet taken once a day
 Optimal duration of adjuvant therapy is unknown
ATAC Trial: Efficacy Summary (Median
Follow-up of 68 Months)
 ARIMIDEX® (anastrozole) shows:
– Significantly improved disease-free survival over
tamoxifen
– Significant reduction in the event rate in hormone
receptor-positive patients (hazard ratio 0.83 [95% CI,
0.73-0.94], P=.005)
– Significant reduction in the event rate seen in the
overall population (hazard ratio 0.87 [95% CI,
0.78-0.97], P=.01)
 These study results are based on patients
followed for a median of 68 months
ATAC Trial: Safety Summary
(Median Treatment of 60 months)
 ARIMIDEX® (anastrozole) showed increased incidence of:
– Joint disorders (including arthritis, arthrosis, and arthralgia)
– Fractures, including fractures of the spine, hip and wrist
 ARIMIDEX showed decreased incidence of:
– Hot flashes
– Vaginal bleeding and discharge
– Venous thromboembolic events, including deep venous
thromboembolic events
– Ischemic cerebrovascular events
– Endometrial cancer
Conclusions: in Early Breast Cancer
 The ASCO 2005 Technology Assessment recommends:
– “Based on results from multiple large randomized trials, adjuvant
therapy for postmenopausal women with hormone receptorpositive breast cancer should include an aromatase inhibitor in
order to lower the risk of tumor recurrence”
– “It is unknown if the three available drugs are interchangeable in
clinical practice. In general, the Panel favors using the
aromatase inhibitor that has been studied in the setting most
closely approximating any individual patient’s clinical
circumstances.”
Conclusions: ARIMIDEX® (anastrozole)
in Early Breast Cancer
 In the ATAC Trial, at a median follow-up of 68 months,
ARIMIDEX significantly improved disease-free survival
over tamoxifen in postmenopausal women with hormone
receptor-positive early breast cancer
 ARIMIDEX is the first aromatase inhibitor approved as
primary adjuvant therapy for early breast cancer in
postmenopausal women with hormone receptor-positive
disease