ARIMIDEXARIMIDEX®® (anastrozole) (anastrozole) in the Treatment of in the Treatment of Early Breast Cancer Early Breast Cancer

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.

US Breast Cancer StatisticsUS Breast Cancer Statistics ~211,240 women will develop invasive breast cancer ~211,240 women will develop invasive breast cancer

in 2005in 200511

~40,410 women will die of breast cancer in 2005~40,410 women will die of breast cancer in 200511

Five-year survival rate by stageFive-year survival rate by stage22::– In situ In situ 95% to 99%95% to 99%– Stage I Stage I 90% to 94%90% to 94%– Stage II Stage II 68% to 86%68% to 86%– Stage IIIStage III 42% to 55%42% to 55%– Stage IVStage IV 15% to 18%15% to 18%

Treatment Options for Early Treatment Options for Early Breast CancerBreast Cancer

National Cancer Institute. Breast Cancer (PDQ®): Treatment 2004.www.nci.nih.gov/cancertopics/pdq/treatment/breast/healthprofessional.

Surgery to remove tumorSurgery to remove tumorSurgery to remove tumorSurgery to remove tumor

Radiation therapyRadiation therapyRadiation therapyRadiation therapy

Adjuvant therapyAdjuvant therapyAdjuvant therapyAdjuvant therapy

Hormonal therapyHormonal therapyHormonal therapyHormonal therapy ChemotherapyChemotherapyChemotherapyChemotherapy

Estrogen Production in Premenopausal Estrogen Production in Premenopausal and Postmenopausal Patientsand Postmenopausal Patients

HypothalamusHypothalamus

GonadotropinsGonadotropins(FSH + LH)(FSH + LH)

OvaryOvary

EstrogensEstrogensProgesteroneProgesterone

ProlactinProlactinGrowth HormoneGrowth Hormone

Pituitary glandPituitary gland

Adrenal glandAdrenal gland

ProgesteroneProgesterone

AndrogensAndrogensEstrogensEstrogens

CorticosteroidsCorticosteroids

AdrenocorticotropicAdrenocorticotropichormone (ACTH)hormone (ACTH)

PremenopausalPremenopausalPremenopausalPremenopausal Premenopausal and Premenopausal and PostmenopausalPostmenopausal

Premenopausal and Premenopausal and PostmenopausalPostmenopausal

FSH=follicle-stimulating hormone; LH=luteinizing hormone.

Hormone Receptor Status:Hormone Receptor Status:Relationship to Menopausal StatusRelationship to Menopausal Status

Menopausal Menopausal StatusStatus Receptor Status (%)Receptor Status (%)

ER+/PgR+ER+/PgR+ ER+/PgR-ER+/PgR- ER-/PgR+ER-/PgR+ ER-/PgR-ER-/PgR-

PrePre(n=488)(n=488)

4545 1212 1515 2828

PostPost(n=826)(n=826)

6363 1515 55 1717

ER=estrogen receptor; PgR=progesterone receptor.

Bland KI et al. Surg Forum. 1981;32:410-412.

Hormonal Therapies for Postmenopausal Hormonal Therapies for Postmenopausal Women With Hormone Receptor-Positive Women With Hormone Receptor-Positive Early Breast CancerEarly Breast Cancer

TherapyTherapy Mechanism of ActionMechanism of Action

Antiestrogens Antiestrogens (eg, tamoxifen)(eg, tamoxifen)

Compete with endogenous Compete with endogenous estrogen for binding sites estrogen for binding sites on estrogen receptorson estrogen receptors

Aromatase inhibitors Aromatase inhibitors (eg, ARIMIDEX(eg, ARIMIDEX®® [anastrozole])[anastrozole])

Inhibit conversion of Inhibit conversion of androgens to estrogensandrogens to estrogens

EBCTCG. Lancet. 1992;339:1-15;71-85; ARIMIDEX® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE.

Aromatase InhibitionAromatase Inhibition

The aromatase enzyme selectively catalyzes The aromatase enzyme selectively catalyzes only the production of estrogens (not other only the production of estrogens (not other steroid hormones)steroid hormones)

Types of aromatase inhibitorsTypes of aromatase inhibitors– Selective vs nonselectiveSelective vs nonselective– Competitive vs noncompetitive (irreversible)Competitive vs noncompetitive (irreversible)

Selective vs NonselectiveSelective vs NonselectiveAromatase InhibitionAromatase Inhibition

Federman DD. The Adrenal. In: Dale DC, Federman DD, eds. Scientific American Medicine. New York, NY: Scientific American Inc.; 1997.

Multiple steps involving cytochrome P450 enzymes Multiple steps involving cytochrome P450 enzymes and production of steroid intermediatesand production of steroid intermediates

CortisolCortisol AndrostenedioneAndrostenedioneAldosteroneAldosterone

TestosteroneTestosterone

EstroneEstrone EstradiolEstradiol

Selective inhibitorsSelective inhibitors

Nonselective inhibitorsNonselective inhibitors

CholesterolCholesterol

AromataseAromataseAromataseAromatase

Noncompetitive vs Competitive Noncompetitive vs Competitive Aromatase InhibitorsAromatase Inhibitors

Noncompetitive (“suicide”)Noncompetitive (“suicide”)

SteroidalSteroidal

Daily administrationDaily administration

Covalent bond irreversibly Covalent bond irreversibly inactivates enzymeinactivates enzyme

Enzyme activity is restored by Enzyme activity is restored by new enzyme synthesisnew enzyme synthesis

Partial lack of cross- Partial lack of cross- resistance with nonsteroidal resistance with nonsteroidal inhibitorsinhibitors

CompetitiveCompetitive

Nonsteroidal or steroidalNonsteroidal or steroidal

Daily administrationDaily administration

Reversibly binds to the active Reversibly binds to the active enzyme binding siteenzyme binding site

Enzyme binding depends on Enzyme binding depends on relative concentrations and relative concentrations and affinities of inhibitor and affinities of inhibitor and substratesubstrate

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 Aromatase Inhibitors*: Characteristics and Approved Indicationsand Approved Indications

AgentAgent CompetitiveCompetitiveSteroidalSteroidal

EBCEBC

ABCABCPrimaryPrimaryAdjuvantAdjuvant

ExtendedExtendedAdjuvantAdjuvant

Anastrozole Anastrozole (ARIMIDEX (ARIMIDEX))

YesYes NoNo ––

LetrozoleLetrozole (Femara (Femara))

YesYes NoNo ––

Exemestane Exemestane (Aromasin (Aromasin))

NoNo YesYes –– ––

AminoglutethimideAminoglutethimide (Cytadren (Cytadren))

YesYes NoNo –– ––

=indicated ; – =not indicated.*Available in the United States.EBC=early breast cancer; ABC=advanced breast cancer.

ARIMIDEXARIMIDEX®® (anastrozole) (anastrozole) Potent nonsteroidal inhibitor of Potent nonsteroidal inhibitor of

aromatase aromatase

Achiral triazole derivativeAchiral triazole derivative

Selective and competitiveSelective and competitive

Orally activeOrally active

Half-life = 50 hours Half-life = 50 hours

Steady state in 7 daysSteady state in 7 days

Hepatic metabolism (85%)Hepatic metabolism (85%)

Available in United States since 1996Available in United States since 1996

Approved dosage = 1 mg/dayApproved dosage = 1 mg/day

ARIMIDEX® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE.

AnastrozoleAnastrozole(C(C1717HH1919NN55))

CNCN CNCN

NNNN

NN

CHCH33 CHCH33

CHCH33

CHCH33

Effect of ARIMIDEXEffect of ARIMIDEX®® (anastrozole) on (anastrozole) on Aromatase and Plasma EstrogensAromatase and Plasma Estrogens

% Reduction (Mean)% Reduction (Mean)

ARIMIDEXARIMIDEX1 mg (n=12)1 mg (n=12)

ARIMIDEXARIMIDEX10 mg (n=12)10 mg (n=12)

AromataseAromatase 96.796.7 98.198.1

EstradiolEstradiol 84.084.0 83.583.5

EstroneEstrone 86.886.8 86.586.5

Estrone sulfateEstrone sulfate 93.593.5 95.795.7

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 ARIMIDEXCurrent Indications for ARIMIDEX®® (anastrozole)(anastrozole) Primary adjuvant treatment of postmenopausal women with Primary adjuvant treatment of postmenopausal women with

hormone receptor-positive early breast cancer based on an analysis hormone receptor-positive early breast cancer based on an analysis of disease-free survival in patients treated for a median of 31 of disease-free survival in patients treated for a median of 31 months. Further follow-up of study patients is required to determine months. Further follow-up of study patients is required to determine long-term outcomeslong-term outcomes

First-line treatment of postmenopausal women with hormone First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancermetastatic breast cancer

Second-line treatment of advanced breast cancer in Second-line treatment of advanced breast cancer in postmenopausal women with disease progression following postmenopausal women with disease progression following tamoxifen therapy. Patients with ER-negative disease and patients tamoxifen therapy. Patients with ER-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded who did not respond to previous tamoxifen therapy rarely responded to ARIMIDEXto ARIMIDEX

ARIMIDEX® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE.

The ATAC TrialThe ATAC Trial ATAC – ARIMIDEX, Tamoxifen Alone or in CombinationATAC – ARIMIDEX, Tamoxifen Alone or in Combination

– One of the largest breast cancer treatment trials ever One of the largest breast cancer treatment trials ever conducted (N=9366) involving 881 centers in 21 countriesconducted (N=9366) involving 881 centers in 21 countries

– First trial of adjuvant treatment of early operable breast cancer First trial of adjuvant treatment of early operable breast cancer in postmenopausal women using a selective aromatase in postmenopausal women using a selective aromatase inhibitorinhibitor

– Indication in early breast cancer based on median of 31 months Indication in early breast cancer based on median of 31 months of treatment; median follow-up now extends to 68 monthsof treatment; median follow-up now extends to 68 months

Designed to determine:Designed to determine:1.1. ARIMIDEXARIMIDEX®® (anastrozole) (anastrozole) at least as effective or more effective at least as effective or more effective

than tamoxifenthan tamoxifen2.2. Safety for ARIMIDEX compared with tamoxifenSafety for ARIMIDEX compared with tamoxifen3.3. Safety and efficacy of the combination compared with tamoxifenSafety and efficacy of the combination compared with tamoxifen

ATAC Trial: DesignATAC Trial: DesignPostmenopausal women with operable invasive

breast cancer (N=9366)Postmenopausal women with operable invasive

breast cancer (N=9366)

Surgery ± radiotherapy ± chemotherapySurgery ± radiotherapy ± chemotherapy

randomization 1:1:1 for 5 yearsrandomization 1:1:1 for 5 years

Regular follow-upRegular follow-up

Primary trial endpoints Disease-free survival Safety/tolerability

Primary trial endpoints Disease-free survival Safety/tolerability

ARIMIDEXARIMIDEX®® (anastrozole) (anastrozole)1 mg qd1 mg qd

++Tamoxifen placeboTamoxifen placebo

ARIMIDEXARIMIDEX®® (anastrozole) (anastrozole)1 mg qd1 mg qd

++Tamoxifen placeboTamoxifen placebo

ARIMIDEX 1 mg qdARIMIDEX 1 mg qd++

Tamoxifen 20 mg qd Tamoxifen 20 mg qd

ARIMIDEX 1 mg qdARIMIDEX 1 mg qd++

Tamoxifen 20 mg qd Tamoxifen 20 mg qd

Secondary trial endpoints Incidence of contralateral breast cancer Time to distant recurrence Survival

ARIMIDEX placeboARIMIDEX placebo++

Tamoxifen 20 mg qd Tamoxifen 20 mg qd

ARIMIDEX placeboARIMIDEX placebo++

Tamoxifen 20 mg qd Tamoxifen 20 mg qd

ATAC Trial: Combination ArmATAC Trial: Combination Arm

Discontinued after initial analysis (median follow-Discontinued after initial analysis (median follow-up of 33 months)up of 33 months)

Rationale for discontinuationRationale for discontinuation– No significant difference between tamoxifen and No significant difference between tamoxifen and

combination arm in efficacy or tolerabilitycombination arm in efficacy or tolerability

ATAC Trial: Efficacy EndpointsATAC Trial: Efficacy Endpoints

Primary EndpointPrimary Endpoint

Disease-free survivalDisease-free survival

(Locoregional or distant recurrence, new primary breast (Locoregional or distant recurrence, new primary breast cancer, or death from any cause [as a first event])cancer, or death from any cause [as a first event])

Secondary EndpointsSecondary Endpoints

Overall survivalOverall survival

Distant disease-free survivalDistant disease-free survival

Incidence of new (contralateral) breast cancersIncidence 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 CharacteristicsATAC Trial: Patient Characteristics

*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.

ARIMIDEXARIMIDEX®®

(anastrozole)(anastrozole)(n=3125)(n=3125)

TamoxifenTamoxifen(n=3116)(n=3116)

CombinationCombination(n=3125)(n=3125)

Mean age (years)Mean age (years) 64.164.1 64.164.1 64.364.3

Mean weight (kg)Mean weight (kg) 70.870.8 71.171.1 71.371.3

Receptor status (%)Receptor status (%)

Positive*Positive* 83.583.5 83.183.1 83.883.8

NegativeNegative†† 7.47.4 8.08.0 7.07.0

OtherOther‡‡ 8.88.8 8.68.6 9.19.1

ATAC Trial: Patient Characteristics ATAC Trial: Patient Characteristics (cont’d)(cont’d)

*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.

Primary Treatment (%)Primary Treatment (%)

ARIMIDEXARIMIDEX®® (anastrozole)(anastrozole)

(n=3125)(n=3125)TamoxifenTamoxifen(n=3116)(n=3116)

CombinationCombination(n=3125)(n=3125)

Mastectomy Mastectomy 47.847.8 47.347.3 48.148.1

Breast conservation*Breast conservation* 52.352.3 52.852.8 5252

Axillary surgeryAxillary surgery 95.595.5 95.795.7 95.295.2

RadiotherapyRadiotherapy 63.363.3 62.562.5 6262

ChemotherapyChemotherapy 22.322.3 20.820.8 20.820.8

Prior tamoxifenPrior tamoxifen 1.61.6 1.61.6 1.71.7

ATAC Trial: Table of First Events in ITT ATAC Trial: Table of First Events in ITT Population (Median Follow-up of 33 Months)Population (Median Follow-up of 33 Months)

ARIMIDEXARIMIDEX®® (anastrozole)(anastrozole)

(n=3125)(n=3125)TamoxifenTamoxifen(n=3116)(n=3116)

Total first eventsTotal first events 318318 379379

Locoregional*Locoregional* 6767 8383

DistantDistant 157157 181181

New contralateral primariesNew contralateral primaries 1414 3333

Contralateral (invasive)Contralateral (invasive) 99 3030

Contralateral (DCIS)Contralateral (DCIS) 55 33

Deaths from breast cancerDeaths from breast cancer†† 44 11

Deaths for other reasonDeaths for other reason‡‡ 7676 8181DCIS=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 ATAC Trial: All Recurrence and Death Events in HR+ Population (Median Follow-up of 68 Months)HR+ Population (Median Follow-up of 68 Months)

ARIMIDEXARIMIDEX®® (anastrozole)(anastrozole)

(n=2618)(n=2618)TamoxifenTamoxifen(n=2598)(n=2598)

Locoregional recurrence*Locoregional recurrence* 7676 101101

Distant recurrenceDistant recurrence** 226226 265265

Contralateral breast cancerContralateral breast cancer 2626 5454

Death from any causeDeath from any cause 296296 301301

**Distant recurrence is defined as the time between randomization and the earliest occurrence of distant recurrence or death following a locoregional occurrence.

Howell A et al. Presentation at the 27th Annual San Antonio Breast Cancer Symposium; December 8-11, 2004; San Antonio, Tex.

At risk:At risk:

ARIMIDEXARIMIDEX 26182618 25402540 24482448 23552355 22682268 20142014 830830

TamoxifenTamoxifen 25982598 25162516 23982398 23042304 21892189 19321932 774774

ATAC Trial: Disease-Free Survival in HR-Positive ATAC Trial: Disease-Free Survival in HR-Positive Subpopulation Subpopulation (Median Follow-up of 68 Months)(Median Follow-up of 68 Months)

Number of events:Number of events:ARIMIDEX vs tamoxifenARIMIDEX vs tamoxifen Hazard ratioHazard ratio 95% CI95% CI PP

HR+HR+ITTITT

424 vs 497424 vs 497575 vs 651575 vs 651

0.830.830.870.87

0.73-0.940.73-0.940.78-0.970.78-0.97

.005.005.01.01

Probability of a first event (HR-positive subgroup) Probability of a first event (HR-positive subgroup)

Follow-up time (years)Follow-up time (years)

0

5

10

15

20

25

0 1 2 3 4 5 6

Absolute difference:

1.6% 2.6% 2.5% 3.3%

Pro

po

rtio

n w

ith

fir

st e

ven

t (%

)P

rop

ort

ion

wit

h f

irst

eve

nt

(%)

ARIMIDEX®

Tamoxifen

ARIMIDEXARIMIDEX% (n=3092)% (n=3092)

TamoxifenTamoxifen % (n=3094)% (n=3094)

Odds RatioOdds Ratio(A vs T)(A vs T) 95% CI95% CI PP

All fractures*All fractures* 11.011.0 7.77.7 1.491.49 1.25-1.771.25-1.77 <.0001<.0001

Fractures of Fractures of

HipHip†† 1.21.2 1.01.0 1.201.20 0.74-1.930.74-1.93 .5.5

SpineSpine 1.51.5 0.90.9 1.681.68 1.04-2.711.04-2.71 .03.03

Wrist/ CollesWrist/ Colles 2.32.3 2.02.0 1.151.15 0.81-1.610.81-1.61 .4.4

All other sitesAll other sites‡‡ 7.17.1 4.64.6 1.591.59 1.28-1.981.28-1.98 <.0001<.0001

Musculoskeletal-Musculoskeletal-disorders: Arthralgiadisorders: Arthralgia

35.635.6 29.429.4 1.321.32 1.19-1.471.19-1.47 <.0001<.0001

*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: Increased Incidence of Prespecified Adverse ATAC Trial: Increased Incidence of Prespecified Adverse Events With ARIMIDEXEvents With ARIMIDEX®® (anastrozole) Compared With (anastrozole) Compared With Tamoxifen (Tamoxifen (Median Treatment of 60 Months)Median Treatment of 60 Months)

ATAC Trial: Decreased Incidence of Prespecified Adverse ATAC Trial: Decreased Incidence of Prespecified Adverse Events With ARIMIDEXEvents With ARIMIDEX®® (anastrozole) Compared With (anastrozole) Compared With Tamoxifen (Tamoxifen (Median Treatment of 60 Months)Median Treatment of 60 Months)

ARIMIDEXARIMIDEX% (n=3092)% (n=3092)

TamoxifenTamoxifen % (n=3094)% (n=3094)

Odds RatioOdds Ratio(A vs T)(A vs T) 95% CI95% CI PP

Hot flashesHot flashes 35.735.7 40.940.9 0.800.80 0.73- 0.890.73- 0.89 <00001<00001

Vaginal bleedingVaginal bleeding 5.45.4 10.210.2 0.500.50 0.41-0.610.41-0.61 <.0001<.0001

Vaginal dischargeVaginal discharge 3.53.5 13.213.2 0.240.24 0.19-0.300.19-0.30 <.0001<.0001

Venous thromboembolic eventsVenous thromboembolic events 2.82.8 4.54.5 0.610.61 0.47-0.800.47-0.80 .0004.0004

Deep venous thromboembolic Deep venous thromboembolic

events events

1.61.6 2.42.4 0.640.64 0.45-0.930.45-0.93 .02.02

Ischemic cerebrovascular Ischemic cerebrovascular eventsevents

2.02.0 2.82.8 0.700.70 0.50-0.970.50-0.97 .03.03

Endometrial cancer*Endometrial cancer* 0.20.2 0.80.8 0.290.29 0.11-0.800.11-0.80 .02.02

*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 ATAC Trial: Comparable Incidence of Prespecified Adverse Events With ARIMIDEXEvents With ARIMIDEX®® (anastrozole) Compared With (anastrozole) Compared With Tamoxifen (Tamoxifen (Median Treatment of 60 Months)Median Treatment of 60 Months)

ARIMIDEXARIMIDEX% (n=3092)% (n=3092)

TamoxifenTamoxifen % (n=3094)% (n=3094)

Odds RatioOdds Ratio(A vs T)(A vs T) 95% CI95% CI PP

Ischemic Ischemic cardiovascular cardiovascular diseasedisease

4.14.1 3.43.4 1.231.23 0.95-1.600.95-1.60 .1.1

Mood disturbancesMood disturbances 19.319.3 17.917.9 1.101.10 0.97-1.250.97-1.25 .2.2

Nausea and vomitingNausea and vomiting 12.712.7 12.412.4 1.031.03 0.88-1.190.88-1.19 .7.7

Fatigue/tirednessFatigue/tiredness 18.618.6 17.617.6 1.071.07 0.94-1.220.94-1.22 .3.3

CataractsCataracts 5.95.9 6.96.9 0.850.85 0.69-1.040.69-1.04 .1.1

*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 Important Safety Information About ARIMIDEXARIMIDEX®® (anastrozole) (anastrozole)

Analysis performed at a median treatment of 60 monthsAnalysis performed at a median treatment of 60 months

Patients receiving ARIMIDEX had a mean decrease in Patients receiving ARIMIDEX had a mean decrease in both lumbar spine and total hip bone mineral density both lumbar spine and total hip bone mineral density (BMD) compared with baseline. Patients receiving (BMD) compared with baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and tamoxifen had a mean increase in both lumbar spine and total hip BMD compared with baselinetotal hip BMD compared with baseline

More patients receiving ARIMIDEX were reported to More patients receiving ARIMIDEX were reported to have an elevated serum cholesterol compared with have an elevated serum cholesterol compared with patients receiving tamoxifen patients receiving tamoxifen (9% vs 3.5%, respectively)(9% vs 3.5%, respectively)

Other Important Safety InformationOther Important Safety Information

Women must be postmenopausal to take ARIMIDEXWomen must be postmenopausal to take ARIMIDEX®® (anastrozole). ARIMIDEX can cause fetal harm when (anastrozole). ARIMIDEX can cause fetal harm when administered to a pregnant womanadministered to a pregnant woman

Estrogen-containing therapies should not be used with Estrogen-containing therapies should not be used with ARIMIDEX as they may diminish its pharmacologic ARIMIDEX as they may diminish its pharmacologic action action

Tamoxifen should not be co-administered with Tamoxifen should not be co-administered with ARIMIDEXARIMIDEX

Other Important Safety Information Other Important Safety Information (cont’d)(cont’d) At a median treatment of 60 months, the most common At a median treatment of 60 months, the most common

side effects seen with ARIMIDEXside effects seen with ARIMIDEX®® (anastrozole) vs (anastrozole) vs tamoxifen in the ATAC Trial includetamoxifen in the ATAC Trial include– Hot flashes (36% vs 41%)Hot flashes (36% vs 41%)– Joint disorders (including arthritis, arthrosis, and arthralgia) Joint disorders (including arthritis, arthrosis, and arthralgia)

(36% vs 29%)(36% vs 29%)– Fatigue/asthenia (19% vs 18%)Fatigue/asthenia (19% vs 18%)– Mood disturbances (19% vs 18%)Mood disturbances (19% vs 18%)– Pain (17% vs 16%)Pain (17% vs 16%)– Nausea and vomiting (13% vs 12%)Nausea and vomiting (13% vs 12%)– Pharyngitis (14% vs 14%)Pharyngitis (14% vs 14%)– Depression (13% vs 12%)Depression (13% vs 12%)– Fractures, including fractures of the spine, hip, and wrist Fractures, including fractures of the spine, hip, and wrist

(10% vs 7%)(10% vs 7%)

Current Indications for NOLVADEXCurrent Indications for NOLVADEX®® (tamoxifen citrate)(tamoxifen citrate) Treatment of node-positive breast cancer in Treatment of node-positive breast cancer in

postmenopausal women following total mastectomy or postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast segmental mastectomy, axillary dissection, and breast irradiationirradiation

Treatment of axillary node-negative breast cancer in Treatment of axillary node-negative breast cancer in women following total mastectomy or segmental women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiationmastectomy, axillary dissection, and breast irradiation

NOLVADEX reduces the occurrence of contralateral NOLVADEX reduces the occurrence of contralateral breast cancer in patients receiving adjuvant therapy with breast cancer in patients receiving adjuvant therapy with NOLVADEX for breast cancerNOLVADEX for breast cancer

NOLVADEX® (tamoxifen citrate) full Prescribing information, AstraZeneca Pharmaceuticals LP, Wilmington, DE

Important Safety Information Important Safety Information About TamoxifenAbout Tamoxifen Serious and life-threatening events associated with NOLVADEXSerious and life-threatening events associated with NOLVADEX (tamoxifen (tamoxifen

citrate) include uterine malignancies, stroke, and pulmonary emboli, some of citrate) include uterine malignancies, stroke, and pulmonary emboli, some of which have been fatal. In clinical trials, uterine malignancies, including which have been fatal. In clinical trials, uterine malignancies, including endometrial cancer and uterine sarcomas (see WARNINGS, Effects on the endometrial cancer and uterine sarcomas (see WARNINGS, Effects on the Uterus—Endometrial Cancer and Uterine Sarcoma, in full Prescribing Uterus—Endometrial Cancer and Uterine Sarcoma, in full Prescribing Information), and venous thrombotic events, including pulmonary emboli, Information), and venous thrombotic events, including pulmonary emboli, occurred 2 to 4 times more often with NOLVADEX than placebo, but each in 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 less then 1% of women. Stroke, cataracts, and cataract surgery also occurred more often with NOLVADEX. The most frequently reported adverse reactions more often with NOLVADEX. The most frequently reported adverse reactions were hot flashes and vaginal discharge were hot flashes and vaginal discharge

Women who are pregnant or plan to become pregnant should not take Women who are pregnant or plan to become pregnant should not take NOLVADEX. Women who have a history of deep vein thrombosis or NOLVADEX. Women who have a history of deep vein thrombosis or pulmonary embolism or who currently use anticoagulants should not take pulmonary embolism or who currently use anticoagulants should not take NOLVADEX to reduce their risk of breast cancer (see CONTRAINDICATIONS NOLVADEX to reduce their risk of breast cancer (see CONTRAINDICATIONS section of full Prescribing Information)section of full Prescribing Information)

Dosage and Duration of ARIMIDEXDosage and Duration of ARIMIDEX®® (anastrozole) Therapy(anastrozole) Therapy

Dosage: 1-mg tablet taken once a dayDosage: 1-mg tablet taken once a day

Optimal duration of adjuvant therapy is unknownOptimal duration of adjuvant therapy is unknown

ATAC Trial: Efficacy Summary ATAC Trial: Efficacy Summary (Median Follow-up of 68 Months)(Median Follow-up of 68 Months) ARIMIDEXARIMIDEX®® (anastrozole) shows: (anastrozole) shows:

– Significantly improved disease-free survival over Significantly improved disease-free survival over tamoxifentamoxifen

– Significant reduction in the event rate in hormone Significant reduction in the event rate in hormone receptor-positive patients (hazard ratio 0.83 [95% CI, receptor-positive patients (hazard ratio 0.83 [95% CI, 0.73-0.94], 0.73-0.94], PP=.005)=.005)

– Significant reduction in the event rate seen in the Significant reduction in the event rate seen in the overall population (hazard ratio 0.87 [95% CI, overall population (hazard ratio 0.87 [95% CI, 0.78-0.97], 0.78-0.97], PP=.01)=.01)

These study results are based on patients These study results are based on patients followed for a median of 68 monthsfollowed for a median of 68 months

ATAC Trial: Safety SummaryATAC Trial: Safety Summary(Median Treatment of 60 months)(Median Treatment of 60 months)

ARIMIDEXARIMIDEX®® (anastrozole) (anastrozole) showed showed increasedincreased incidence of: incidence of:– Joint disorders (including arthritis, arthrosis, and arthralgia) Joint disorders (including arthritis, arthrosis, and arthralgia) – Fractures, including fractures of the spine, hip and wristFractures, including fractures of the spine, hip and wrist

ARIMIDEX showed ARIMIDEX showed decreaseddecreased incidence of: incidence of:– Hot flashesHot flashes– Vaginal bleeding and discharge Vaginal bleeding and discharge – Venous thromboembolic events, including deep venous Venous thromboembolic events, including deep venous

thromboembolic eventsthromboembolic events– Ischemic cerebrovascular eventsIschemic cerebrovascular events– Endometrial cancerEndometrial cancer

Conclusions: in Early Breast CancerConclusions: in Early Breast Cancer The ASCO 2005 Technology Assessment recommends:The ASCO 2005 Technology Assessment recommends:

– ““Based on results from multiple large randomized trials, adjuvant Based on results from multiple large randomized trials, adjuvant therapy for postmenopausal women with hormone receptor-therapy for postmenopausal women with hormone receptor-positive breast cancer should include an aromatase inhibitor in positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence”order to lower the risk of tumor recurrence”

– ““It is unknown if the three available drugs are interchangeable in It is unknown if the three available drugs are interchangeable in clinical practice. In general, the Panel favors using the clinical practice. In general, the Panel favors using the aromatase inhibitor that has been studied in the setting most aromatase inhibitor that has been studied in the setting most closely approximating any individual patient’s clinical closely approximating any individual patient’s clinical circumstances.”circumstances.”

Conclusions: ARIMIDEXConclusions: ARIMIDEX®® (anastrozole) (anastrozole) in Early Breast Cancerin Early Breast Cancer In the ATAC Trial, at a median follow-up of 68 months, In the ATAC Trial, at a median follow-up of 68 months,

ARIMIDEX significantly improved disease-free survival ARIMIDEX significantly improved disease-free survival over tamoxifen in postmenopausal women with hormone over tamoxifen in postmenopausal women with hormone receptor-positive early breast cancerreceptor-positive early breast cancer

ARIMIDEXARIMIDEX is the first aromatase inhibitor approved as is the first aromatase inhibitor approved as primary adjuvant therapy for early breast cancer in primary adjuvant therapy for early breast cancer in postmenopausal women with hormone receptor-positive postmenopausal women with hormone receptor-positive diseasedisease