Breast Medical OncologyBreast Medical OncologyBreast Medical OncologyBreast Medical Oncology

Third generation Aromatase Inhibitors

in

advanced & early Breast Cancer

Aman U. Buzdar, MD

Potential Sites of Action of Selective* and Non-Selective Aromatase Inhibitors

Cholesterol

Pregnenolone

Progesterone

11-Deoxycorticosterone

Corticosterone

Aldosterone

17-Hydroxypregnenolone

17-Hydroxyprogesterone

11-Deoxycortisol

Cortisol

Dehydroepiandrosterone

Androstenedione Testosterone

Estrone Estradiol

20,22-Lyase

17-Hydroxylase

21-Hydroxylase

11-Hydroxylase

18-Hydroxylase

17,20-Lyase

AROMATASE

Pharmacologic Target

*

ExemestaneO

CH2

O

Nonsteroidal

Steroidal

Chemical Structures

N

N

N

CH3

CN

CH3

CN

Anastrozole

N

N

NC CN

NLetrozole

CH3CH3

Limit of detection

1 2 3 4 6 8 10 14 20

Geo

met

ric

mea

n o

estr

adio

l (p

mo

l/l)

Trial day

40

32

24

16

8

015161718

0.5mg1.0mg

Adapted from Yates RA et al. Br J Cancer 1996; 73: 543–548

Anastrozole: potent and sustained suppression of plasma oestradiol

Aromatase Inhibitors vs MA: Trial Designs

Anastrozole Letrozole Exemestane

EuropeanEuropean N AmericanN American EuropeanEuropean USUS InternationalInternational

Number ofNumber ofpatients patients vs MAvs MA 135 135 vs 125vs 125 128 128 vs 128vs 128 174 174 vs 189vs 189 202 and 199 202 and 199

vs 201vs 201366 366 vs 403vs 403

Data reportedData reported All dataAll data All dataAll data All dataAll data All dataAll data All dataAll data

Median follow-upMedian follow-up +33 mos+33 mos +33 mo+33 mo 45 mo45 mo 11 mos11 mos

Inclusion criteria for all trials included postmenopausal women Inclusion criteria for all trials included postmenopausal women with advanced breast cancer whose neoplasms failed to respond on tamoxifenwith advanced breast cancer whose neoplasms failed to respond on tamoxifen

??

0 1 2 3 4

Years from randomizationYears from randomization

0

20

40

60

80

100

Pro

po

rtio

n a

live

(%)

Pro

po

rtio

n a

live

(%)

p valuevs MAAnastrozole 1 mg

Megestrol acetate

Patients 263 248 253

Deaths 151 151 171

0.0248 0.0951

Buzdar A, Buzdar A, et alet al. . Cancer. Cancer. 1998;83:1142-1152.1998;83:1142-1152.

Anastrozole vs MA: Overall Survival by Randomized Treatment

(Combined Analysis)

Kaufmann M, Kaufmann M, et alet al. . J Clin Oncol. J Clin Oncol. 2000;18:1399-1411.2000;18:1399-1411.

Pro

bab

ility

Exemestane MA100/366 130/403Not reached 30.85

P=.039

Exemestane vs MA: Overall Survival by Randomized Treatment

0 20 40 60 80 100 120 160

Weeks

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Exemestane

No. of events/patientsMedian (months)

Log rank probability

140

MA

Letrozole vs MA: Overall Survival by Randomized Treatment

European Trial

Letrozole 0.5 mg

Megestrol acetate

Letrozole 2.5 mg

Patients Deaths188 126

174

189

103

128

Dombernowsky P, Dombernowsky P, et alet al. . J Clin Oncol. J Clin Oncol. 2000;16:453-461.2000;16:453-461.

MonthsMonths

Pro

bab

ility

Pro

bab

ility

0 3 6 9 12 15 18 21 24 27 30 33 36 390

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

PP =.15 (NS) =.15 (NS)

Letrozole vs MA: Overall Survival by Randomized Treatment

US Trial

Buzdar A. et al. Buzdar A. et al. J Clin Oncol.J Clin Oncol. 2001;19:3357-3366. 2001;19:3357-3366.

Safety Data: Comparison of AIs (%)

* Commonly reported adverse events, irrespective of causality* Commonly reported adverse events, irrespective of causality† † Adverse experiences in >5% of patients irrespective of causalityAdverse experiences in >5% of patients irrespective of causality** Adverse events considered drug-related** Adverse events considered drug-related*** Incidence of weight gain of >20% from baseline*** Incidence of weight gain of >20% from baselineNA = data not available in published literatureNA = data not available in published literature

AdverseAdverseeventevent

HeadacheHeadache

Hot flashesHot flashes

NauseaNausea

VomitingVomiting

DiarrheaDiarrhea

Weight gainWeight gain

RashRash

DyspneaDyspnea

AstheniaAsthenia

FatigueFatigue

AnastrozoleAnastrozole1 mg*1 mg*

141413131818101099336611111818NANA

LetrozoleLetrozole2.5 mg2.5 mg

13136611118866666699

NANA1111

3–283–28

MegestrolMegestrolacetateacetate

9–139–134–114–115–235–235–75–73–113–119–179–173–123–12

7–207–2010–2210–22

ExemestaneExemestane25 mg**25 mg**

NANA13139933

NANA 8***8***

2211

NANA88

††

Clinical Pharmacology

Anastrozole Letrozole ExemestaneDaily clinicaldose

1 mg od 2.5 mg od 25 mg od

Monthly dose 30 mg 75 mg 750 mg

Time to steadystate plasmalevels

7 days 14-42 days 4 days

Half-life 48–50 hours 2–4 days 24 hours

Time to maximalE2 suppression 3–4 days 2–3 days 7 days

Intratumoralactivity

Yes Yes No data

Endocrine Selectivity - At Clinical Dose

*Males only

AnastrozoleAnastrozole LetrozoleLetrozole ExemestaneExemestaneAndrogenic propertiesAndrogenic properties NoNo NoNo YesYes

Effect on SHBGEffect on SHBG No or No or ** (p=0.003)(p=0.003) (p=0.0001)(p=0.0001)

Effect on basal cortisolEffect on basal cortisol NoNo No or No or NoNo(p<0.03)(p<0.03)

Effect on basal aldosteroneEffect on basal aldosterone NoNo No or No or NoNo(p=0.025)(p=0.025)

Effect on ACTH-stim. Effect on ACTH-stim. NoNo No dataNo datacortisolcortisol (p=0.015)(p=0.015)

Effect on ACTH-stim.Effect on ACTH-stim. NoNo No dataNo dataaldosteronealdosterone (p=0.04)(p=0.04)

Ratio dose affecting cortisolRatio dose affecting cortisol >10>10 11 >32>32or aldosterone/clinical doseor aldosterone/clinical dose

ACTH Stimulation: Results with Anastrozole

Pre-dose 30 60

Baseline (n=19)Day 14 (5 mg) (n=19)Day 28 (10 mg) (n=17)

Time (minutes after ACTH administration)

35

30

25

20

15

10

5

0

Ald

ost

ero

ne

(µg

/dl)

Plourde, et al. J Ster Biochem Mol Biol 1995;53:175–179

ACTH Stimulation: Results with Anastrozole

(n=17)

Plourde, et al. J Ster Biochem Mol Biol 1995;53:175–179

Baseline (n=19)Day 14 (5 mg) (n=19)Day 28 (10 mg)

40

30

20

10

0Pre-dose 30 60

Co

rtis

ol (

µg

/ml)

Time (minutes after ACTH administration)

Bajetta E, et al. Eur J Cancer 1999;35:208–213

ACTH Stimulation: Results with Letrozole

800

600

400

200

030 60

Ald

ost

ero

ne

(n

mo

l/L) Baseline

1 month3 months

1000 2.5mg

Time (minutes after ACTH administration)

p=0.04

ACTH Stimulation: Results with Letrozole

Bajetta E, et al. Eur J Cancer 1999;35:208–213

Time (minutes after ACTH administration)

800

600

400

200

030 60

Co

rtis

ol (

nm

ol/L

)1000 2.5mg

Baseline1 month3 months

p=0.015

Conclusions (1)

New-generation AIs represent a step forward over MA and AG in the treatment of postmenopausal women with advanced breast cancer

More effective

Better tolerated

Anastrozole 1 mg/dayAnastrozole 1 mg/dayplusplus

tamoxifen placebo dailytamoxifen placebo daily

Tamoxifen 20 mg/dayTamoxifen 20 mg/dayplusplus

anastrozole placebo dailyanastrozole placebo daily

Randomized 1:1 (double blind)Randomized 1:1 (double blind)

First-line Trials 0027 and 0030: Study Design

Primary objectives: - Time to tumor progression- Objective response (CR+PR)- Safety

Secondary objectives: -Duration of clinical benefit (CR+PR+SD?24 wk)- Duration of tumor response- Time to treatment failure

Bonneterre J, et al. J Clin Oncol. 2000;18:3748-3757; Nabholtz JM, et al. J Clin Oncol. 2000;18:3758-3767.Bonneterre J, et al. J Clin Oncol. 2000;18:3748-3757; Nabholtz JM, et al. J Clin Oncol. 2000;18:3758-3767.

Anastrozole Tamoxifen(n=340) (n=328)

Median age (yr) 67 66

Median weight (kg) 67 67

Prior adjuvant therapy (%) 30.9 29.6

Prior endocrine therapy (%) 12.0 10.7

ER+ and/or PR+ (%) 45.3 43.9

ER and PR unknown (%) 54.4 55.8

Measurable disease (%) 88.5 87.2

First-line Trial 0027: Patient Characteristics

Bonneterre J, et al. Bonneterre J, et al. J Clin OncolJ Clin Oncol. 2000;18:3748-3757.. 2000;18:3748-3757.

First-line Trial 0027: Clinical Efficacy Results at Median Follow-up of 19 Months

Objective response (CR+PR)Objective response (CR+PR) 32.932.9 32.632.6

Clinical benefit*Clinical benefit* 56.156.1 55.555.5

Complete response (CR)Complete response (CR) 5.65.6 4.94.9

Partial response (PR)Partial response (PR) 27.427.4 27.727.7

Stable disease (SD) Stable disease (SD) >>24 wk24 wk 23.223.2 22.922.9

Stable disease <24 wkStable disease <24 wk 2.62.6 2.42.4

Progression Progression 41.241.2 42.142.1

*CR+PR+SD *CR+PR+SD >>24 weeks24 weeks

‘Arimidex’ Tamoxifen1 mg (n=340) 20 mg (n=328)

% %

Per

cent

age

Not

Pro

gres

sed

Per

cent

age

Not

Pro

gres

sed

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

00 66 1212 1818 2424 3030 3636 4242

Time to Progression (mo)Time to Progression (mo)

AnastrozoleAnastrozole TamoxifenTamoxifen

No. of patientsNo. of patients 340340 328328Median TTPMedian TTP 8.2 mo8.2 mo 8.3 mo8.3 mo PP=.920=.920CR+PR CR+PR 32.9%32.9% 32.6%32.6%

First-line Trial 0027: Kaplan-Meier Probability of Time to Progression

From Bonneterre J, et al. From Bonneterre J, et al. J Clin OncolJ Clin Oncol. 2000;18:3748-3757.. 2000;18:3748-3757.

Anastrozole Tamoxifen(n=171) (n=182)

Median age (yr) 68 67

Median weight (kg) 72 69

Prior adjuvant therapy (%) 39.8 38.5

Prior endocrine therapy (%) 21.1 18.1

ER+ and/or PR+ (%) 88.3 89.0

ER and PR unknown (%) 11.1 11.0

Measurable disease (%) 68.4 76.9

First-line Trial 0030: Patient Characteristics

Nabholtz JM, et al. Nabholtz JM, et al. J Clin OncolJ Clin Oncol. 2000;18:3758-3767.. 2000;18:3758-3767.

Per

cent

age

Not

Pro

gres

sed

Per

cent

age

Not

Pro

gres

sed

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

00 66 1212 1818 2424 3030 3636 4242

Time to Progression (mo)Time to Progression (mo)

AnastrozoleAnastrozole TamoxifenTamoxifenNo. of patientsNo. of patients 171171 182182Median TTP*Median TTP* 11.1 mo11.1 mo 5.6 mo5.6 mo PP=.006 =.006 CR+PR+SDCR+PR+SD 59.1%59.1% 45.6%45.6% PP=.0098=.0098

AnastrozoleAnastrozoleTamoxifenTamoxifen

* Hazard ratio (tam:‘Arimidex’) 1.44, lower CL 1.16* Hazard ratio (tam:‘Arimidex’) 1.44, lower CL 1.16Study ‘powered’ for equivalence Study ‘powered’ for equivalence Median follow-up of 18 months; 71% progressedMedian follow-up of 18 months; 71% progressedFrom Nabholtz JM, et al. From Nabholtz JM, et al. J Clin OncolJ Clin Oncol. 2000;18:3758-3767.. 2000;18:3758-3767.

First-line Trial 0030: Kaplan-Meier Probability of Time to Progression

TTP of Patients with Receptor-positive Tumors: Trials 0030 and 0027 Combined

* Based on sub-group analysisBuzdar et al. Proc ASCO 2000; 19:154a, Abstr 609D.

Median TTP:Median TTP:‘‘Arimidex’ Arimidex’ 10.7 months10.7 monthstamoxifen tamoxifen 6.4 months6.4 months

PP=.022 (2-sided)*=.022 (2-sided)*

Per

cen

tag

e n

ot

pro

gre

ssed

Per

cen

tag

e n

ot

pro

gre

ssed

0

10

20

30

40

50

60

70

80

90

100

‘Arimidex’ (n=305)

Tamoxifen (n=306)

0 6 12 18 24 30 36 42

Time to progression (months)Time to progression (months)

Predefined Adverse Events: Predefined Adverse Events: Trials 0027/0030Trials 0027/0030

4040

3535

3030

2525

2020

1515

1010

55

00

Dep

ress

ion

Dep

ress

ion

Tum

or F

lare

Tum

or F

lare

Thr

ombo

embo

licT

hrom

boem

bolic

Dis

ease

Dis

ease

Gas

troi

ntes

tinal

Gas

troi

ntes

tinal

Dis

turb

ance

Dis

turb

ance

Hot

Flu

shes

Hot

Flu

shes

Vag

inal

Vag

inal

Dry

ness

Dry

ness

Leth

argy

Leth

argy

Vag

inal

Vag

inal

Ble

edin

gB

leed

ing

Wei

ght G

ain

Wei

ght G

ain

Pa

tient

s S

uffe

ring

Adv

erse

Eve

nt (

%)

Pa

tient

s S

uffe

ring

Adv

erse

Eve

nt (

%)

AnastrozoleAnastrozole

TamoxifenTamoxifen

Thromboembolic disease 18 (3.5) 33 (6.5)Venous 5 15pulmonary embolus,thrombophlebitis,retinal vein thrombosis

Coronary and cerebral 13 19myocardial infarction,myocardial ischemia,angina pectoris,cerebrovascular accident,cerebral ischemia,cerebral infarct

AstraZeneca Pharmaceuticals LP. Full Prescribing Information for ARIMIDEXAstraZeneca Pharmaceuticals LP. Full Prescribing Information for ARIMIDEX ?? (anastrozole), 2000. (anastrozole), 2000.

First-line Trials 0027 and 0030:Thromboembolic Disease

Anastrozole 1 mgAnastrozole 1 mg Tamoxifen 20 mgTamoxifen 20 mg(n=506)(n=506) (n=511)(n=511)n (%)n (%) n (%)n (%)

Letrozole First-line Study Design

Study PopulationStudy Population

CoreCoreTreatmentTreatmentDouble-blindDouble-blind

DiscontinuationDiscontinuationfrom Core Phasefrom Core Phase

Postmenopausal;Postmenopausal;Stage IIIB locallyStage IIIB locallyadvanced or Stage IVadvanced or Stage IVbreast cancer or loco-breast cancer or loco-regional recurrenceregional recurrence;;ER and/or PgRER and/or PgRpositive or unknownpositive or unknown

LetrozoleLetrozole 2.5 mg po2.5 mg poOD until progressionOD until progression

TamoxifenTamoxifen 20 mg po 20 mg poOD until progressionOD until progression

Cross-over treatmentCross-over treatmentDouble-blind untilDouble-blind untilprogressionprogression

Follow-up for survivalFollow-up for survivalevery 6 monthsevery 6 months

Follow-up forFollow-up forsurvival everysurvival every6 months6 months

Letrozole First-line: Summary of Results

LetrozoleLetrozolen (%)n (%)

TamoxifenTamoxifenn (%)n (%) PP value value

Intent-to-treatIntent-to-treat 453 (100%)453 (100%) 454 (100%)454 (100%)

Time to progressionTime to progression (median)(median)

9.4 mo9.4 mo 6.0 mo6.0 mo .0001.0001 11

Objective responseObjective response 137 (30%)137 (30%) 92 (20%)92 (20%) .0006.0006 22

11 Hazard ratioHazard ratio22 Odds ratio, Mantel HaenszelOdds ratio, Mantel Haenszel

Novartis Pharmaceuticals. Letrozole prescribing information, 2001.Novartis Pharmaceuticals. Letrozole prescribing information, 2001.

Time to progression

Arrows denote censored observations

Treatment

0.00.10.20.30.40.50.60.70.80.91.0

MonthsStart 3 6 9 12 15 18 21 24

0.00.10.20.30.40.50.60.70.80.91.0FEMARA®, n=453, m=9.4 months,

events=69%

Tamoxifen , n=454, m=6.0 months,

events=77%

Progression-free

Pro

gres

sion

-fre

e

Exemestane as Initial Therapy for MBC: Randomized EORTC Phase II/III Trial

RAND

I

OM

ZATION

Exemestane 25 mg po once daily

Tamoxifen 20 mg po once daily

Paridaens et al. Proc Am Soc Clin Oncol. 2000;19:83a.

EXEEXE TAMTAM(n=56)(n=56) (n=56)(n=56)

nn %% nn %%

Complete response 5 8.9 1 1.8

Partial response 20 35.7 7 12.5

Objective response rate 25 44.6 8 14.3(95% confidence interval) (38.2-51) (9.7-18.9)

Clinical benefit 31 55.3 22 39.3(CR + PR + NC 6 months)

Median TTP*, months 8.9 5.2

Phase II Trial of Exemestane and Tamoxifen : Peer-Reviewed Tumor Response and Time to

Tumor Progression

*Based on 63 patients

Anastrozole vs Letrozole:Inhibition of Estrogen Production

Letrozole

Anastrozole

Randomization Crossover

6

Blood samplingDetermination of aromatization

Anastrozole

120

Letrozole

n=6

n=6

Weeks

Geisler et al. J Clin Oncol 2002;20:751.

Letrozole vs Anastrozole, P=0.003

92

94

96

98

100

ANA LET

Cross-over 192

94

96

98

100

ANALET

Cross-over 2

(%)

Inhibition of AromatizationEstrogen Plasma Levels

Estrone80

75

20

15

10

5

014

.8

(12.

4-17

.7)

12.3

(1

1.2-

13.5

)

P=0.019

Pla

sma

con

cen

trat

ion

(p

mol

/L)

78.1

(5

6.1-

108.

7)

Estrone Sulfate425

40

30

20

10

P=0.0037420

422.

8 (

182.

4-98

0.4)

27.6

(1

4.0-

54.3

)

8.9

(4.9

-16.

0)

2.6

(1.

9-3.

5)

Estradiol

2.1

(2.

1-2.

1)

18

17

16

3

2

1

0

17.2

(9

.2-3

2.1)

0

P=NS

PRE ANA LET

Letrozole vs Anastrozole in Second-Line Treatment of MBC: FEM-INT-01

Postmenopausalwomen with ER/PgR+ or unknown metastatic breast cancer who have progressed on TAM

RANDOMIZE

Letrozole 2.5 mg

Anastrozole 1 mg

End Points

TTPORR

Response DurationSurvival

Enrollment

Recruited from 105 centers in 19 countries

713 patients entered the trial

Anastrozole n=357

Letrozole n=356

Data collection stopped at visit 12 (30 months)

Letrozole vs Anastrozole:Time Events

ITT Population P value

Letrozole Anastrozole (n=356) (n=357)

Median TTP (mo) 5.7 5.7 0.92090% CI 5.1-6.0 4.6-6.1

Median TTF (mo) 5.6 5.6 0.76190% CI 4.4-5.8 4.0-6.0

Median OS (mo) 22.0 20.3 0.62490% CI 19.6-24.6 18.0-23.1

Letrozole vs Anastrozole:Response Rate

8.7%12.4%

3.6%

6.7%

0%

10%

20%

n=356 n=357

PR CR

Letrozole 19.1%

Anastrozole 12.3%

P=0.013

0

Letrozole vs Anastrozole:Response Rate

ITT Patients (%) Letrozole Anastrozole

(n=356) (n=357)

ORR (CR + PR) 19.1% 12.3%CR 24 (6.7) 13 (3.6)PR 44 (12.4) 31 (8.7)

Odds ratio 1.70 90% CI 1.20-2.42 P value 0.013

Note: An odds ratio >1 favors letrozole, while an odds ratio <1 favors anastrozole. Adjusted analysis based on baseline covariates of receptor status and dominant site of disease. Analysis based on logistic regression model.

Overall Tumor Response by Predefined Covariates

No. of CR + PR/Total No. Pts (%)

Baseline Covariate Letrozole Anastrozole P Value

Receptor status 0.014 ER and/or PgR+

30/173 (17.3) 28/167 (16.8)Unknown 38/183 (20.8) 16/190 (8.4)

Dominant site 0.012 Soft tissue 31/85 (36.5) 16/84 (19.0)Bone 11/85 (12.9) 10/87 (11.5)Viscera 26/185 (14.1) 18/186 (9.7)

Analysis based on Cochran-Mantel-Haenszel.

* Surgery + radiotherapy + chemotherapy(Patients may start trial therapy while still receiving radiotherapy)

+

Postmenopausal women with invasive breast cancerPostmenopausal women with invasive breast cancer

Completion of primary therapy*Completion of primary therapy*

Randomization 1:1:1 for 5 yearsRandomization 1:1:1 for 5 years

Anastrozole 1mg od+

Tamoxifen placebo

Anastrozole placebo+

Tamoxifen 20mg od

Anastrozole 1mg od+

Tamoxifen 20mg od

Regular follow-up monitoring adverse eventsRegular follow-up monitoring adverse events

Trial endpointsTrial endpoints

ATAC Trial Design

ATAC Trial – Study EndpointsPrimary Endpoints Disease-free survival

– Locoregional or distant recurrence, new primary breast cancer, or death from any cause

Safety/Tolerability

Secondary Endpoints Incidence of new breast (contralateral) primaries Time to distant recurrence Survival (data will be mature in ~ 2 years)

Hormone receptor-positive population (protocol-defined sub-group)

Statistical Methodology

Disease-free survival:

– Log rank test

– 1056 events required

– 95.2% CI used to adjust for one interim analysis pre-specified in the Protocol

Incidence of new breast (contralateral) primaries:

– Logistic regression analysis

Incidence of pre-defined adverse events:

– Logistic regression analysis

TamoxifenTamoxifen

Equivalence/Equivalence/SuperioritySuperiority

SuperioritySuperiority

AnastrozoleAnastrozole CombinationCombinationnon-protocollednon-protocolled

comparisoncomparison

Patient Recruitment

Patients recruited from 381 centres in 21 countries

Patients recruited between July 1996 and March 2000

9366 patients entered the trial Anastrozole n=3125Tamoxifen n=3116Combination n=3125

Patient Characteristics

Mean age (years) 64.1 64.1 64.3

Mean weight (kg) 70.8 71.1 71.3

Receptor status (%)

Positive 83.7 83.3 84.0

Negative 7.4 8.0 6.9

Other 8.9 8.7 9.1

Primary treatment (%)

Mastectomy 47.8 47.3 48.1

Axillary surgery 95.5 95.7 95.2

Radiotherapy 63.3 62.5 62.0

Chemotherapy 22.3 20.8 20.8

Prior tamoxifen 1.6 1.7 1.7

Tamoxifen(n=3116)

Anastrozole(n=3125)

Combination(n=3125)

Disease Characteristics

Tamoxifen(n=3116)

Anastrozole(n=3125)

Combination(n=3125)

Primary tumour size (%)

T1 (2cm) 63.9 62.9 64.1

T2 (>2cm and 5cm) 32.6 34.2 32.9

T3 (>5cm) 2.7 2.2 2.3

Nodal status (%)

Node +ve 34.9 33.6 33.5

Grading (%)

Well differentiated 20.8 20.5 21.2

Moderately differentiated 46.8 47.8 46.6

Poorly/undifferentiated 23.7 23.3 23.7

Not assessed/recorded 8.7 8.4 8.5

ATAC Trial - Recruitment Per CountryATAC Trial - Recruitment Per Country

3228

2222

654

626

417

366

291

243

201

195

194

174

121

117

107

74

53

41

30

0 300 600 900 1200 1500 1800 2100 2400 2700 3000 3300 3600

UK

Italy

Spain

Sweden

South Africa

Belgium

Germany

Poland

Turkey

Argentina

Eire

Portugal

Czech/Slovak

ANZBCTG

Netherlands

Hungary

France

Canada

USA

Number of Patients

Country

Total No. Patients = 9366Total No. Centres = 380Total No. Countries = 21

USA

Data Maturity at First Analysis

1056 events required for statistical power

Total number of first events: 1079

– Total number of first events in receptor-positive population: 766

Median duration of therapy: 30.7 months

Median follow-up: 33.3 months

First Events in ITT Population

First event 317 379 383

Locoregional 67 83 81

Distant 158 182 204

Contralateral (invasive) 9 30 23

Contralateral (DCIS) 5 3 5

Death (non-breast cancer) 78 81 70

Tamoxifen(n=3116)

Anastrozole(n=3125)

Combination(n=3125)

Kaplan-Meier curves for disease-free survival (ie, all first events) in the intention-to-treat Kaplan-Meier curves for disease-free survival (ie, all first events) in the intention-to-treat populationpopulation

Probability of recurrence Probability of recurrence in the intention-to-treat populationin the intention-to-treat population

Probability of a first event Probability of a first event in hormone-receptor-positive patientsin hormone-receptor-positive patients

Probability of recurrence Probability of recurrence in hormone-receptor-positive patientsin hormone-receptor-positive patients

Annual Recurrence RatesAnnual Recurrence Rates

Annual recurrenceAnnual recurrence Hazard Ratio (95% Cl)Hazard Ratio (95% Cl)

AnastrozoleAnastrozole(n=3125)(n=3125)

TamoxifenTamoxifen(n=3116)(n=3116)

CombinationCombination(n=3125)(n=3125)

YearYear

A/TA/T C/TC/T A/CA/C

11 77 (2.49%)77 (2.49%) 7171 (2.30%)(2.30%) 8787 (2.82%)(2.82%) 1.081.08 1.231.23 0.880.88

22 78 (2.61%)78 (2.61%) 127127 (4.28%)(4.28%) 123123 (4.11%)(4.11%) 0.610.61 0.960.96 0.630.63

33 64 (2.94%)64 (2.94%) 7777 (3.72%)(3.72%) 8080 (3.71%)(3.71%) 0.770.77 1.001.00 0.770.77

A=anastrozole; T=tamoxifen; C=combination. Percentage are events per A=anastrozole; T=tamoxifen; C=combination. Percentage are events per woman-year at risk.woman-year at risk.

New Primary Cancers With An Incidence New Primary Cancers With An Incidence of More Than 0.2% before Recurrence of More Than 0.2% before Recurrence

in All Patients Who Received Trial Treatmentin All Patients Who Received Trial Treatment

AnastrozoleAnastrozole(n=3092)(n=3092)

TamoxifenTamoxifen(n=3094)(n=3094)

CombinationCombination(n=3097)(n=3097)

TotalTotal(n=9283)(n=9283)

ColorectalColorectal 2424 (0.8%)(0.8%) 1919 (0.6%)(0.6%) 99 (0.3%)(0.3%) 5252 (0.6%)(0.6%)Head & neckHead & neck 55 (0.2%)(0.2%) 55 (0.2%)(0.2%) 55 (0.2%)(0.2%) 1515 (0.2%)(0.2%)LungLung 88 (0.3%)(0.3%) 77 (0.2%)(0.2%) 44 (0.1%)(0.1%) 1919 (0.2%)(0.2%)MelanomaMelanoma 00 66 (0.2%)(0.2%) 11 (0.0%)(0.0%) 77 (0.1%)(0.1%)OvaryOvary 66 (0.2%)(0.2%) 99 (0.3%)(0.3%) 66 (0.2%)(0.2%) 2121 (0.2%)(0.2%)SkinSkin 3939 (1.3%)(1.3%) 3232 (1.0%)(1.0%) 2727 (0.9%)(0.9%) 9898 (1.1%)(1.1%)OthersOthers 2222 (0.7%)(0.7%) 2828 (0.9%)(0.9%) 2929 (0.9%)(0.9%) 7979 (0.9%)(0.9%)TotalTotal 104104 (3.5%)(3.5%) 106106 (3.4%)(3.4%) 8181 (2.6%)(2.6%) 291291 (3.2%)(3.2%)

Disease-free Survival* in Receptor-positive Population

Curves truncated at 42 months

Anastrozole

Tamoxifen

Combination

HR 95.2% CI p-value

AN vs TAM 0.78 0.65–0.93 0.005Comb vs TAM 1.02 0.87–1.21 0.78

Time to event (months)

Pro

po

rtio

n e

ven

t fr

ee (

%)

0

80

85

90

95

100

0 6 12 18 24 30 36 42

*Disease-free survival defined as the time to the earliest occurrence of local or distant recurrence, new primary breast cancer or death

Breast Cancer Events* in Receptor-positive Population

HRHR LowerLower UpperUpper pp-value-value95% Cl95% Cl 95% Cl95% Cl

AN vs TAMAN vs TAM 0.730.73 0.590.59 0.900.90 0.0030.003Comb vs TAMComb vs TAM 1.091.09 0.900.90 1.321.32 0.40.4

0

86

88

90

92

94

96

98

100

Rec

urr

ence

fre

e (%

)R

ecu

rren

ce f

ree

(%)

Time to event (months)Time to event (months)

Anastrozole

Tamoxifen

Combination

* Breast cancer events including new contralateral tumours, but censoring patients who had died from non-breast cancer causes before recurrence

Indirect Comparison of ATAC data with EBCTCG 1995 Overview1

(Hormone Receptor +ve Patients >50 Years)

100

80

00 1 2 3 4 5+ years

Est

imat

ed p

erce

nta

ge

still

wit

ho

ut

recu

rren

ce a

s fi

rst

even

t

90

70

84.6%

70.5%

*ATAC data truncated at 42 months

3-year event-free rate:

90%

1EBCTCG. The Lancet 1998; 351: 1451–1467

92%

Anastrozole (ATAC data)

Tamoxifen (ATAC data)

Tamoxifen (EBCTCG overview)

Control (EBCTCG overview)

Incidence of New (Contralateral) Breast Primaries in ITT population

9 Invasive

33

28

0

5

10

15

20

25

30

35

Tamoxifen(n=3116)

Anastrozole(n=3125)

Combination(n=3125)

5 DCIS

14

3 DCIS

23Invasive

5 DCIS

OR 95% CI p-value

AN vs TAM 0.42 0.22–0.79 0.007Comb vs TAM 0.84 0.51–1.40 0.51

30 Invasive

Nu

mb

er o

f ca

ses

Breast Cancer Events for Different Prognostic Factors

Hazard ratio (AN / TAM)Hazard ratio (AN / TAM)

0 0.5 1 1.5 2

Overall

T1Tumour Size T2T3

Grade(differentiated)

WellModerate

Poor

Age <64>65

Hysterectomy YesNo

HRT YesNo

Local therapy MastectomyConservation

Axillary dissection SamplingClearance

Radiotherapy YesNo

Breast Cancer Events for Different Prognostic Factors

Hazard ratio (AN / TAM)Hazard ratio (AN / TAM)

0 0.5 1 1.5 2

0Nodal Status

1–3

>4

Receptor Status +

–

Adjuvant chemo No

Yes

Safety/Tolerability Results Pre-defined Adverse Events 1: In favour of Anastrozole

Anastrozole(n=3092)

Tamoxifen(n=3093)

P-value

N % N %

Venous thromboembolic events

64 (2.1) 109 (3.5) 0.0006

Ischaemic cerebrovascular events

31 (1.0) 65 (2.1) 0.0006

Endometrial cancer 2 (0.1) 11 (0.5) 0.03

Vaginal bleeding 138 (4.5) 251 (8.1) <0.0001

Vaginal discharge 86 (2.8) 353 (11.4) <0.0001

Hot flushes 1061 (34.3) 1227 (39.7) <0.0001

Safety/Tolerability Results Pre-defined Adverse Events

2: In favour of Tamoxifen

Anastrozole (n=3092)

Tamoxifen (n=3093)

P-value

N % N %

Musculoskeletal disorders

860 (27.8) 657 (21.2) <0.0001

Fractures 180 (5.8) 113 (3.7) <0.0001

Safety/Tolerability Results Pre-defined Adverse Events

3: No difference detected

Anastrozole(n=3092)

Tamoxifen(n=3093)

P-value

N % N %

Cataract 107 (3.5) 116 (3.8) 0.54

Ischaemic cardiovascular disease

76 (2.5) 59 (1.9) 0.14

Fatigue/tiredness (asthenia)

484 (15.7) 466 (15.1) 0.52

Mood disturbances 480 (15.5) 469 (15.2) 0.69

Nausea and vomiting 324 (10.5) 315 (10.2) 0.67

Tolerability Results:Overall Adverse Events (%)

All adverse eventsAll adverse events 91.391.3 92.0 92.0 91.991.9

Serious adverse eventsSerious adverse events 22.222.2 24.424.4 24.324.3

Drug-related: Drug-related: All adverse eventsAll adverse events 56.156.1 63.463.4 63.963.9

Serious adverse Serious adverse 2.82.8 5.95.9 5.1 5.1 events events

Withdrawals due to: Withdrawals due to: Adverse EventAdverse Event 7.87.8 11.111.1 10.810.8

Drug-Related Drug-Related 5.15.1 7.27.2 7.37.3 Adverse EventsAdverse Events

Tamoxifen(n=3093)

Anastrozole(n=3092)

Combination(n=3098)

Hazard ratio (anastrozole vs tamoxifen)

0 0.5 1.0 1.2

Contralateral

Breast cancer events (receptor-positive)

DFS (receptor-positive)

DFS (ITT)

Summary I (Efficacy)

HR=0.83

HR=0.78

HR=0.73

OR=0.42

Summary II (Safety)

Anastrozole significantly better tolerated with respect to:– Endometrial cancer– Vaginal bleeding– Vaginal discharge– Ischaemic cerebrovascular

events– Venous thromboembolic

events– Hot flushes

Tamoxifen better tolerated with respect to:– Musculoskeletal disorders– Fractures

Thank You !Thank You !