De beste aromataseremmer? Natuurlijk exemestaan! J.W.R.Nortier 4e jaarlijks mammacarcinoom symposium 29 juni 2005.

De beste aromataseremmer?Natuurlijk exemestaan!

J.W.R.Nortier

4e jaarlijks mammacarcinoom symposium

29 juni 2005

AROMATASE INHIBITIONandrostenedionetestosterone

estroneestradiol

NADPH

NADP

catalytic site

"steroidal inhibitor"

"non-steroidal inhibitor"

Molecule structure aromatase inhibitors

steroidal / aromatase-inactivator

non-steroidal / aromatase-inhibitors

androsteendion exemestane anastrozol letrozol

Lecture Outline

•Sequential studies

•Sequential vs upfront studies

•Safety

Postmenopausal HR+ breast cancer:Studies of adjuvant aromatase inhibition

HR+: hormone receptor-positive

Primary

randomisation

trials

Switching trials Extension trials

ATAC ITA MA-17

BIG 1-98 (FEMTA) ABCSG/ARNO

IES

ITA: Design

RANDOMISE

A: anastrazole; DFS: disease-free survival; HR: hazard ratio; T: tamoxifen

T (2–3 years)

T (2–3 years)

A (2–3 years)

• n=440• DFS: HR 0.40, p=0.0002 in favour of anastrozole• Serious adverse events more common in women continued on tamoxifen (29 vs 14)

Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003.

No. and distribution of events

TAM n=45 ANA n=17

Local-regional

(includes ipsilateral breast recurrences, relapses in local-

regional nodes)

13 2

Distant metastases

(with or without local-regional recurrences)

19 10

Second primaries

contra lateral breast

endometrium

other

10

2

5

3

5

1

1

3

Deaths Breast cancer related

Deaths without relapse

7

3

4

-


Event-free survivalEvent-free survival

ANA

Years

% S

urv

ivin

g

N° pts. Obs p= TAM 225 45ANA 223 17 0.0002

TAM




Primary

randomisation

trials


ATAC ITA MA-17


IES

ABCSG/ARNO: Design

RANDOMISE

T (2 years)

T (3 years) (n=1,606)

A (3 years) (n=3,224)

• Median follow-up 28 m

• No preceding CT

• Tumour size <2 cm: 70%; grade 1/2: 95%

• LN–: 75%

• HR+: 100%; ER+/PgR+: 81%; ER–/PgR+: 0.6%; ER+ /PR–: 18.3%

• n=3,224 (T=1,606 and A=1,618)

A: anastrazole; DFS: disease-free survival; HR: hazard ratio; T: tamoxifen

Jakesz R. et al. San Antonio Breast Cancer Symposium 2004.

Event-free survival

*Zero point = 2 years after surgery

0

75

80

85

90

95

100

0 1 2 3 4 5

Event-free survival (%)

ANA vs TAM p=0.0009 HR 0.60 [95% CI 0.44-0.81]

EFS time in years*

ANA

TAM

At risk:1606 343 176TAM

ANA 161812171243

858874

593623 375 178

Jakesz R. et al. San Antonio Breast Cancer Symposium 2004.

Total TAM ANAn=3,224 n=1,606 n=1,618

Events 177 110 67Locoregional 44 24 20Contralateral BC 28 16 12Distant recurrences 121 75 46

Localization of events

events occuring simultaneously are included twice

Jakesz R. et al. San Antonio Breast Cancer Symposium, December 2004.

ABCSG/ARNO: Summary

• Efficacy results favour switch to anastrozole

• EFS: HR 0.60 (95% CI: 0.44, 0.81); p=0.0009 with:

• 20% fewer locoregional recurrences

• 20% less contralateral breast cancer

• Distant RFS: HR 0.61

• Regardless of nodal stage or age

• Switch especially beneficial in ER+/PgR–

Serious adverse events more common in women continued

on tamoxifen (29 vs 14)

CI: confidence interval; EFS: event-free survival; RFS: recurrence-free survival

Jakesz R. et al. San Antonio Breast Cancer Symposium, December 2004.



Primary

randomisation

trials


ATAC ITA MA-17


IES

Diagnosis and initial treatment of early breast cancer

Tamoxifen therapy for 2-3 years

IES: Design

RANDOMISATION

* Intent to treat population

Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.

Tamoxifen 2-3 y20 mg po qd (n=2,372)*

Exemestane 2-3 y 25 mg po qd(n=2,352)*

5 Years Total Hormone Treatment5 Years Total Hormone Treatment

IES: demographics


IES: DFS

Years from randomisation

DF

S (

%)

0 1 2 3 40

25

50

75

100

Hazard ratio: 0.73 (95% CI: 0.62, 0.86)Log-rank test: p=0.0001

Exemestane (262 events)

Tamoxifen (353 events)

No. events/at risk

Exemestane 0 / 2,352 57 / 2,233 65 / 2,081 75 / 1,413 41+24† / 661

Tamoxifen 0 / 2,372 82 / 2,243 105 / 2,062 96 / 1,359 47+23† / 650

†Events occurring more than 4 years after randomisation


IES: Subgroup analysis


IES: Overall survival

Years from randomisation

‘wo

men

aliv

e’ (

%)

0 1 2 3 40

25

50

75

100

Hazard ratio: 0.83 (95% CI: 0.67, 1.02)Log-rank test: p=0.08

Exemestane (152 deaths)

Tamoxifen (187 deaths)

No. events/at risk

Exemestane 0 / 2,352 18 / 2,270 41 / 2,137 41 / 1,469 37+15† / 690

Tamoxifen 0 / 2,372 23 / 2,300 53 / 2,165 49 / 1,465 41+21† / 701

†Events occurring more than 4 years after randomisation


Exemestane Tamoxifen Total

Total number of deaths 152 187 339

Breast cancer deaths

Inc. other COD

in patients with

recurrence/CLB

95

11

124

12

219

23

Intercurrent (without

recurrence/CLB)

Vascular

Cardiac

Other cancer

Other

Unknown

57

15

13

13

11

5

63

7

12

22

14

8

120

22

25

35

25

13

IES: Causes of death

CLB: contralateral breast cancer; COD: cause of death.


IES: Safety profile – CV events and MI

p-values not statistically significant;

Coombes et al. San Antonio Breast Cancer Symposium 2004.

Exemestane

n (%)

Tamoxifen

n (%)

Cardiovascular medical history 775 (32.9) 729 (30.7)

All myocardial infarction 20 (0.9) 8 (0.4)

Myocardial infarction on treatment 14 (0.7) 7 (0.3)

Cardiac deaths on study 13 (0.5) 12 (0.6)

IES: Comparison of adverse events

Difference between statistically significant adverse events (%)

In favour of exemestane In favour of tamoxifen

Thromboembolic diseaseThromboembolic disease

CrampsCramps

DiarrhoeaDiarrhoea

ArthralgiaArthralgia

Gynaecologic symptomsGynaecologic symptoms

Pain in limbPain in limb

Presentation of events where the difference between treatment groups (in either incident case analysis or treatment emergent analysis) p<0.01; Coombes et al. San Antonio Breast Cancer Symposium;2004.

-3.5

6.7

-1.4

2.5

2.3

-2.1

-6 -4 -2 0 2 4 6 8

IES: Efficacy conclusions

• Switching to exemestane reduces the risk of:

• Distant metastases by 34% (p=0.0001)

• Contralateral breast cancer by 50% (p=0.04)

• Switching to exemestane reduces the chances of dying

(p=0.08) but, although more convincing than the March 2004

analysis (p=0.41), is not yet significant at the 0.05 level

Coombes et al. San Antonio Breast Cancer Symposium;2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.

IES: Safety conclusions

• No excess of intercurrent deaths

• Endocrine effects similar to tamoxifen

• Musculoskeletal side effects more common in exemestane

arm

• No significant difference in the incidence of fractures:

Exemestane 3.1%, tamoxifen 2.3% p=0.08

• Cardiovascular – more data are required but serious events

are very rare

• Exemestane associated with a reduction in gynaecological

and thromboembolic side effects


Summary SWITCH studies AIs vs tamoxifen

Study AI Number of

patients

Design Number of

countries

Patient

population

IES-031 Exemestane 4712 Double-blind,

randomised

37 N: +, -

CT: +, -

ITA Anastrozole 426 randomised 1 N: + only

CT: +, -

ARNO/

ABCSG

Anastrozole 3224 Retrospective,

pooled analysis

2 N: +, -

(neg: 74%)

CT: not

allowed

Switch vs. Upfront - level A2 evidence studies

IES:

ATAC:

BIG 1-98:

2-3 yr tamoxifen 3-2 yr exemestane5 yr tamoxifen

5 yr tamoxifen

5 yr anastrozole

5 yr tamoxifen & anastrozole

5 yr tamoxifen

5 yr letrozole

2 yr letrozole 3 yr tamoxifen

3 yr letrozole2 yr tamoxifen

Disease Free Survival (DFS)

Parameter UPFRONT SWITCH

BIG 1-98

(F vs.T)

ATAC*

(A vs. T)

IES

(E vs. T)

DFS – relative risk

reduction

HR 0.81 (P=0.003) HR 0.83 (P=0.005) HR 0.73

(p=0.0001)

DFS – absolute risk

reduction

2.6% 3.3% 30,6 months: 4,7%**

37,4 months: NA

Distant Recurrences HR 0.73

(P=0.006)

HR 0.84

(P=0.06)

E: N= 150

T: N= 208 ***

Contralateral BC 0.4% vs 0.7%

(p=0.125)

HR 0.47

(P=0.001)

HR 0.50

(p=0.04)

•ATAC: mediane FU: 68 months; only HR+ population

•** FU: 37.4 months (NEJM) *** HR not reported

Retrospective analysis of time to recurrence for ER/PgR subgroups (Howell T et al, ATAC, SABCS 2004)

At risk:A 451 435 417 400 390 347 124T 429 412 375 353 327 276 96

Follow-up time (years)

25

0

5

10

15

20

0 1 2 3 4 5 6

Anastrozole (A)Tamoxifen (T)

Pat

ient

s (%

)

Patient group HR+ ER+PgR+ ER+PgR-

Hazard ratio 0.79 0.84 0.43

ER+/PgR-

Smoothed hazard rates for recurrenceHR+ patients

0.5

1.0

1.5

2.0

2.5

3.0

0 1 2 3 4 5 6

Follow-up time (years)

Anastrozole Tamoxifen

0Ann

ual h

azar

d ra

tes

(%)

Which patients are these? •HER2neu+++?•Should have been treated with CT?•ER+PgR-?

Howell T. et al., ATAC trial , San Antonio Breast Cancer Symposium 2004.

Overall Survival

UPFRONT SWITCH

BIG I-98

(F vs.T)

ATAC

(A vs. T)

IES

(E vs. T)

Mediane FU:

26 months

Mediane FU:

68 months

Mediane FU*:

37,4 months

HR 0.86

(NS; p=?)

HR 0.97

(p=0.7)

HR 0.83

(p=0.08)

* after randomisation after Tam

IES: Model effect addition AI after 3 years Tam in PR+

% recurrence

-free

0 2 4 6 8 10 12 14

1,0

0,9

0,8

0,7

Presentation of K. Osborne, St. Gallen Conference January 2005

jaar

tamoxifen

AI

Safety

Upfront and Switch - Summary of fracture risk

Objective: To compare the effects of a steroidal or a nonsteroidal aromatase inhibitor on serum biomarkers of bone resorption and bone formation

Study subjects were randomized at two investigative sites in Germany to one of four single-blind treatment groups (target enrollment = 80)

Treated for 24 weeks Re-assessed at 36 weeks Primary Endpoint: Percent change from baseline in bone turnover markers at assessment weekSecondary Endpoints: Baseline-adjusted area under the curve (AUC) for 0-12 weeks and 0-24 weeks of

treatment calculated for all bone turnover markers, Percent change from baseline in bone turnover makers at assessment weeks 12

and 36,Percent change from baseline in lipid profiles at assessment weeks 12, 24 and

36, Percent of baseline estrogen concentrations at assessment weeks 12, 24 and 36

and safety

Healthy Postmenopausal Volunteers

Anastrozole 1 mg po qd

Exemestane 25 mg po qd

Letrozole2.5 mg po qd

Placebo po qd

Subar M. et al. Oral presentation ASCO 2004, abstract # 8038

-10.00

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

Anastrozole Exemestane Letrozole Placebo

Treatment

*p = 0.182

*Difference across active treatment groups

Bone Resorption Marker: % Change Week 24 from Baseline serum CTX-I

Median with 95% CI


Bone Formation Marker:%Change Week 24 from Baseline Serum PINP

Median with 95% CI

-10.00

-5.00

0.00

5.00

10.00

15.00

20.00

25.00

30.00

35.00

Anastrozole Exemestane Letrozole Placebo

Treatment*p = 0.093

*Difference across active treatment groups


A total of 128 BMD-evaluable postmenopausal women with early breast cancer at low risk of relapse not given adjuvant therapy routinely during inclusion period or DCIS

Exemestane 25 mg po daily for 24 months

Placebo po daily for 24 months

• Patients were followed up for a total of 36 months for BMD and 5 years for DFS.

The study data were reviewed yearly by a Data Monitoring Committee.• Primary endpoint: Mean annual BMD loss• Secondary endpoints: lipid metabolism parameters / cardiovascular risk

parameters, bone metabolism markers, coagulation parameters, sex hormones profile, DFS

• BMD, bone markers, hormones, lipids, coagulation markers were measured at 0, 6, 12, 18, 24 and 36 months (follow-up)

027: Study design

Lonning PE et al. ASCO 2004:Abstract 518.

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

Months

Lumbar spine

Femoral neck

Placebo

Placebo

Exemestane

Exemestane

0 6 2412

BM

D (

g/c

m2 )

027: BMD


027: T-score mean changes from baseline at 2 years


Exemestane n=62 Placebo

n=66

Difference

Lumbar spine –0.30 –0.21 0.09

Femoral neck –0.21 –0.11 0.10

4 fractures in exemestane group; 5 fractures in placebo group

-6

-5

-4

-3

-2

-1

0

24 months 36 months (1-yr FU)

Lumbar Spine

Placebo Exemestane Placebo Exemestane

Femoral Neck

%

BM

D C

han

ge

fro

m B

asel

ine

(Mea

n, 9

5% C

I)

p=0.0003NS NSNS

027: 1-yr follow-up

Lonning PE et al. ASCO 2005: poster # 531

027: Conclusions

• Exemestane moderately increases bone loss in the lumbar spine

(non-significant) and the femoral neck.

• No patient with normal BMD at baseline became osteoporotic on

either treatment.

• There was no difference in the frequency of osteopenic patients

becoming osteoporotic.

“We conclude that pharmacodynamic effects of exemestane therapy

on bone are mostly reversible within one year after treatment

withdrawal. This suggests exemestane adjuvant therapy should not

have long-term detrimental effects on bone metabolism.”

Lonning PE et al. ASCO 2004: Abstract 518. Lonning PE et al. ASCO 2005: poster # 531

Molecule structure aromatase inhibitors

The metabolite of exemestane is weak androgenic.

steroidal / aromatase-inactivator

non-steroidal / aromatase-inhibitors

androsteendion exemestane anastrozol letrozol

Effect of Estrogen Concentration on Androgen Sensitivity in Bone

ASCO assessment of aromatase inhibitors

(Journal of Clinical Oncology, 20 Jan 2005)

“Optimal adjuvant hormonal therapy for a postmenopausal

woman with hormone

receptor-positive breast cancer includes an aromatase inhibitor

as initial therapy or after treatment with tamoxifen.”

AIs: Consensus guidelines

AIs: Consensus guidelines

St. Gallen consensus panel (January 2005)

Tamoxifen 2–3 years AI 2–3 years 72%

Tamoxifen 5 years AI in high risk 93%

AI irrespective of risk 50%

Upfront tamoxifen 58%

ER+, PR+ upfront tamoxifen 65%

ER+, PR– upfront tamoxifen 14%

HER2 overexpression upfront tamoxifen 10%

Final conclusions

• Exemestane is superior in the sequential studies after

tamoxifen.

• Exemestane has the most favourable tolerability

profile, in particular on the skeleton.

• The TEAM trial will answer the question whether 5

years of exemestane is superior to the sequence

tamoxifen followed by exemestane.

Back up slides

De beste aromataseremmer? Natuurlijk exemestaan! J.W.R.Nortier 4e jaarlijks mammacarcinoom symposium 29 juni 2005.

Documents