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
-
Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003.
Event-free survivalEvent-free survival
ANA
Years
% S
urv
ivin
g
N° pts. Obs p= TAM 225 45ANA 223 17 0.0002
TAM
Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003.
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
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.
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
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
Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.
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
Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.
IES: Subgroup analysis
Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.
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
Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.
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.
Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.
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
Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.
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
Subar M. et al. Oral presentation ASCO 2004, abstract # 8038
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
Subar M. et al. Oral presentation ASCO 2004, abstract # 8038
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
Lonning PE et al. ASCO 2004:Abstract 518.
027: T-score mean changes from baseline at 2 years
Lonning PE et al. ASCO 2004:Abstract 518.
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
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