Transcript De beste aromataseremmer? Natuurlijk exemestaan!

De beste aromataseremmer?
Natuurlijk exemestaan!
J.W.R.Nortier
4e jaarlijks mammacarcinoom symposium
29 juni 2005
AROMATASE INHIBITION
androstenedione
testosterone
"steroidal inhibitor"
catalytic site
NADPH
"non-steroidal
inhibitor"
NADP
estrone
estradiol
Molecule structure aromatase inhibitors
steroidal /
aromataseinactivator
androsteendion exemestane
non-steroidal /
aromataseinhibitors
anastrozol
letrozol
Lecture Outline
•Sequential studies
•Sequential vs upfront studies
•Safety
Postmenopausal HR+ breast cancer:
Studies of adjuvant aromatase inhibition
Primary
randomisation
trials
Switching trials
Extension trials
ATAC
ITA
MA-17
BIG 1-98 (FEMTA)
ABCSG/ARNO
IES
HR+: hormone receptor-positive
ITA: Design
T (2–3 years)
R
A
N
D
O
M
I
S
E
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)
A: anastrazole; DFS: disease-free survival; HR: hazard ratio; T: tamoxifen
Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003.
No. and distribution of events
TAM n=45
ANA n=17
13
2
19
10
10
5
contra lateral breast
2
1
endometrium
5
1
other
3
3
Deaths Breast cancer related
7
4
Deaths without relapse
3
-
Local-regional
(includes ipsilateral breast recurrences, relapses in localregional nodes)
Distant metastases
(with or without local-regional recurrences)
Second primaries
Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003.
Event-free survival
ANA
TAM
TAM
ANA
N° pts. Obs
225
45
223
17
p=
0.0002
Years
Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003.
Postmenopausal HR+ breast cancer:
Studies of adjuvant aromatase inhibition
Primary
randomisation
trials
Switching trials
Extension trials
ATAC
ITA
MA-17
BIG 1-98 (FEMTA)
ABCSG/ARNO
IES
HR+: hormone receptor-positive
ABCSG/ARNO: Design
T (2 years)
R
A
N
D
O
M
I
S
E
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
Event- 100
free
survival 95
(%)
ANA
90
TAM
85
80
ANA vs TAM
p=0.0009 HR 0.60 [95% CI 0.44-0.81]
75
0
0
At risk:
TAM
ANA
1
2
3
4
5
343
375
176
178
EFS time in years*
1606
1618
1217
1243
*Zero point = 2 years after surgery
858
874
593
623
Jakesz R. et al. San Antonio Breast Cancer Symposium 2004.
Localization of events
Events
Locoregional
Contralateral BC
Distant recurrences
Total
n=3,224
TAM
n=1,606
ANA
n=1,618
177
44
28
121
110
24
16
75
67
20
12
46
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
Primary
randomisation
trials
Switching trials
Extension trials
ATAC
ITA
MA-17
BIG 1-98 (FEMTA)
ABCSG/ARNO
IES
HR+: hormone receptor-positive
IES: Design
Diagnosis and initial
treatment of early
breast cancer
Tamoxifen
therapy
for 2-3 years
R
A
N
D
O
M
I
S
A
T
I
O
N
Exemestane 2-3 y
25 mg po qd
(n=2,352)*
Tamoxifen 2-3 y
20 mg po qd
(n=2,372)*
5 Years Total Hormone Treatment
* Intent to treat population
Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.
IES: demographics
Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.
IES: DFS
DFS (%)
100
Exemestane (262 events)
Tamoxifen (353 events)
75
50
25
Hazard ratio: 0.73 (95% CI: 0.62, 0.86)
Log-rank test: p=0.0001
0
0
1
2
3
Years from randomisation
4
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
Exemestane (152 deaths)
‘women alive’ (%)
100
Tamoxifen (187 deaths)
75
50
25
Hazard ratio: 0.83 (95% CI: 0.67, 1.02)
Log-rank test: p=0.08
0
0
1
2
3
Years from randomisation
4
No. events/at risk
Exemestane
0 / 2,352
Tamoxifen
0 / 2,372
†Events
18 / 2,270
23 / 2,300
41 / 2,137
41 / 1,469
37+15† / 690
53 / 2,165
49 / 1,465
41+21† / 701
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: Causes of death
Exemestane
Tamoxifen
Total
152
187
339
95
124
219
11
12
23
Intercurrent (without
recurrence/CLB)
57
63
120
Vascular
15
7
22
Cardiac
13
12
25
Other cancer
13
22
35
Other
11
14
25
Unknown
5
8
13
Total number of deaths
Breast cancer deaths
Inc. other COD
in patients with
recurrence/CLB
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
Exemestane
Tamoxifen
n (%)
n (%)
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)
Cardiovascular medical history
p-values not statistically significant;
Coombes et al. San Antonio Breast Cancer Symposium 2004.
IES: Comparison of adverse events
In favour of tamoxifen
In favour of exemestane
Pain in limb
2.5
Thromboembolic disease
-1.4
Cramps
-2.1
Diarrhoea
2.3
Arthralgia
6.7
Gynaecologic symptoms
-6
-3.5
-4
-2
0
2
4
6
8
Difference between statistically significant adverse events (%)
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.
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
Design
patients
IES-031
ITA
Exemestane
Anastrozole
4712
426
Number of Patient
countries
Double-blind,
randomised
37
randomised
1
population
N:
+, -
CT: +, -
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:
5 yr tamoxifen
2-3 yr tamoxifen
3-2 yr exemestane
ATAC:
5 yr tamoxifen
5 yr anastrozole
5 yr tamoxifen & anastrozole
BIG 1-98:
5 yr tamoxifen
5 yr letrozole
2 yr letrozole
3 yr tamoxifen
2 yr tamoxifen
3 yr letrozole
Disease Free Survival (DFS)
Parameter
UPFRONT
SWITCH
BIG 1-98
ATAC*
IES
(F vs.T)
(A vs. T)
(E vs. T)
DFS – relative risk
reduction
HR 0.81 (P=0.003)
HR 0.83 (P=0.005)
HR 0.73
DFS – absolute risk
reduction
2.6%
Distant Recurrences
HR 0.73
HR 0.84
E: N= 150
(P=0.006)
(P=0.06)
T: N= 208 ***
0.4% vs 0.7%
HR 0.47
HR 0.50
(p=0.125)
(P=0.001)
(p=0.04)
Contralateral BC
(p=0.0001)
3.3%
30,6 months: 4,7%**
37,4 months: NA
•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)
Patient group
HR+
ER+PgR+
ER+PgR-
Hazard ratio
0.79
0.84
0.43
Patients (%)
25
Anastrozole (A)
Tamoxifen (T)
20
ER+/PgR-
15
10
5
0
0
At risk:
A
451
T
429
1
2
3
4
5
6
347
276
124
96
Follow-up time (years)
435
412
417
375
400
353
390
327
Annual hazard rates (%)
Smoothed hazard rates for recurrence
HR+ patients
Which patients are these?
•HER2neu+++?
•Should have been treated with CT?
•ER+PgR-?
3.0
2.5
2.0
1.5
1.0
Anastrozole
Tamoxifen
0.5
0
0
1
2
3
4
5
6
Follow-up time (years)
Howell T. et al., ATAC trial , San Antonio Breast Cancer Symposium 2004.
Overall Survival
UPFRONT
SWITCH
BIG I-98
ATAC
IES
(F vs.T)
(A vs. T)
(E vs. T)
Mediane FU:
Mediane FU:
Mediane FU*:
26 months
68 months
37,4 months
HR 0.86
HR 0.97
HR 0.83
(NS; p=?)
(p=0.7)
(p=0.08)
* after randomisation after Tam
IES: Model effect addition AI after 3 years Tam in PR+
1,0
AI
%
recurrence
-free
0,9
tamoxifen
0,8
0,7
0
2
4
6
8
10
12
Presentation of K. Osborne, St. Gallen Conference January 2005
14
jaar
Safety
Upfront and Switch - Summary of fracture risk
Healthy Postmenopausal Volunteers
Subar M. et al. Oral presentation ASCO 2004, abstract # 8038
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 week
Secondary 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
Anastrozole
1 mg po qd
Exemestane
25 mg po qd
Letrozole
2.5 mg po qd
Placebo
po qd
Bone Resorption Marker:
% Change Week 24 from Baseline serum CTX-I
Median with 95% CI
70.00
60.00
50.00
40.00
30.00
20.00
10.00
0.00
-10.00
Anastrozole
Exemestane
Letrozole
Placebo
Treatment
*p = 0.182
*Difference across active treatment groups
Subar M. et al. Oral presentation ASCO 2004, abstract # 8038
Bone Formation Marker:
%Change Week 24 from Baseline Serum PINP
Median with 95% CI
35.00
30.00
25.00
20.00
15.00
10.00
5.00
0.00
-5.00
-10.00
Anastrozole
Exemestane
Letrozole
Placebo
Treatment
*p = 0.093
*Difference across active treatment groups
Subar M. et al. Oral presentation ASCO 2004, abstract # 8038
027: Study design
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)
Lonning PE et al. ASCO 2004:Abstract 518.
027: BMD
Lumbar spine
1.2
1.1
BMD (g/cm2)
1.0
Placebo
Exemestane
0.9
0.8
Placebo
0.7
Exemestane
0.6
Femoral neck
0.5
0
6
12
Months
Lonning PE et al. ASCO 2004:Abstract 518.
24
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
Lonning PE et al. ASCO 2004:Abstract 518.
% BMD Change from Baseline (Mean, 95% CI)
027: 1-yr follow-up
Lumbar Spine
Placebo
Exem estane
Femoral Neck
Placebo
Exem estane
0
-1
-2
-3
-4
-5
-6
NS
p=0.0003
24 months
NS
NS
36 months (1-yr FU)
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
steroidal /
aromataseinactivator
androsteendion exemestane
non-steroidal /
aromataseinhibitors
anastrozol
letrozol
The metabolite of exemestane is weak androgenic.
Effect of Estrogen Concentration on Androgen
Sensitivity in Bone
AIs: Consensus guidelines
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
St. Gallen consensus panel (January 2005)
Tamoxifen 2–3 years
Tamoxifen 5 years
AI 2–3 years
72%
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