Transcript Document

‘Arimidex’, Tamoxifen, Alone or
in Combination (ATAC) trial:
Completed Treatment Analysis
Introduction
Which problems does ATAC address?
 Is tamoxifen still the best adjuvant therapy
for early breast cancer (EBC)?
 How do we reduce recurrences in the first
few years of treatment?
 Can we improve upon the tolerability
problems associated with adjuvant
tamoxifen?
 Is anastrozole superior to tamoxifen
in the adjuvant setting?
If tamoxifen is not the best
adjuvant treatment:
 Should anastrozole be considered
the preferred initial endocrine therapy?
 When should anastrozole be given?
 Is there robust and mature data to
support the use of anastrozole in this
setting?
Trial design & patient
recruitment
ATAC trial design
9366 Postmenopausal women with invasive breast cancer
mean age 64 years; 84% hormone receptor positive
61% node negative; 64% with tumour 2 cm in diameter

Surgery  radiotherapy  chemotherapy

Randomisation 1:1:1 for 5 years

Anastrozole
n=3125

Tamoxifen
n=3116


Discontinued
following initial
Combination
analysis
as no efficacy or
n=3125
tolerability
benefit compared
with tamoxifen arm
Regular follow-up

Primary trial endpoints:
• Disease-free survival
• Safety / tolerability
Secondary trial endpoints:
• Incidence of contralateral breast cancer
• Time to distant recurrence
• Overall survival
• Time to breast cancer death
ATAC completed treatment analysis
 Follow-up:
– Data cut-off 31st March 2004, based on at least 704 deaths in
the two monotherapy arms combined
– 68 months’ median follow-up – beyond completion of
treatment
– 59 months’ median treatment duration
– Only 8% of patients remain on treatment – the great majority
of these nearing completion
 Results:
– Anastrozole demonstrates superior efficacy to tamoxifen
– Anastrozole demonstrates superior tolerability to tamoxifen
– The results of this analysis are mature and the overall
risk:benefit profile of anastrozole can be considered final
Efficacy analysis
Smoothed hazard rates for recurrence
(HR*-positive population)
Annual
hazard
rates
(%)
3.0
2.5
2.0
1.5
1.0
Anastrozole
Tamoxifen
0.5
0
0
*HR=hormone receptor
1
2
3
4
Follow-up time (years)
5
6
Disease-free survival
(HR*-positive population)
25
A vs T
Patients (%)
20
15
HR
95% CI
p-value
0.83
(0.73–0.94)
0.005
Anastrozole (A)
Tamoxifen (T)
10
5
Absolute difference: 1.6%
0
0
At risk:
A
2618
T
2598
1
2
2540
2516
2448
2398
*HR=hormone receptor
2.6%
3
4
Follow-up time (years)
2355
2304
2268
2189
2.5%
3.3%
5
6
2014
1932
830
774
Recurrence
(HR*-positive population)
25
A vs T
Patients (%)
20
15
HR
95% CI
p-value
0.74
(0.64–0.87)
0.0002
Anastrozole (A)
Tamoxifen (T)
10
5
Absolute difference: 1.7%
0
0
At risk:
A
2618
T
2598
1
2
2540
2516
2448
2398
*HR=hormone receptor
2.4%
3
4
Follow-up time (years)
2355
2304
2268
2189
2.8%
3.7%
5
6
2014
1932
830
774
Analysis of time to recurrence for
subgroups of the HR*-positive population
Nodal status
+ve
-ve
unknown**
Tumour size
2 cm
2–5 cm
>5 cm*
Previous
chemotherapy
Yes
No
All patients
Hazard ratio (A:T) and 95% CI
0.40
*HR=hormone receptor
**Confidence limit extends beyond plot
0.60
0.80
Anastrozole better
1.00
1.25 1.50 1.75
Tamoxifen better
Time to distant recurrence
(HR*-positive population)
25
A vs T
Patients (%)
20
15
HR
95% CI
p-value
0.84
(0.70–1.00)
0.06
Anastrozole (A)
Tamoxifen (T)
10
5
0
0
At risk:
A
2618
T
2598
1
2
2549
2533
2463
2437
*HR=hormone receptor
3
4
Follow-up time (years)
2385
2359
2308
2255
5
6
2051
2005
845
816
Overall survival
(HR*-positive population)
25
A vs T
Patients (%)
20
15
HR
95% CI
p-value
0.97
(0.83–1.14)
0.7
Anastrozole (A)
Tamoxifen (T)
10
5
0
0
At risk:
A
2618
T
2598
1
2
2566
2549
2505
2502
*HR=hormone receptor
3
4
Follow-up time (years)
2437
2430
2377
2333
5
6
2117
2080
867
855
Incidence of new (contralateral) breast
primaries in HR*-population
AN vs TAM
HR
95% CI
p-value
0.47
0.29–0.75
0.001
Number 60
of cases
50
53
5 DCIS
40
30
20
10
26
5 DCIS
48
Invasive*
21
Invasive*
0
Anastrozole (AN)
(n=3125)
Tamoxifen (TAM)
(n=3116)
*p=0.001 for invasive cancers.
*HR=hormone receptor
Most recurrences occur within the
first 5 years of primary therapy
Recurrence 16
rate/year
14
(%)
Node (–)
Node (+)
12
Need to give most effective treatment first
to reduce risk of recurrence
10
8
6
4
2
0
0
1
2
3
4
5
Year
6
7
8
9
10
Saphner et al JCO 1996; 14: 2738-2746
Disease-free survival
(HR*-positive population)
25
A vs T
Patients (%)
20
15
HR
95% CI
p-value
0.83
(0.73–0.94)
0.005
Anastrozole (A)
Tamoxifen (T)
10
5
Absolute difference: 1.6%
0
0
At risk:
A
2618
T
2598
1
2
2540
2516
2448
2398
*HR=hormone receptor
2.6%
3
4
Follow-up time (years)
2355
2304
2268
2189
2.5%
3.3%
5
6
2014
1932
830
774
Anastrozole demonstrates
superior efficacy to tamoxifen
 Anastrozole is more effective than tamoxifen in
reducing the risk of recurrence, distant
recurrence and contralateral breast cancer
 The absolute difference between anastrozole and
tamoxifen continues to increase over time, and
extends beyond completion of treatment
 As expected, overall survival is similar for both
treatments, with a trend in favour of anastrozole
for breast cancer death
 There are no significant subgroup interactions
Added benefit versus tamoxifen
EBCTCG
ATAC
Benefit for
tamoxifen vs
placebo
Additional benefit
of anastrozole vs
tamoxifen
Reduction in risk of
recurrence
50%
26%
Reduction in risk of breast
cancer mortality
28%
13%
Reduction in risk of
contralateral breast cancer
47%*
52%
Hormone receptor-positive
population
*hormone receptor-positive and -negative patients
EBCTCG = Early Breast Cancer Trialists’ Collaborative Group
Added benefit versus tamoxifen
38% risk of recurrence with no adjuvant treatment
50% reduction in risk with tamoxifen
Further 26% risk
reduction with
anastrozole
When to treat?
 Recurrence rates I early breast cancer are
highest in the first 5 years after surgery,
with a peak at 2 years, regardless of
baseline prognostic factors
 Tamoxifen is associated with higher rates
of recurrence, AEs and withdrawals than
anastrozole
 Substantial benefit with anastrozole in the
first 3 years justifies offering the most
effective therapy at the earliest
opportunity
Tolerability analysis
Overview of adverse events*
Anastrozole (%) Tamoxifen (%)
(n=3092)
(n=3094)
p-value
All adverse events
93.9
94.6
0.2
Adverse events leading to
withdrawal
11.1
14.3
0.0002
6.5
8.9
0.0005
33.3
36.0
0.03
Serious adverse events
leading to withdrawal
4.7
5.9
0.04
Serious adverse events
leading to death
3.3
3.6
0.6
Drug-related serious adverse
events leading to death
0.2
0.3
0.5
Drug-related adverse events
leading to withdrawal
All serious adverse events
*Adverse events on treatment or within 14 days of discontinuation
Pre-defined adverse events
Completion
analysis
p-value
A
T
Hot flushes
35.7
40.9
<0.0001
Vaginal bleeding
5.4
10.2
<0.0001
Vaginal discharge
3.5
13.2
<0.0001
Endometrial cancer*
0.2
0.8
0.01
Ischaemic cerebrovascular
event
2.0
2.8
0.03
Venous thromboembolic
events
2.8
4.5
0.0004
Deep venous
thromboembolic events
1.6
2.4
0.02
Joint symptoms
35.6
29.4
<0.0001
Total fractures
11.0
7.7
<0.0001
*Excludes patients with prior hysterectomy and includes on- and off-therapy AEs
Pre-defined adverse events
Venous thromboembolic events
Ischaemic cerebrovascular events
Endometrial cancer
Vaginal bleeding
Vaginal discharge
Hot flushes
Joint symptoms
Fractures
0.2
0.4
In favour of anastrozole
0.6
0.8 1.0
1.5
2.0
In favour of tamoxifen
Relative risk (anastrozole / tamoxifen)
Tolerability summary
 Compared with tamoxifen, anastrozole is associated with
significantly fewer:
– SAEs, treatment-related AEs and withdrawals due to SAEs or
AEs
– potentially life threatening AEs such as endometrial cancer,
thromboembolic, and cerebrovasular events
 No new safety concerns have emerged with long-term
follow-up
 Only anastrozole has a tolerability profile of this
robustness and maturity, as it covers the full 5 year
treatment period
 Anastrozole now has a known, predictable and manageable
safety profile
Summary
ATAC summary
 ATAC Completed Treatment Analysis extends
and strengthens the evidence that 5 years of
anastrozole is significantly more effective and
better tolerated than 5 years of tamoxifen
 Overall risk:benefit profile remains clearly in
favour of anastrozole
 The absolute benefits for anastrozole over and
above those of tamoxifen continue to increase
with time and extend beyond the completion of
therapy
ATAC in context
 Anastrozole is a more effective and
better-tolerated adjuvant treatment than
tamoxifen
 These findings provide a basis for
establishing anastrozole as the standard
of care for the initial 5 years’ adjuvant
treatment of postmenopausal women with
hormone receptor-sensitive early breast
cancer
Howell, SABCS 2004
Back-up slides
Definition of endpoints (1)
 Disease-free survival (DFS)
– loco-regional recurrence (inc. ipsilateral new breast
cancer) or new contralateral breast cancer
– distant recurrence or death (for any reason)
 Distant disease-free survival (DDFS)
– distant recurrence
– death (for any reason)
 Time to recurrence (TTR)
– loco-regional recurrence (inc. ipsilateral new breast
cancer) or new contralateral breast cancer
– distant recurrence or death due to breast cancer
Definition of endpoints (2)
 Overall survival (OS)
– death (for any reason)
 Time to distant recurrence (TTDR)
– distant recurrence or any death following a locoregional recurrence (inc. ipsilateral new breast cancer)
– breast cancer death
 Time to breast cancer death (TTBCD)
– any death following a loco-regional (inc. ipsilateral
new breast cancer) or distant recurrence
– breast cancer death
ATAC: patient characteristics
Mean age (years)
Mean weight (kg)
Receptor status (%)
positive
negative
unknown
Primary treatment (%)
mastectomy
axillary surgery
radiotherapy
chemotherapy
prior tamoxifen
Anastrozole
(n=3125)
Tamoxifen
(n=3116)
64.1
70.8
64.1
71.1
83.7
8.3
8.0
83.4
8.7
7.9
47.8
95.5
63.3
22.3
1.6
47.3
95.7
62.5
20.8
1.6
ATAC: baseline disease characteristics
Anastrozole
(n=3125)
Tamoxifen
(n=3116)
T1 (2 cm)
63.9
62.9
T2 (2 cm to 5 cm)
32.6
34.2
T3 (5 cm)
2.7
2.2
34.9
33.6
well differentiated
20.8
20.5
moderately differentiated
46.8
47.8
poorly / undifferentiated
23.7
23.3
not assessed / recorded
8.5
8.3
Primary tumour size (%)
Nodal status (%)
node-positive
Grading (%)
ATAC trial analysis history
First analysis – June 2002
Median follow-up : 33 months1
Updated analysis – November 2003
Median follow-up : 47 months2
Completion analysis – November 2004
Median follow-up : 68 months
Women years’ follow up: 49,941
Total events: 1867
1.The ATAC Trialists’ Group. Lancet 2002; 359: 2131–2139
2.The ATAC Trialists’ Group. Cancer 2003; 98: 1802 – 1810
Smoothed hazard rates for recurrence
(ITT* population)
Annual
hazard
rates
(%)
3.0
2.5
2.0
1.5
1.0
Anastrozole
Tamoxifen
0.5
0
0
*ITT=intent-to-treat
1
2
3
4
Follow-up time (years)
5
6
Disease-free survival (ITT* population)
25
A vs T
Patients (%)
20
15
HR
95% CI
p-value
0.87
(0.78–0.97)
0.013
Anastrozole (A)
Tamoxifen (T)
10
5
Absolute difference: 1.5%
0
0
At risk:
A
3125
T
3116
1
2
3004
2992
2874
2835
Includes non breast cancer deaths
*ITT=intent-to-treat
2.0%
3
4
Follow-up time (years)
2757
2709
2645
2575
2.4%
2.9%
5
6
2350
2273
984
933
Recurrence (ITT* population)
25
Patients (%)
20
A vs T
15
HR
95% CI
p-value
0.79
(0.70–0.90)
0.0005
Anastrozole (A)
Tamoxifen (T)
10
5
Absolute difference: 1.6%
0
0
At risk:
A
3125
T
3116
*ITT=intent-to-treat
1
2
3004
2992
2874
2835
2.1%
3
4
Follow-up time (years)
2757
2709
2645
2575
2.8%
3.4%
5
6
2350
2273
984
933
Analysis of time to recurrence for
subgroups of the ITT* population
Nodal status
+ve
-ve
unknown
Tumour size
≤ 2 cm
>2 cm
unknown**
Receptor status
+ve
-ve
unknown
Previous
chemotherapy
yes
no
All patients
0.40
Hazard ratio (A:T) and 95% CI
*ITT=intent-to-treat
**Confidence limit extends beyond plot
0.60
0.80
Anastrozole better
1.00
1.25 1.50 1.75
Tamoxifen better
Time to distant recurrence
(ITT* population)
25
Patients (%)
20
A vs T
15
HR
95% CI
p-value
0.86
(0.74–0.99)
0.043
Anastrozole (A)
Tamoxifen (T)
10
5
0
0
At risk:
A
3125
T
3116
*ITT=intent-to-treat
1
2
3
4
Follow-up time (years)
3022
3020
2899
2890
2802
2783
2703
2656
5
6
2406
2364
1009
985
Overall survival (ITT* population)
25
Patients (%)
20
A vs T
15
HR
95% CI
p-value
0.97
(0.85–1.12)
0.7
Anastrozole (A)
Tamoxifen (T)
10
5
0
0
1
2
3
4
Follow-up time (years)
At risk:
A
3125
2956
3051
T
3116
2972
3048
Includes non breast cancer deaths
*ITT=intent-to-treat
2865
2872
2784
2747
5
6
2479
2461
1037
1037
Time to breast cancer death
(ITT* population)
25
Patients (%)
20
A vs T
15
HR
95% CI
p-value
0.88
(0.74–1.05)
0.2
Anastrozole (A)
Tamoxifen (T)
10
5
0
0
At risk:
A
3125
T
3116
*ITT=intent-to-treat
1
2
3
4
Follow-up time (years)
3051
3048
2956
2972
2865
2872
2784
2747
5
6
2479
2461
1037
1037
Incidence of new (contralateral) breast
primaries in ITT* population
AN vs TAM
HR
95% CI
p-value
0.58
0.38–0.88
0.01
58
6 DCIS
Number 60
of cases
50
40
35
30
8 DCIS
52
Invasive*
20
10
27
Invasive*
0
Anastrozole (AN)
(n=3125)
Tamoxifen (TAM)
(n=3116)
*p=0.004 for invasive cancers.
*ITT=intent-to-treat
Summary of efficacy endpoints
 In the overall ITT population, compared
with tamoxifen, anastrozole provides
significantly reduced risk of :
– all events: 13% (p=0.013)
– recurrence: 21% (p=0.0005)
– distant recurrence: 14% (p=0.043)
– contralateral recurrence: 42% (p=0.01)