Transcript ATAC

‘Arimidex’, Tamoxifen, Alone or
in Combination (ATAC) trial:
Completed Treatment Analysis
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

Randomization 1:1:1 for 5 years

‘Arimidex’
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 trial analysis history
First analysis – Dec 2001
Median follow-up : 33 months1
Updated analysis – November 2002
Median follow-up : 47 months2
Treatment 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
3. The ATAC Trialists’ Group. Lancet 2005; 365: 60-62
ATAC completed treatment analysis
 Data cut off: 31st March 2004:
– prospectively defined based on at least 704
deaths in the two monotherapy arms combined
 Follow-up:
– 68 months’ median follow-up – i.e. extends
beyond completion of treatment
– 59 months’ median treatment duration
– Only 8% of patients remain on treatment – the
great majority of these nearing completion
Efficacy analysis
Disease-free survival
Curves shown for HR+ patients
HR#
95% CI
p-value
HR+*
0.83
(0.73–0.94)
0.005
ITT**
0.87
(0.78-0.97)
0.01
25
Patients (%)
20
17%
RR
15
‘Arimidex’ (A)
Tamoxifen (T)
10
5
Absolute
difference:
0
0
At risk:
A
2618
T
2598
1
2
1.6%
2.6%
3
4
2.5%
3.3%
5
6
2014
1932
830
774
Follow-up time (years)
2540
2516
2448
2398
2355
2304
2268
2189
*ITT = Intention-to-treat population; **HR+ = Hormone receptor-positive patients; #A vs T
Time to Recurrence
Curves shown for HR+ patients
25
Patients (%)
20
HR
95% CI
p-value
HR+
0.74
(0.64–0.87)
0.0002
ITT
0.79
(0.79-0.90)
0.0005
26% RR
15
‘Arimidex’ (A)
Tamoxifen (T)
10
5
Absolute
difference:
0
0
1
2
1.7%
2.4%
3
2.8%
4
3.7%
5
6
Follow-up time (years)
At risk:
A
2618
2540
2448
2355
2268
2014
830
T
2598
2516
2398
2304
2189
1932
774
Smoothed hazard rates for recurrence
(HR+ population)
Annual
hazard
rates
(%)
3.0
2.5
2.0
1.5
1.0
‘Arimidex’ (A)
Tamoxifen (T)
0.5
0
0
1
2
3
4
Follow-up time (years)
5
6
Time to Distant Recurrence
Curves shown for HR+ patients
25
Patients (%)
20
15
HR
95% CI
p-value
HR+
0.84
(0.70–1.00)
0.06
ITT
0.87
(0.74-0.99)
0.04
‘Arimidex’ (A)
Tamoxifen (T)
10
5
0
0
1
2
3
4
5
6
A
2618
2550
2464
2386
2309
2051
845
T
2598
2533
2438
2361
2257
2005
816
At risk:
Overall Survival*
Curves shown for HR+ patients
HR
95% CI
p-value
HR+
0.97
(0.83–1.14)
0.7
ITT
0.97
(0.85-1.12)
0.7
25
Patients (%)
20
15
‘Arimidex’ (A)
Tamoxifen (T)
10
5
0
0
1
2
3
4
5
6
Follow-up time (years)
At risk:
A
2618
T
2598
2566
2505
2437
2377
2117
867
2549
2502
2430
2333
2080
855
* Includes non breast cancer deaths
Time to Breast Cancer Death
Curves shown for HR+ patients
25
Patients (%)
20
HR
95% CI
p-value
HR+
0.87
(0.70–1.09)
0.2
ITT
0.88
(0.74-1.05)
0.2
15
‘Arimidex’ (A)
Tamoxifen (T)
10
5
0
0
1
2
3
4
5
6
Follow-up time (years)
At risk:
A
2618
2566
2505
2437
2377
2117
867
T
2598
2549
2502
2430
2333
2080
855
Incidence of new (contralateral) breast
primaries in HR+ population
A vs T
Number 60
of cases
50
HR
95% CI
p-value
0.47
(0.29–0.75)
0.001
54
40
30
26
20
10
0
‘Arimidex’ (A)
(n=2618)
Tamoxifen (T)
(n=2598)
Efficacy analysis – ITT and HR+ populations
ITT population
Disease-free survival
HR+ population
Time to recurrence
Time to distant recurrence
Overall survival
Time to breast cancer death
Contralateral breast cancer
0.2
*ITT= intent-to-treat
*HR+=hormone receptor-positive
0.4
0.6 0.8 1.0 1.2 1.5 2.0
Hazard Ratio (A:T) and 95% CI
‘Arimidex’ (A) better
Tamoxifen (T) better
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
Hazard ratio (A:T) and 95% CI
0.40
0.60
0.80
‘Arimidex’ better
*Confidence limit extends beyond plot
1.00
1.25 1.50 1.75
Tamoxifen better
Summary of efficacy endpoints
 In the HR+ population, compared with tamoxifen,
‘Arimidex’ reduces the risk of :
– all events: 17% (p=0.005)
– recurrence: 26% (p=0.0002)
– distant recurrence: 16% (p=0.06)
– contralateral recurrence: 53% (p=0.001)
 There is also a (non-significant trend for a
reduction in breast cancer mortality: 13% (p=0.2)
‘Arimidex’ demonstrates
superior efficacy to tamoxifen
 ‘Arimidex’ is more effective than tamoxifen in
reducing the risk of recurrence, distant
recurrence and contralateral breast cancer
 The absolute difference between ‘Arimidex’ and
tamoxifen continues to increase over time, and
extends beyond completion of treatment
 As expected, overall survival is similar for both
treatments, i.e. ‘Arimidex’ maintains the
significant survival benefit already established
for tamoxifen, with a trend in favour of ‘Arimidex’
for breast cancer death
 There are no significant subgroup interactions
Added benefit versus tamoxifen
HR+ve population
Reduction in risk of
recurrence
Reduction in risk of breast
cancer mortality
Reduction in risk of
contralateral breast cancer
EBCTCG
ATAC
Benefit for
tamoxifen vs
placebo
Additional benefit
of ‘Arimidex’ vs
tamoxifen
50%
26%
28%
13%
47%*
53%
*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% risk reduction with tamoxifen
Further 26% risk
reduction with
‘Arimidex’
When to treat?
 Recurrence rates in 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 ‘Arimidex’
 Substantial benefit with ‘Arimidex’ in the first 3
years justifies offering the most effective therapy
at the earliest opportunity
Best treatment first !
Annual hazard of recurrence peaks at 2 years
regardless of baseline prognostic factors
Need to give most effective treatment first
to reduce risk of recurrence
Adapted from Saphner et al, 1996
Tolerability analysis
Overview of adverse events*
'Arimidex' (%)
(n=3092)
Tamoxifen (%)
(n=3094)
p-value
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
Adverse events leading to
withdrawal
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
Hot flushes
Vaginal bleeding
Vaginal discharge
Endometrial cancer**
Ischaemic cerebrovascular
event
Venous thromboembolic
events
Deep venous
thromboembolic events
Joint symptoms
Total fractures***
p-value
A
35.7
5.4
3.5
0.2
2.0
T
40.9
10.2
13.2
0.8
2.8
<0.0001
<0.0001
<0.0001
0.02
0.03
2.8
4.5
0.0004
1.6
2.4
0.02
35.6
11.0
29.4
7.7
<0.0001
<0.0001
*Adverse events on treatment or within 14 days of discontinuation; **Excludes patients with prior
hysterectomy and includes on- and off-therapy AEs; ***Fractures occurring at anytime prior to
recurrence (includes patients no longer receiving treatment)
Tolerability summary
 Compared with tamoxifen, 'Arimidex' is associated
with significantly fewer:
– SAEs, treatment-related AEs and withdrawals
– potentially life threatening AEs such as endometrial cancer,
thromboembolic, and cerebrovasular events
 No new safety concerns with long-term follow-up
 Only 'Arimidex' has a tolerability profile this robust
and mature, covering the full 5 year treatment period
 'Arimidex' now has a known, predictable and
manageable safety profile
Tolerability profile not only different
but SUPERIOR
Summary
ATAC summary
 ATAC Completed Treatment Analysis extends
and strengthens the evidence that 5 years of
'Arimidex' is significantly more effective and
better tolerated than 5 years of tamoxifen
 Overall risk:benefit profile remains clearly in
favour of 'Arimidex'
 The absolute benefits for 'Arimidex' over and
above those of tamoxifen continue to increase
with time and extend beyond the completion of
therapy
ATAC in context
 'Arimidex' is a more effective and
better-tolerated adjuvant treatment than
tamoxifen
 These findings provide a basis for
establishing 'Arimidex' 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
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