Transcript Clinical trial work from the Austrian Breast & Colorectal Cancer

Best first ?
The ATAC completed
treatment analysis
Professor Jack Cuzick
Wolfson Institute of Preventive Medicine,
London, UK
Aims of the ATAC trial
 Can we improve on tamoxifen as adjuvant
therapy for early breast cancer?
 Can we reduce recurrences, especially in
the first few years of treatment?
 Can we improve the tolerability profile of
adjuvant tamoxifen?
Is anastrozole superior to tamoxifen
in the initial adjuvant setting?
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
Combination arm
Combination
discontinued
following initial
n=3125
analysis
as no efficacy or
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
– 68 months’ median follow-up – beyond
completion of treatment
– only 8% of patients remain on treatment
the great majority of these nearing
completion
Efficacy analysis
Disease-free survival
(HR-positive population)
Events 25
(%)
HR
20
15
95% CI
p-value
HR+
0.83
(0.73–0.94) 0.005
ITT
0.87
(0.78–0.97)
0.01
Anastrozole (A)
10
Tamoxifen (T)
5
Absolute difference: 1.6%
0
0
At risk:
A
2618
T
2598
1
2
2540
2516
2448
2398
HR=hormone receptor; ITT=intent-to-treat
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)
Events 25
(%)
HR
20
15
95% CI
p-value
HR+
0.74
(0.64–0.87) 0.0002
ITT
0.79
(0.70–0.90) 0.0005
Anastrozole (A)
10
Tamoxifen (T)
5
Absolute difference: 1.7%
0
0
At risk:
A
2618
T
2598
1
2
2540
2516
2448
2398
2.4%
3
4
Follow-up time (years)
2355
2304
2268
2189
2.8%
3.7%
5
6
2014
1932
830
774
Incidence of contralateral breast cancer
(HR-positive population)
HR
No. of
cases
60
95% CI
p-value
HR+
0.47
(0.29–0.75) 0.001
ITT
0.58
(0.38–0.88)
0.01
54
6 DCIS
50
40
30
26
20
5 DCIS
21
Invasive*
10
0
Anastrozole
(n=2618)
*p=0.001 for invasive cancers
48
Invasive*
Tamoxifen
(n=2598)
Time to distant recurrence
(HR-positive population)
Patients 25
(%)
20
15
HR
95% CI
p-value
HR+
0.84
(0.70–1.00)
0.06
ITT
0.86
(0.74–0.99)
0.04
Anastrozole (A)
10
Tamoxifen (T)
5
0
0
At risk:
A
2618
T
2598
1
2
3
4
Follow-up time (years)
2550
2533
2464
2438
2386
2361
2309
2257
5
6
2051
2005
845
816
Patients 25
(%)
Time to breast cancer death
(HR-positive population)
20
15
A
T
HR
95% CI
p-value
HR+
152
172
0.87
(0.70–1.09)
0.2
ITT
235
265
0.88
(0.74–1.05)
0.2
10
Anastrozole (A)
Tamoxifen (T)
5
0
0
At risk:
A
2618
T
2598
1
2566
2549
2
3
4
Follow-up time (years)
2505
2502
2437
2430
2377
2333
5
2117
2080
6
867
855
Overall survival
(HR-positive population)
Patients 25
(%)
20
15
A
T
HR
95% CI
p-value
HR+
296
301
0.97
(0.83–1.14)
0.7
ITT
411
420
0.97
(0.85–1.12)
0.7
Anastrozole (A)
10
Tamoxifen (T)
5
0
0
At risk:
A
2618
T
2598
1
2
2566
2549
2505
2502
Includes non breast cancer deaths
3
4
Follow-up time (years)
2437
2430
2377
2333
5
6
2117
2080
867
855
Summary of efficacy endpoints
In the HR + population, compared
with tamoxifen, anastrozole lowers
the risk of :
– all events: 17% (p=0.005)
– recurrence: 26% (p=0.0002)
– distant recurrence: 16% (p=0.06)
– contralateral tumours: 53% (p=0.001)
Yearly risk of recurrence in early
breast cancer in untreated patients
10
9
8
7
6
5
4
3
2
1
0
1
5
Years
10
Adapted from EBCTCG meta-analysis. Lancet, 1998; 351:1451
Event rates for recurrence
(HR-positive population)
Annual
hazard
rate
(%)
3.0
 Substantial benefit with anastrozole in the first
3 years
2.5
2.0
1.5
1.0
Anastrozole
Tamoxifen
0.5
0
0
1
2
3
4
Follow-up time (years)
5
6
Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1
Tolerability analysis
Overview of adverse events
Anastrozole (%) Tamoxifen (%)
(n=3092)
(n=3094)
Adverse events leading to
withdrawal*
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
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
*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); pink text
indicates p-value in favour of anastrozole and blue text in favour of tamoxifen
Annual fracture rates over time
Annual
rates, %*
3
2.5
2
1.5
1
Anastrozole 1 mg od
Tamoxifen 20 mg od
0.5
0
0
Number at risk
Years
0
Arimidex
3092
Tamoxifen
3094
1
2
3
4
5
6
5
2070
2100
6
845
846
Years since randomisation
1
2923
2932
*Calculated using Kaplan-Meier estimates
2
2724
2741
3
2553
2579
4
2393
2401
Indirect fracture rate comparison
Clinical
study
Setting
Average age (years)
Annual Fracture rate
(%)
ATAC
(n=6,186)
Early breast cancer (adjuvant)
Anastrozole = 2.26
Tamoxifen = 1.56
PI
(n=13,175)
Breast cancer prevention
WHI
(n=16,608)
Healthy women
Age = 64
Age >50 (61%)
Age = 63
Tamoxifen = 1.80
Placebo = 1.84
HRT = 1.48
Placebo = 1.91
ATAC Trialists’ Group. Lancet 2005; 365: 60–62
Fisher et al. J Natl Cancer Inst 1998; 90: 1371–1388
Women's Health Initiative Writing Group. JAMA 2002; 288: 321–333
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
 Anastrozole is the only AI that has a mature
tolerability profile covering the full 5 year
treatment period
ATAC Conclusions
 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
 Substantial benefits for anastrozole were
seen within the first 3 years
 The efficacy benefit continues to increase
with time and extends beyond the completion
of therapy
These data support using anastrozole
as initial adjuvant therapy