Transcript The ATAC Trial: 100-month median follow

The ATAC Trial:
100-month median follow-up
Professor John F Forbes
University of Newcastle, Australia
on behalf of the ATAC Trialists’ Group
Date of Preparation: December 2007 C14001
ATAC trial design
Anastrozole
(n = 3125)
Postmenopausal
women with
invasive breast
cancer
(n = 9366)
ITT population
n = 3125
Safety population
n = 3092
HR+ subpopulation
n = 2618
Randomised*
Tamoxifen
(n = 3116)
* The combination arm was discontinued following the 33 month analysis as no
efficacy or tolerability benefit was seen compared with the tamoxifen arm
ITT, intent-to-treat; HR+, hormone receptor-positive
ITT population
n = 3116
Safety population
n = 3094
HR+ subpopulation
n = 2598
Background
 Anastrozole is more effective, has less serious
side effects and is better tolerated than
tamoxifen during the active treatment period
 It is not known whether efficacy benefits or side
effects persist after treatment completion
Time to recurrence
HR+ patients
Patients 30
(%)
25
HR
95% CI
30
p-value
HR+ 0.76 (0.67, 0.87) 0.0001
21.8%
20
25
20
Tamoxifen (T)
Anastrozole (A)
15
12.5%
17.0%
10
15
10
9.7%
5
5
4.8%
0
0
0
1
2
3
4
5
6
Follow-up time (years)
7
8
At risk:
A
2618 2541 2453 2361 2278 2159 1995 1801 1492
T
2598 2516 2400 2306 2196 2075 1896 1711 1396
9
608
547
Time to recurrence
HR+ patients
Patients 30
(%)
25
HR
95% CI
30
p-value
HR+ 0.76 (0.67, 0.87) 0.0001
21.8%
20
25
20
Tamoxifen (T)
Anastrozole (A)
15
12.5%
17.0%
10
15
10
9.7%
5
5
Absolute
difference 2.8%
0
0
1
2
3
4
5
6
Follow-up time (years)
4.8%
0
7
8
At risk:
A
2618 2541 2453 2361 2278 2159 1995 1801 1492
T
2598 2516 2400 2306 2196 2075 1896 1711 1396
9
608
547
Time to recurrence:
smoothed hazard estimates
HR+ patients
Annual 4.0
hazard
rates
3.0
(%)
4.0
2.0
2.0
3.0
Tamoxifen (T)
Anastrozole (A)
1.0
1.0
0.0
0.0
0
1
2
3
4
5
6
Follow-up time (years)
7
8
9
TTR: Carryover effect in post-treatment period
 Recurrence rates continued to be lower with anastrozole after
treatment completion
 In the HR+ subgroup, the absolute difference in recurrence
increased from 2.8% after 5 years to 4.8% after 9 years
 Tamoxifen has a known carryover effect in years 5-9, of about
two-thirds the size of that during active treatment1
 There is a statistically significant larger carryover effect for
anastrozole (HR=0.75, 95% CI 0.61-0.94, p=0.01)
1Early
Breast Cancer Trialists’ Collaborative Group. Lancet 2005; 365: 1687-1717
Time to distant recurrence
HR+ patients
Patients 30
(%)
25
30
HR
95% CI
HR+ 0.84 (0.72, 0.97)
p-value
25
0.022
20
20
Tamoxifen (T)
Anastrozole (A)
15
15.6%
15
9.1%
10
13.2%
7.8%
5
5
Absolute
difference 1.3%
0
0
1
2
3
4
5
6
Follow-up time (years)
10
2.4%
7
8
At risk:
A
2618 2551 2470 2393 2320 2201 2042 1854 1536
T
2598 2533 2440 2363 2263 2151 1982 1809 1484
9
636
591
0
Contralateral breast cancer
HR+ patients
Patients
(%)
5
5
HR
95% CI
HR+ 0.60 (0.42, 0.85)
4
3
Tamoxifen (T)
Anastrozole (A)
2
p-value
4.2%
0.004
4
3
2.5%
1.8%
2
1.0%
1
1
AD 0.8%
0
0
1
2
3
4
5
6
Follow-up time (years)
1.7%
7
8
At risk:
A
2618 2541 2453 2361 2278 2159 1995 1801 1493
T
2598 2516 2400 2306 2196 2075 1896 1711 1396
AD, absolute difference
9
608
547
0
Death: all causes
HR+ patients
Patients 30
(%)
25
30
HR
95% CI
HR+ 0.97 (0. 86, 1.11)
p-value
25
0. 70
20
20
Tamoxifen (T)
Anastrozole (A)
15
15
10
10
5
5
0
0
0
1
2
3
4
5
6
Follow-up time (years)
7
8
At risk:
A
2618 2567 2511 2445 2389 2274 2102 1911 1586
T
2598 2549 2504 2432 2339 2227 2068 1888 1551
9
659
620
Competing causes of mortality
Age ≥ 50 years and ER+
Probability 0.4
Breast cancer deaths
Other deaths
0.3
0.2
0.1
0
0
5
10
Time from diagnosis (years)
15
Hanrahan et al. J Clin Oncol 2007; 25: 4952-4960
Serious adverse events: on and off treatment
(Number – safety population)
On treatment
Serious adverse event Anastrozole Tamoxifen
Treatment-related
Off treatment
Anastrozole Tamoxifen
153
284
49
57
Endometrial cancer
4
12
1
12
Myocardial infarction
34
33
26
28
Cerebrovascular accident
20
34
22
20
Fracture episodes*
375
234
146
143
*A fracture episode comprised one or more fractures on the same day based on adverse events and
serious adverse event reports
Fracture episode rates throughout
the study
Annual
fracture
episode
rates (%)
4
Anastrozole (A)
Tamoxifen (T)
3
2
1
0
0
1
At risk:
A
2984
T
2976
2
2859
2824
3
4
5
6
7
Time since randomization (years)
2745
2699
2640
2572
2496
2419
2306
2208
2077
2000
8
9
1713
1645
702
659
Conclusions
 At 100-month median follow-up, data show anastrozole
is significantly superior to tamoxifen at preventing all
forms of recurrence
 The absolute difference in recurrence rates continues to
increase after treatment completion:
 HR+ population: 2.8% at 5 years to 4.8% after 9 years
 HR = 0.75; p=0.01
 Anastrozole is well tolerated long term:
 No excess fracture rate seen after treatment completion
 No new morbidity or mortality increases seen after treatment
completion
Thank you to all the patients for their
participation in the trial and to the ATAC trial
investigators, nurses,
data managers, pharmacists and
other support staff at local sites
Prescribing Information
ARIMIDEX® 1MG FILM-COATED TABLETS (anastrozole)
Consult Summary of Product Characteristics before prescribing.
Use Treatment of advanced breast cancer in postmenopausal women.
Efficacy has not been demonstrated in oestrogen receptor negative
patients unless they had a previous positive clinical response to
tamoxifen. Adjuvant treatment of postmenopausal women with hormone
receptor positive early invasive breast cancer. Adjuvant treatment of
early breast cancer in hormone receptor positive postmenopausal
women who have received 2 to 3 years of adjuvant tamoxifen.
Undesirable events Side effects mainly mild or moderate in nature:
hot flushes, asthenia, joint pain/stiffness, vaginal dryness, hair thinning,
rash, nausea, diarrhoea, headache, hypercholesterolaemia, vomiting,
somnolence. Carpal tunnel syndrome. Anorexia mainly mild in nature.
Elevated alkaline phosphatase, alanine aminotransferase, aspartate
aminotransferase, gamma-GT and bilirubin. Uncommon cases of
hepatitis. Additionally, very rare cases of erythema multiforme,
Stevens-Johnson syndrome and allergic reactions including
angioedema, urticaria and anaphylaxis. Vaginal bleeding has been
reported uncommonly, mainly in advanced breast cancer - evaluate
further if persists. As Arimidex lowers oestrogen, it may reduce bone
mineral density placing some patients at higher risk of fracture.
Presentation Film-coated tablets containing 1mg of anastrozole.
Legal category POM
Dosage and Administration 1mg orally once a day. For early disease,
recommended treatment duration is 5 years.
Contraindications Pre-menopausal, pregnant or lactating women,
patients with severe renal impairment, patients with moderate or severe
hepatic disease and patients with hypersensitivity to anastrozole or any
excipients. Co-administration with oestrogen-containing therapies.
Concurrent tamoxifen therapy.
Precautions Not recommended for use in children. Contains lactose.
Menopause should be defined biochemically where doubt about
hormonal status. Care in driving or operating machinery. No data to
support safety in patients with moderate or severe hepatic impairment or
severe renal function impairment. Assess bone mineral density by bone
densitometry e.g. DEXA scanning at start of treatment and at regular
intervals in women with or at risk of osteoporosis. No data for use with
LHRH analogues. Do not use this combination outside clinical trials. As
'Arimidex' lowers oestrogen it may reduce bone mineral density. Effect
of bisphosphonates on bone mineral density loss caused by anastrozole,
or their utility when used prophylactically, is not currently available.
Marketing Authorisation number 17901/0002
Basic NHS cost 28 tablets: £68.56
Further information is available from the Marketing Authorisation Holder
AstraZeneca UK Limited, 600 Capability Green, Luton, LU1 3LU, UK
ARIMIDEX is a trade mark of the AstraZeneca group of companies. AZ
07/2007
Adverse events should be reported to AstraZeneca UK Medical
Information
(Tel: 0800 783 0033).
In addition, information about adverse event reporting can be found at
www.yellowcard.gov.uk .