1
Arimidex, Tamoxifen, Alone or in Combination
(ATAC) trial Completed Treatment Analysis
2
Introduction
3
Which problems does ATAC address?

• Is tamoxifen still the best adjuvant therapy for
  early breast cancer (EBC)?

• How do we reduce recurrences in the firstfew
  years of treatment?

• Can we improve upon the tolerability problems
  associated with adjuvant tamoxifen?

• Is anastrozole superior to tamoxifenin the
  adjuvant setting?

4
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?

5
Trial design patient recruitment
6
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
â

â
Randomisation 111 for 5 years
å
æ
â
Discontinued following initial analysis as no
efficacy or tolerability benefit compared with
tamoxifen arm
â
Regular follow-up
â

• Secondary trial endpoints
• Incidence of contralateral breast cancer
• Time to distant recurrence
• Overall survival
• Time to breast cancer death

• Primary trial endpoints
• Disease-free survival
• Safety / tolerability

7
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 riskbenefit profile of anastrozole can
  be considered final

8
Efficacy analysis
9
Smoothed hazard rates for recurrence
(HR-positive population)
Annualhazardrates()
Anastrozole
Tamoxifen
0
1
2
3
4
5
6
Follow-up time (years)
HRhormone receptor
10
Disease-free survival (HR-positive population)
1.6
2.6
2.5
3.3
Absolute difference
0
1
2
3
4
5
6
Follow-up time (years)
At risk
A
2618
2540
2448
2355
2268
2014
830
T
2598
2516
2398
2304
2189
1932
774
HRhormone receptor
11
Recurrence (HR-positive population)
1.7
2.4
2.8
3.7
Absolute difference
0
1
2
3
4
5
6
Follow-up time (years)
At risk
A
2618
2540
2448
2355
2268
2014
830
T
2598
2516
2398
2304
2189
1932
774
HRhormone receptor
12
Analysis of time to recurrence for subgroups of
the HR-positive population
Nodal status
ve -ve unknown
Tumour size
?2 cm 25 cm gt5 cm
Previouschemotherapy
Yes No
All patients
HRhormone receptor
Hazard ratio (AT) and 95 CI
0.80
0.60
0.40
1.00
1.25
1.50
1.75
Anastrozole better
Tamoxifen better
Confidence limit extends beyond plot
13
Time to distant recurrence (HR-positive
population)
0
1
2
3
4
5
6
Follow-up time (years)
At risk
A
2618
2549
2463
2385
2308
2051
845
T
2598
2533
2437
2359
2255
2005
816
HRhormone receptor
14
Overall survival (HR-positive population)
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
HRhormone receptor
15
Incidence of new (contralateral) breast primaries
in HR-population
HR 95 CI p-value
AN vs TAM 0.47 0.290.75 0.001
Number of cases
53
5 DCIS
26
48 Invasive
5 DCIS
21 Invasive
Tamoxifen (TAM) (n3116)
Anastrozole (AN) (n3125)
p0.001 for invasive cancers.
HRhormone receptor
16
Most recurrences occur within the first 5 years
of primary therapy
Recurrence rate/year()
Need to give most effective treatment firstto
reduce risk of recurrence
Year
Saphner et al JCO 1996 14 2738-2746
17
Disease-free survival (HR-positive population)
1.6
2.6
2.5
3.3
Absolute difference
0
1
2
3
4
5
6
Follow-up time (years)
At risk
A
2618
2540
2448
2355
2268
2014
830
T
2598
2516
2398
2304
2189
1932
774
HRhormone receptor
18
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

19
Added benefit versus tamoxifen
ATACAdditional benefit of anastrozole vs
tamoxifen 26 13 52
EBCTCGBenefit for tamoxifen vs placebo
50 28 47
  Hormone receptor-positive population
Reduction in risk of recurrence Reduction in
risk of breast cancer mortality Reduction in risk
of contralateral breast cancer

hormone receptor-positive and -negative
patientsEBCTCG Early Breast Cancer Trialists
Collaborative Group
20
Added benefit versus tamoxifen
38 risk of recurrence with no adjuvant treatment
50 reduction in risk with tamoxifen
Further 26 risk reduction with anastrozole
21
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

22
Tolerability analysis
23
Overview of adverse events
All adverse events Adverse events leading to
withdrawal Drug-related adverse events leading
to withdrawal All serious adverse events Serious
adverse events leading to withdrawal Serious
adverse events leading to death Drug-related
serious adverse events leading to death
p-value 0.2 0.0002 0.0005 0.03 0.04 0.6 0.5
Tamoxifen ()(n3094) 94.6 14.3 8.9 36.0
5.9 3.6 0.3
Anastrozole ()(n3092) 93.9 11.1 6.5 33.3
4.7 3.3 0.2
Adverse events on treatment or within 14 days of
discontinuation
24
Pre-defined adverse events
Hot flushes Vaginal bleeding Vaginal
discharge Endometrial cancer Ischaemic
cerebrovascular event Venous thromboembolic
events Deep venous thromboembolic events Joint
symptoms Total fractures
Excludes patients with prior hysterectomy and
includes on- and off-therapy AEs
25
Pre-defined adverse events
0.2
0.4
0.6
0.8
1.0
2.0
1.5
In favour of anastrozole
In favour of tamoxifen
Relative risk (anastrozole / tamoxifen)
26
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

27
Summary
28
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 riskbenefit 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

29
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
30
Back-up slides
31
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

32
Definition of endpoints (2)

• Overall survival (OS)
• death (for any reason)
• Time to distant recurrence (TTDR)
• distant recurrence or any death following a
  loco-regional 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

33
ATAC patient characteristics
Tamoxifen (n3116)
Anastrozole (n3125)
Mean age (years) Mean weight (kg) Receptor status
() positive negative unknown Primary
treatment () mastectomy axillary
surgery radiotherapy chemotherapy prior
tamoxifen
64.1 70.8 83.7 8.3 8.0 47.8 95.5 63.3 22.3 1.6
64.1 71.1 83.4 8.7 7.9 47.3 95.7 62.5 20.8 1.6
34
ATAC baseline disease characteristics
Tamoxifen (n3116)
Anastrozole (n3125)
Primary tumour size () T1 (?2 cm) T2 (?2 cm to
?5 cm) T3 (?5 cm) Nodal status
() node-positive Grading () well
differentiated moderately differentiated poorly
/ undifferentiated not assessed / recorded
63.9 32.6 2.7 34.9 20.8 46.8 23.7 8.5
62.9 34.2 2.2 33.6 20.5 47.8 23.3 8.3
35
ATAC trial analysis history
1.The ATAC Trialists Group. Lancet 2002 359
21312139 2.The ATAC Trialists Group. Cancer
2003 98 1802 1810
36
Smoothed hazard rates for recurrence (ITT
population)
3.0
Annualhazardrates()
2.5
2.0
1.5
1.0
0.5
0
0
1
2
3
4
5
6
Follow-up time (years)
ITTintent-to-treat
37
Disease-free survival (ITT population)
25
20
15
Patients ()
10
5
1.5
2.0
2.4
2.9
Absolute difference
0
0
1
2
3
4
5
6
Follow-up time (years)
At risk
A
3125
3004
2874
2757
2645
2350
984
T
3116
2992
2835
2709
2575
2273
933
Includes non breast cancer deathsITTintent-to-t
reat
38
Recurrence (ITT population)
25
20
15
Patients ()
10
5
1.6
2.1
2.8
3.4
Absolute difference
0
0
1
2
3
4
5
6
Follow-up time (years)
At risk
A
3125
3004
2874
2757
2645
2350
984
T
3116
2992
2835
2709
2575
2273
933
ITTintent-to-treat
39
Analysis of time to recurrence for subgroups of
the ITT population
All patients
0.40
1.50
1.75
0.80
1.00
1.25
ITTintent-to-treat
Hazard ratio (AT) and 95 CI
Confidence limit extends beyond plot
40
Time to distant recurrence (ITT population)
25
20
15
Patients ()
10
5
0
0
1
2
3
4
5
6
Follow-up time (years)
At risk
A
3125
3022
2899
2802
2703
2406
1009
T
3116
3020
2890
2783
2656
2364
985
ITTintent-to-treat
41
Overall survival (ITT population)
25
20
15
Patients ()
10
5
0
0
1
2
3
4
5
6
Follow-up time (years)
At risk
A
3125
2956
2865
2784
2479
1037
3051
T
3116
2972
2872
2747
2461
1037
3048
Includes non breast cancer deathsITTintent-to-t
reat
42
Time to breast cancer death (ITT population)
25
20
15
Patients ()
10
5
0
0
1
2
3
4
5
6
Follow-up time (years)
At risk
A
3125
3051
2956
2865
2784
2479
1037
T
3116
3048
2972
2872
2747
2461
1037
ITTintent-to-treat
43
Incidence of new (contralateral) breast primaries
in ITT population
HR 95 CI p-value
AN vs TAM 0.58 0.380.88 0.01
58
Number of cases
6 DCIS
35
8 DCIS
52 Invasive
27 Invasive
Tamoxifen (TAM) (n3116)
Anastrozole (AN) (n3125)
p0.004 for invasive cancers.
ITTintent-to-treat
44
Summary of efficacy endpoints

• In the overall ITT population, compared with
  tamoxifen, anastrozole provides significantly
  reduced risk of
• all events 13 (p0.013)
• recurrence 21 (p0.0005)
• distant recurrence 14 (p0.043)
• contralateral recurrence 42 (p0.01)