‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial:

Completed Treatment Analysis

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

Combinationn=3125

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

Discontinued following initial analysis as no efficacy or

tolerability benefit compared with tamoxifen arm

ATAC trial designATAC trial design

ATAC trial analysis history

First analysis – Dec 2001

Median follow-up : 33 months1

1. The ATAC Trialists’ Group. Lancet 2002; 359: 2131–2139

Updated analysis – November 2002

Median follow-up : 47 months2

2. The ATAC Trialists’ Group. Cancer 2003; 98: 1802 – 1810

Treatment Completion analysis – November 2004

Median follow-up : 68 monthsWomen years’ follow up: 49,941

Total events: 1867

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 survivalCurves shown for HR+ patients

*ITT = Intention-to-treat population; **HR+ = Hormone receptor-positive patients; #A vs T

At risk:A 2618 2540 2448 2355 2268 2014 830T 2598 2516 2398 2304 2189 1932 774

0

5

10

15

20

25

0 1 2 3 4 5 6

Absolute difference: 1.6% 2.6% 2.5% 3.3%

‘Arimidex’ (A)

Tamoxifen (T)

Pat

ient

s (%

)

Follow-up time (years)

HR#

0.83

0.87

HR+*

95% CI

(0.73–0.94)

(0.78-0.97)

p-value

0.005

0.01ITT**

17% RR

At risk:

A 2618 2540 2448 2355 2268 2014 830

T 2598 2516 2398 2304 2189 1932 774

0

5

10

15

20

25

0 1 2 3 4 5 6

Absolute difference: 1.7% 2.4% 2.8% 3.7%

Pat

ient

s (%

)

Time to RecurrenceCurves shown for HR+ patients

HR

0.74

0.79

HR+

95% CI

(0.64–0.87)

(0.79-0.90)

p-value

0.0002

0.0005ITT

Follow-up time (years)

‘Arimidex’ (A)

Tamoxifen (T)

26% RR

Smoothed hazard rates for recurrence (HR+ population)

0 1 2 3 4 5 6Follow-up time (years)

Annualhazardrates(%)

0.5

1.0

1.5

2.0

2.5

3.03.0

0

‘Arimidex’ (A)

Tamoxifen (T)

At risk:

A 2618 2550 2464 2386 2309 2051 845

T 2598 2533 2438 2361 2257 2005 816

0

5

10

15

20

25

0 1 2 3 4 5 6

Pat

ient

s (%

)

HR

0.84

0.87

HR+

95% CI

(0.70–1.00)

(0.74-0.99)

p-value

0.06

0.04ITT

Time to Distant RecurrenceCurves shown for HR+ patients

‘Arimidex’ (A)

Tamoxifen (T)

Overall Survival* Curves shown for HR+ patients

At risk:

A 2618 2566 2505 2437 2377 2117 867

T 2598 2549 2502 2430 2333 2080 855

Follow-up time (years)

0

5

10

15

20

25

0 1 2 3 4 5 6

* Includes non breast cancer deaths

HR

0.97

0.97

HR+

95% CI

(0.83–1.14)

(0.85-1.12)

p-value

0.7

0.7ITT

Pat

ient

s (%

)

‘Arimidex’ (A)

Tamoxifen (T)

Time to Breast Cancer DeathCurves shown for HR+ patients

At risk:

A 2618 2566 2505 2437 2377 2117 867

T 2598 2549 2502 2430 2333 2080 855

Follow-up time (years)

0

5

10

15

20

25

0 1 2 3 4 5 6

HR

0.87

0.88

HR+

95% CI

(0.70–1.09)

(0.74-1.05)

p-value

0.2

0.2ITT

Pat

ient

s (%

)

‘Arimidex’ (A)

Tamoxifen (T)

Incidence of new (contralateral) breast primaries in HR+ population

0

10

20

30

40

50

6054

Tamoxifen (T)(n=2598)

‘Arimidex’ (A)(n=2618)

26

HR 95% CI p-value

A vs T 0.47 (0.29–0.75) 0.001

Number of cases

Hazard Ratio (A:T) and 95% CI

Disease-free survival

Time to recurrence

Time to distant recurrence

Overall survival

Time to breast cancer death

Contralateral breast cancer

0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0

ITT population

HR+ population

*ITT= intent-to-treat *HR+=hormone receptor-positive

Efficacy analysis – ITT and HR+ populations

‘Arimidex’ (A) better Tamoxifen (T) better

*Confidence limit extends beyond plot

Analysis of time to recurrence for subgroups of the ITT* population

Hazard ratio (A:T) and 95% CI

Nodal status +ve

-ve

unknown

All patients

Tumour size ≤ 2 cm

>2 cm

unknown*

Receptor status +ve

-ve

unknown

Previous chemotherapy

yes

no

0.40 1.50 1.750.80 1.00 1.250.60

‘Arimidex’ better 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

Benefit for tamoxifen vs

placebo

50%

28%

47%*

ATAC

Additional benefit of ‘Arimidex’ vs

tamoxifen

26%

13%

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

Adapted from Saphner et al, 1996

 

Need to give most effective treatment first

to reduce risk of recurrence

Tolerability analysis

Overview of 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

0.0002

0.0005

0.03

0.04

0.6

0.5

Tamoxifen (%)(n=3094)

14.3

8.9

36.0

5.9

3.6

0.3

'Arimidex' (%)(n=3092)

11.1

6.5

33.3

4.7

3.3

0.2

*Adverse events on treatment or within 14 days of discontinuation

T40.910.213.20.82.8

4.5

2.4

29.47.7

A35.75.43.50.22.0

2.8

1.6

35.611.0

Completion analysis

p-value

<0.0001<0.0001<0.0001

0.020.03

0.0004

0.02

<0.0001<0.0001

Hot flushesVaginal bleedingVaginal dischargeEndometrial cancer**Ischaemic cerebrovascular eventVenous thromboembolic eventsDeep venous thromboembolic events

Joint symptomsTotal fractures***

*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)

Pre-defined adverse events*

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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