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?

Is anastrozole superior to tamoxifenin the initial adjuvant setting?

Can we improve the tolerability profile of adjuvant tamoxifen?

Can we reduce recurrences, especially in the first few years of treatment?

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

Combinationn=3125

Regular follow-up

Primary trial endpoints:Disease-free survivalSafety / tolerability

Secondary trial endpoints:Incidence of contralateral breast cancerTime to distant recurrenceOverall survival Time to breast cancer death

Combination arm discontinued following initial

analysis as no efficacy or tolerability benefit compared

with tamoxifen arm

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)

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

0 1 2 3 4 5 6

At risk:Follow-up time (years)

0

5

10

15

20

25

Absolute difference: 1.6% 2.6% 2.5% 3.3%

HR=hormone receptor; ITT=intent-to-treat

Events(%)

Anastrozole (A)

Tamoxifen (T)

HR

0.83

0.87

HR+

95% CI

(0.73–0.94)

(0.78–0.97)

p-value

0.005

0.01ITT

Recurrence (HR-positive population)

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

0 1 2 3 4 5 6

Follow-up time (years)At risk:

0

5

10

15

20

25

Absolute difference: 1.7% 2.4% 2.8% 3.7%

Events(%)

Anastrozole (A)

Tamoxifen (T)

HR

0.74

0.79

HR+

95% CI

(0.64–0.87)

(0.70–0.90)

p-value

0.0002

0.0005ITT

Incidence of contralateral breast cancer (HR-positive population)

0

10

20

30

40

50

60

21 Invasive*

54

Tamoxifen(n=2598)

Anastrozole(n=2618)

26

6 DCIS

48 Invasive*

No. ofcases

5 DCIS

*p=0.001 for invasive cancers

HR

0.47

0.58

HR+

95% CI

(0.29–0.75)

(0.38–0.88)

p-value

0.001

0.01ITT

Time to distant recurrence (HR-positive population)

A 2618 2550 2464 2386 2309 2051 845T 2598 2533 2438 2361 2257 2005 816

0 1 2 3 4 5 6

Follow-up time (years)At risk:

0

5

10

15

20

25Patients(%) HR

0.84

0.86

HR+

95% CI

(0.70–1.00)

(0.74–0.99)

p-value

0.06

0.04ITT

Anastrozole (A)

Tamoxifen (T)

Time to breast cancer death (HR-positive population)

Follow-up time (years)

0

5

10

15

20

25

0 1 2 3 4 5 6

Anastrozole (A)

Tamoxifen (T)

HR

0.87

0.88

HR+

95% CI

(0.70–1.09)

(0.74–1.05)

p-value

0.2

0.2ITT

A

152

235

T

172

265

A 2618 2566 2505 2437 2377 2117 867T 2598 2549 2502 2430 2333 2080 855

At risk:

Patients(%)

Overall survival (HR-positive population)

A 2618 2566 2505 2437 2377 2117 867T 2598 2549 2502 2430 2333 2080 855

0 1 2 3 4 5 6

Follow-up time (years)At risk:

0

5

10

15

20

25

Includes non breast cancer deaths

Patients(%) HR

0.97

0.97

HR+

95% CI

(0.83–1.14)

(0.85–1.12)

p-value

0.7

0.7ITT

A

296

411

T

301

420

Anastrozole (A)

Tamoxifen (T)

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

Adapted from EBCTCG meta-analysis. Lancet, 1998; 351:1451

10

9

8

7

6

5

4

3

2

1

0

Years51 10

Event rates for recurrence (HR-positive population)

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

Annualhazardrate(%)

Anastrozole

Tamoxifen 0.5

1.0

1.5

2.0

2.5

3.03.0

0

Substantial benefit with anastrozole in the first 3 years

Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1

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

Anastrozole (%)(n=3092)

11.1

6.5

33.3

4.7

3.3

0.2

*Adverse events on treatment or within 14 days of discontinuation

Pre-defined adverse events

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 eventsJoint symptomsTotal fractures**

*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

YearsArimidexTamoxifen

030923094

129232932

227242741

325532579

423932401

520702100

6845846

Number at risk

0

0.5

1

1.5

2

2.5

3

1 2 3 4 5 6

Years since randomisation

*Calculated using Kaplan-Meier estimates

Annual rates, %*

Anastrozole 1 mg odTamoxifen 20 mg od

0

Indirect fracture rate comparison

HRT = 1.48Placebo = 1.91

Healthy womenAge = 63

WHI(n=16,608)

Tamoxifen = 1.80Placebo = 1.84

Breast cancer preventionAge >50 (61%)

PI(n=13,175)

Anastrozole = 2.26Tamoxifen = 1.56

Early breast cancer (adjuvant)Age = 64

ATAC(n=6,186)

Annual Fracture rate(%)

SettingAverage age (years)

Clinical study

ATAC Trialists’ Group. Lancet 2005; 365: 60–62Fisher 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 anastrozoleas initial adjuvant therapy