Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial: Completed Treatment Analysis

Introduction

ATAC diseo del estudio

9366Mujeres posmenopusicas, con CA de mama invasivo, con edad media de 64 aos; 84% receptors hormonales positivos, 61% GG negativos; 64% con tumor 2 cm de dimetro

Ciruga RT QT

Aleatorizadas 1:1:1 por 5 aos

Anastrozol n=3125

Tamoxifeno n=3116

Descontinuada en el anlisis posterior, ya queCombinacin no hubo evidencia de de eficacio o beneficio comparado con el brazo de n=3125 tamoxifeno

Seguimiento regular

Puntos primaries de desenlace: SLE Tolerabilidad y Seguridad Otros puntos de desenlace secundarios: Incidencia de ca de mama contralateral Tiempo para la recaida a distancia SG Tiempo para muerte por ca de mama

ATAC completed treatment analysis

Seguimiento:
El studio termin en marzo 31 del 2004, basado en que hubieron 704 muertes en el brazo de monoterapias combinadas.
El seguimiento promedio fue de 68 meses despus de que se complete el tto. 59 meses de duracin media del tto Slo el 8% no completaron el tto

Results:
Anastrozol demostr superior eficacia que el tamoxifen
Anastrozol demonstr superior tolerancia que tamoxifen

Efficacy analysis

HR para recada (RH*-positive population)

3.0

hazard rate anual (%)

2.5 2.0 1.5 1.0 0.5 0 0 1 2 3 4 Seguimiento en aos) 5 6 Anastrozol Tamoxifeno

*RH=Receptores hormonales

Supervivencia libre de enfermedad (poblacin con RH +)

25 20 Pacientes (%) 15 10 5 0 0
At risk: A 2618 T 2598
Diferencia absoluta: 1.6%

HR A vs T 0.83

95% CI (0.730.94)

p-value 0.005

Anastrozol (A) Tamoxifeno (T)

2.6%

2.5%

3.3%

1
2540 2516

3 4 Seguimiento en aos
2355 2304 2268 2189

5
2014 1932

6
830 774

2448 2398

*RH=Receptores hormonales

Recada (poblacin con RH*-positivos)

25 20 Pacientes (%) 15 10 5 0 0
At risk: A 2618 T 2598
Dierencia Absoluta: 1.7%

HR A vs T 0.74

95% CI (0.640.87)

p-value 0.0002

Anastrozol (A) Tamoxifeno (T)

2.4%

2.8%

3.7%

1
2540 2516

3 4 Aos de seguimiento
2355 2304 2268 2189

5
2014 1932

6
830 774

2448 2398

*RH=Receptores hormonales

Anlisis del tiempo para la recada por subgrupos con RH*-positivos

Estado ganglionar +ve -ve Desconocido**

Tamao tumor

2 cm
25 cm >5 cm*

Previa QT

Si No

All patients Hazard ratio (A:T) and 95% CI 0.40 0.60 0.80 *RH=Receptores hormonales Anastrozol mejor **El intervalo de confianza se extiende ms 1.00 1.25 1.50 1.75

Tamoxifeno mejor

Tiempo para la recada (Poblacin con RH positivos)

25 20 Pacientes (%) 15 10 5 0 0
At risk: A 2618 T 2598

HR A vs T 0.84

95% CI (0.701.00)

p-value 0.06

Anastrozol (A) Tamoxifeno (T)

1
2549 2533

3 4 Seguimiento en aos
2385 2359 2308 2255

5
2051 2005

6
845 816

2463 2437

*RH=Receptores hormonales

Supervivencia Global (Poblacin con RH positivos)

25 20 Pacientes (%) 15 10 5 0 0
At risk: A 2618 T 2598

HR A vs T 0.97

95% CI (0.831.14)

p-value 0.7

Anastrozol (A) Tamoxifeno (T)

1
2566 2549

3 4 Seguimiento en aos
2437 2430 2377 2333

5
2117 2080

6
867 855

2505 2502

*RH=Receptores hormonales

Incidencia de Ca de mama contralateral en la poblacin con RH positivos

HR AN vs TAM 0.47 95% CI 0.290.75 p-value 0.001

Num de 60 casos 50
40 30 20 10 0

53 5 DCIS

26 5 DCIS 21 Invasivo* Anastrozol (AN) (n=3125)

48 Invasivo*

Tamoxifeno (TAM) (n=3116)

*p=0.001 para cancer invasivo.

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

Added benefit versus tamoxifen

EBCTCG Hormone receptor-positive population Reduction in risk of recurrence Reduction in risk of breast cancer mortality Reduction in risk of contralateral breast cancer Benefit for tamoxifen vs placebo ATAC Additional benefit of anastrozole vs tamoxifen 26% 13% 52%

50%
28% 47%*

*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% reduction in risk with tamoxifen

Further 26% risk reduction with anastrozole

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

Tolerability analysis

Overview of adverse events*

Anastrozole (%) Tamoxifen (%) (n=3092) (n=3094) All adverse events Adverse events leading to withdrawal 93.9 11.1 94.6 14.3 p-value 0.2 0.0002

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

6.5
33.3 4.7 3.3 0.2

8.9
36.0 5.9 3.6 0.3

0.0005
0.03 0.04 0.6 0.5

*Adverse events on treatment or within 14 days of discontinuation

Pre-defined adverse events

Completion analysis A T 40.9 10.2 13.2 0.8 2.8 4.5 <0.0001 <0.0001 <0.0001 0.01 p-value

Hot flushes
Vaginal bleeding Vaginal discharge Endometrial cancer* Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events Joint symptoms Total fractures

35.7 5.4 3.5 0.2 2.0 2.8

0.03
0.0004 0.02 <0.0001 <0.0001

1.6
35.6 11.0

2.4
29.4 7.7

*Excludes patients with prior hysterectomy and includes on- and off-therapy AEs

Pre-defined adverse events

Venous thromboembolic events Ischaemic cerebrovascular events Endometrial cancer Vaginal bleeding

Vaginal discharge
Hot flushes Joint symptoms Fractures
0.2 0.4 0.6 0.8 1.0 1.5 2.0

In favour of anastrozole

In favour of tamoxifen

Relative risk (anastrozole / tamoxifen)

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

Summary

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 risk:benefit 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

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

Back-up slides

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

Definition of endpoints (2)

Overall survival (OS)
death (for any reason)

Time to distant recurrence (TTDR)

distant recurrence or any death following a locoregional 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

ATAC: patient characteristics

Anastrozole (n=3125) 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 Tamoxifen (n=3116) 64.1 71.1 83.4 8.7 7.9 47.3 95.7 62.5 20.8 1.6

ATAC: baseline disease characteristics

Anastrozole (n=3125) Primary tumour size (%) T1 (2 cm) T2 (2 cm to 5 cm) T3 (5 cm) Nodal status (%) 63.9 32.6 2.7 62.9 34.2 2.2 Tamoxifen (n=3116)

node-positive
Grading (%) well differentiated moderately differentiated poorly / undifferentiated not assessed / recorded

34.9
20.8 46.8 23.7 8.5

33.6
20.5 47.8 23.3 8.3

ATAC trial analysis history

First analysis June 2002 Median follow-up : 33 months1

Updated analysis November 2003 Median follow-up : 47 months2

Completion analysis November 2004 Median follow-up : 68 months Women years follow up: 49,941 Total events: 1867
1.The ATAC Trialists Group. Lancet 2002; 359: 21312139 2.The ATAC Trialists Group. Cancer 2003; 98: 1802 1810

Smoothed hazard rates for recurrence (ITT* population)

Annual hazard rates (%)
3.0 2.5 2.0 1.5 1.0 0.5 0 0
*ITT=intent-to-treat

Anastrozole Tamoxifen

2 3 4 Follow-up time (years)

Disease-free survival (ITT* population)

25 20 A vs T HR 0.87 95% CI (0.780.97) p-value 0.013

Patients (%)

15 10 5 0 0

Anastrozole (A) Tamoxifen (T)

Absolute difference: 1.5%

2.0%

2.4%

2.9%

1
3004 2992

At risk: A 3125 T 3116

3 4 Follow-up time (years)

2757 2709 2645 2575

5
2350 2273

6
984 933

2874 2835

Includes non breast cancer deaths *ITT=intent-to-treat

Recurrence (ITT* population)

25 20 A vs T HR 0.79 95% CI (0.700.90) p-value 0.0005

Patients (%)

15 10 5 0 0

Anastrozole (A) Tamoxifen (T)

Absolute difference: 1.6%

2.1%

2.8%

3.4%

1
3004 2992

At risk: A 3125 T 3116 *ITT=intent-to-treat

3 4 Follow-up time (years)

2757 2709 2645 2575

5
2350 2273

6
984 933

2874 2835

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

Nodal status +ve -ve unknown Tumour size 2 cm >2 cm unknown** Receptor status +ve -ve unknown

Previous chemotherapy
All patients

yes
no

0.40 Hazard ratio (A:T) and 95% CI *ITT=intent-to-treat **Confidence limit extends beyond plot

0.60

0.80

1.00

1.25 1.50 1.75

Anastrozole better

Tamoxifen better

Time to distant recurrence (ITT* population)

25 20 A vs T HR 0.86 95% CI (0.740.99) p-value 0.043

Patients (%)

15 10 5 0 0

Anastrozole (A) Tamoxifen (T)

1
3022 3020

At risk: A 3125 T 3116 *ITT=intent-to-treat

3 4 Follow-up time (years)

2802 2783 2703 2656

5
2406 2364

6
1009 985

2899 2890

Overall survival (ITT* population)

25 20 A vs T HR 0.97 95% CI (0.851.12) p-value 0.7

Patients (%)

15 10 5 0 0

Anastrozole (A) Tamoxifen (T)

At risk: A 3125 2956 3051 T 3116 2972 3048 Includes non breast cancer deaths *ITT=intent-to-treat

3 4 Follow-up time (years)

2865 2872 2784 2747

5
2479 2461

6
1037 1037

Time to breast cancer death (ITT* population)

25 20 A vs T HR 0.88 95% CI (0.741.05) p-value 0.2

Patients (%)

15 10 5 0 0

Anastrozole (A) Tamoxifen (T)

1
3051 3048

At risk: A 3125 T 3116 *ITT=intent-to-treat

3 4 Follow-up time (years)

2865 2872 2784 2747

5
2479 2461

6
1037 1037

2956 2972

Incidence of new (contralateral) breast primaries in ITT* population

HR AN vs TAM 0.58 95% CI 0.380.88 p-value 0.01

Number 60 of cases 50
40 30 20 10 0

58 6 DCIS

35 8 DCIS 52 Invasive* 27 Invasive* Anastrozole (AN) (n=3125) Tamoxifen (TAM) (n=3116)

*p=0.004 for invasive cancers.

*ITT=intent-to-treat

Summary of efficacy endpoints

In the overall ITT population, compared with tamoxifen, anastrozole provides significantly reduced risk of :
all events: 13% (p=0.013) recurrence: 21% (p=0.0005)

distant recurrence: 14% (p=0.043)

contralateral recurrence: 42% (p=0.01)