Start or Switch?: Latest data from ABCSG/ARNO

Start or Switch?:Latest data from ABCSG/ARNO

Adjuvant endocrine therapy for early breast cancer

Recent trial data has challenged tamoxifen’s position as the gold standard adjuvant therapy1

The ATAC trial has shown that anastrozole provides a new standard of care for newly-diagnosed postmenopausal women

Anastrozole significantly decreases the risk of recurrence, distant recurrence and contralateral breast cancer and has a significantly better tolerability profile

1ATAC Trialists’ Group Lancet 2005; 365: 60–62

Unanswered questions in adjuvant therapy for early breast cancer

Would postmenopausal patients already receiving tamoxifen benefit from switching to AI therapy?

Are AIs more effective if used as initial treatment or sequential to tamoxifen?

Could premenopausal women with breast cancer also benefit from AI therapy?

Switching trials: evidence from 8,414 postmenopausal women

Italian Tamoxifen Anastrozole (ITA) trial

International Exemestane Study (IES)

ABCSG 8/ARNO 95 combined analysis

ITA: study design

Women were regularly followed until they reached a major trial endpoint that included any of the following:

– disease recurrence

– second primary tumour (including a second breast tumour)

– death (from any cause)

Tamoxifen (n=448)

Anastrozole (n=223)

Tamoxifen (n=225)

2–3 years

Therapy blinded atrandomization to A or T

Surgery± RT

± Chemo

3–2 years

All women were:

– postmenopausal

– hormone receptor positive

– node positive

Boccardo F et al. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6–S7 (abs 3)

ITA: disease-free survival

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5 6

AnastrozoleTamoxifen

No. of pts223225

Obs1745

p-value0.0002

Years

Boccardo F et al. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6–S7 (abs 3)

Proportion disease-free

IES: trial designDiagnosis of breast cancer andtreatment for primary disease

2–3 years’ tamoxifen

RANDOMISEDn=4742

Patients followed-up

2–3 years’exemestane

n=2362

2–3 years’tamoxifen

n=2380

2

3

0

5

Years from startof tamoxifen

0

2-3

Years fromrandomisation

Coombes RC et al. N Engl J Med. 2004; 350: 1081–1092

Coombes RC et al. N Engl J Med. 2004; 350: 1081–1092

IES: disease-free survival

0

Exemestane Tamoxifen

Hazard ratio = 0.68 (95% CI: 0.56–0.82)Log rank test: p-value < 0.001

1 2 3 40

25

50

75

100Proportiondisease-free (%)

52/216878/2173

60/169690/1682

44/75776/730

20+6†/2010/23620/2380

ExemestaneTamoxifen

No. of events/at risk:

18+4†/185

Years from randomisation

†events occurring more than 4 years after randomisation

ABCSG 8/ARNO 95 combined analysis

Aim: to prospectively assess whether switching from tamoxifen to anastrozole after 2 years is more effective than continuing on tamoxifen

Pre-planned combined analysis of ABCSG 8 (Austria) and ARNO 95 (Germany)

Patients: postmenopausal women with hormone receptor-positive EBC

Median 28 months’ follow-up

Primarysurgery+/- RTx

TAM 3 yearsn=1606

Total patientsn=3224

ABCSG 8n=2262

+ARNO 95

n=962

ANA 3 yearsn=1618

ABCSG 8/ARNO 95:Combined analysis trial structure

+ TAM

2 years

T1

Node negative

Breast conservation

G1,2,x

Age < 60 yrs

ER+/PgR+

ER+/PgR-

ER-/PgR+

Patient demographics

Gx = lobular carcinoma

69.7

74.0

77.3

93.7

39.9

81.1

18.3

0.6

70.2

74.2

76.4

95.2

38.6

81.3

18.1

0.6

TAMn=1606

%

ANAn=1618

%

Event-free survival

Zero point = 2 years after surgery

0

75

80

85

90

95

100

0 1 2 3 4 5

Event-free survival (%)

ANA vs TAM p=0.0009 HR 0.60 [95% CI 0.44–0.81]

EFS time in years*

ANA

TAM

At risk:1606 343 176TAM

ANA 161812171243

858874

593623 375 178

EventsLocoregionalContralateral BCDistant recurrences

Localisation of events

Events occuring simultaneously are included twice

Totaln=3224

1774428121

ANAn=1618

67201246

TAMn=1606

110 241675

Distant recurrence-free survival

Zero point = 2 years after surgery

ANADistant recurrence-free survival (%)

TAM

ANA vs TAMp=0.0067 HR 0.60 [95% CI 0.42–0.88]

DRFS time in years

84

88

92

96

100

0 1 2 3 4 5

0

ANA vs TAM

At risk:1606 351 181TAM

ANA 161812241247

869879

600631 382 181

Subgroup analysis of EFS*All patients

Receptor (ER / PR) +ve / +ve

+ve / -ve

Nodal status -ve+ve

Grading G1, G2, GxG3

Age <60 years>60 years

0.25

0.50

0.80

1.00

1.25

1.50

2.00

3.00

Hazard ratio (ANA vs TAM)

n

3224

2389

833

3044

167

1265

1959

2519

564

ANA better TAM better*Events: locoregional, metastatic and contralateral recurrences

Tolerability data from ABCSG 8

Both treatments were well tolerated

The incidence of prespecified side effects was low in both groups

As expected, there were significantly more fractures in patients switching to anastrozole: 27 (2.4%) vs 14 (1.2%) for tamoxifen

No significant difference between treatments was seen in gynaecological side effects because – as seen in ATAC – these generally occur soon after starting tamoxifen

These data confirm results from ITA and IES

Switching from TAM to ANA at 2 years is superior to continuing on TAM in terms of:

– EFS (HR=0.60)

– DRFS (HR=0.61)

– Data are not yet sufficiently mature to show a significant difference in OS

The benefits of switching to ANA are seen regardless of baseline prognostic factors

Both treatments are well tolerated

ABCSG 8/ARNO 95: Summary

Conclusions

ATAC: initial adjuvant therapy with anastrozole is superior to tamoxifen

ABCSG/ARNO: switching to anastrozole after 2 years is superior to remaining on tamoxifen

Which of these treatment strategies is more effective?

Can these benefits of anastrozole in postmenopausal women be translated into the premenopausal setting?

What do we know to date?

Premenopausal women:

– Benefit from adjuvant tamoxifen alone or in combination with goserelin

– Combining an LHRHa and tamoxifen confers better efficacy than LHRHa alone in advanced disease

If a patient is rendered postmenopausal, could she also be eligible from the added benefit of

anastrozole?

Jakesz et al JCO 2002;20:4621-4627Klijn et al. JCO 2001; 343–353

Klijn et al. JNCI 2000; 92: 903–911Bonneterre et al. Cancer 2001; 92: 2247–2258

ATAC Trialists Group. Lancet 2005; 365: 60–62

Forward DP et al. Br J Cancer 2004; 90: 590–594

0

50

100

150

200

250

Baseline Goserelin +Tamoxifen

Goserelin +Anastrozole

Me

an

se

rum

oe

stra

dio

l (p

mo

l/L)

p<0.0001

p<0.0001

• Patients deriving clinical benefit from goserelin plus tamoxifen received goserelin plus anastrozole on progression

Goserelin plus anastrozole in 2nd line ABC

Clinical benefit

Partial response [PR]

Stable disease [SD] 6 months

Biochemical response [BR]*

Clinical benefit (CB; PR + SD 6 months + BR) rate

n (%)

1 (6)

9 (56)

2 (13)

75%

N=16

*no evidence of progression beyond 6 months with decreasing blood tumour markers

Median duration of clinical benefit 17 months (range 6-47)

Forward DP et al. Br J Cancer 2004; 90: 590–594

To date median TTP = ~10 months

Patients (%)Objective response 28

Complete response 6Partial response 22

Stable disease 6 months 44Clinical benefit 72

Goserelin plus anastrozole in 1st line ABC

Carlson R et al. Breast Cancer Res Treat 2004; 88 (Suppl 1):S237–238, abs 6052

Phase II trial of 22 patients whose E2 was decreased to postmenopausal levels with goserelin and then received anastrozole

• 3 years adjuvant endocrine treatment +/- bisphosphonate therapy• premenopausal HR-positive patients

Anastrozole 1 mg/dZoledronic acid 4 mg/d q 6 Mo

Random1 : 1 : 1 : 1

Goserelin3.6 mg q 4W

Accruals Target: 1800 (450/arm)Status: 1372 (Jan. 11, 2005)

Tamoxifen 20 mg/dOP

ABCSG 12: trial structure

Anastrozole 1 mg/d

Tamoxifen 20 mg/dZoledronic acid 4 mg/d q 6 Mo

Conclusions

4 trials have reported data suggesting that postmenopausal women receiving adjuvant tamoxifen should switch to an AI after 2–5 years

Postmenopausal women currently receiving tamoxifen are 40% less likely to relapse if switched to anastrozole after 2 years compared with continuing on tamoxifen

For premenopausal women with hormone-sensitive EBC, the combination of goserelin and anastrozole is a promising treatment and warrants further research