These slides are intended to educate the scientific and medical community and keep them fully informed about continuing progress, as is their right, stipulated.

These slides are intended to educate the scientific and medical community and keep them fully informed about continuing progress, as is their right, stipulated by the IFPMA code. However, in some cases, the data may refer to medicines and/or indications which are not

currently approved in your country. Under no circumstances should this information be taken as a recommendation for use of the medicine/indication.

Always consult relevant local prescribing before use.

Fulvestrant (FASLODEX®): an emerging story providing an increasing role

William GradisharRobert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA

Breast Cancer Treatment Strategies:Clinical Decisions and Positive Conversations

E

T

ER

FULLY ACTIVATED TRANSCRIPTION

(increased tumour progression)

dimerisationE E AF1 + AF2

active

Oestradiol

ER

PARTIALLY INACTIVATED

TRANSCRIPTION(reduced rate of

tumour cell division)

dimerisation AF1 activeAF2 inactive

Tamoxifen

T T

ERAF1 +AF2

inactive

FFulvestrant

F F

ACCELERATED RECEPTOR DEGRADATION

attenuated

dimerisation

NO TRANSCRIPTION

(no tumour cell division)

Fulvestrant has a different mode of action

Tamoxifen: post-treatment

Fulvestrant: pre-treatment

Robertson et al. Cancer Res 2001; 61: 6739–6746

Tamoxifen: pre-treatment

Fulvestrant reduces cellular ER levels…

Fulvestrant: post-treatment

250

300

150

200

50

100

0Pre-treatment

(n=29)4–6 weeks

(n=26)6 months

(n=20)PD

(n=8)

Time on treatment

Mean ERH-score

p=0.01

p=0.001

Gutteridge et al. Breast Cancer Res Treat 2004; 86, abs 4086

...and this effect is maintained over time

Could long-term ER downregulation be beneficial to patients?

Breast Cancer Treatment Strategies:Clinical Decisions and Positive Conversations

CoactivatorAF1 AF1

Accelerated tumour growth

HER2EGFR TGF

K K

ER

AKTMAPK

AF2

E EAF2

Phosphorylation

RNAPOL II

Cross-talk between GFR and ER is involved in the development of endocrine resistance

CoactivatorAF1 AF1

Accelerated tumour growth

HER2EGFR TGF

K K

ER

AKTMAPK

AF2

E EAF2

Phosphorylation XFulvestrant

X RNAPOL II

Fulvestrant may delay the onset of resistance resulting in a sustained duration of response

Median follow-up 22.1 months

Proportionof patientsresponding

1.0

0.8

0.6

0.4

0.2

0.00

Time (months)6 12 18 24 30 4236

Fulvestrant 250 mgAnastrozole 1 mg

Robertson et al. Cancer 2003; 98: 229–238

Fulvestrant

16.7

Anastrozole

13.7Median (months)

Trials 0020 / 0021: prospective combined analysis – duration of response

Time (months)At risk:FulvestrantExemestane

Proportion of patients responding

Fulvestrant

Exemestane

0 3 6 9 12 15 18 21 24 27

0.0

0.2

0.4

0.6

0.8

1.0

20 20 16 11 8 3 0 018 18 15 10 5 4 3 3

0 03 3

Fulvestrant

13.5

Exemestane

9.8Median (months)

EFECT (post-AI): duration of response

Predicting which patients may do best on fulvestrant

Breast Cancer Treatment Strategies:Clinical Decisions and Positive Conversations

A new hypothesis (from 1989!)

“It would appear that when considering second-line hormonal therapy the previous effect of

first-line hormone therapy is a more direct and accurate means of identifying patients with hormone-

sensitive tumours than ER status”

Robertson et al. Eur J Cancer Clin Oncol 1989; 25: 469–75

Proportion of patients progression-free

Time (months)At risk:FulvestrantExemestane

HR = 0.963, 95% CI (0.819, 1.133), p=0.6531

Cox analysis, p=0.7021

Fulvestrant

Exemestane

0 3 6 9 12 15 18 21 24 27

0.0

0.2

0.4

0.6

0.8

1.0

351 195 96 50 25 12 4 2342 190 98 41 21 12 8 6

01

00

Fulvestrant

3.7

Exemestane

3.7Median (months)

EFECT: TTP (overall population)

Chia et al. J Clin Oncol 2007; submitted

Proportion of patients progression-free

0 3 6 9 12 15 18 21 24 27

0.0

0.2

0.4

0.6

0.8

1.0

93 54 31 12 7 4 3 1

97 51 23 7 2 0 0 0

Fulvestrant

3.8

Exemestane

3.7Median (months)

HR = 0.73, 99.8% CI *(0.45, 1.19)*CI adjusted for multiple subgroup comparisons

Chia and Gradishar. The Breast 2007; in preparation

EFECT: TTP (subset of 2nd-line and AI-sensitive patients)

At risk:FulvestrantExemestane

Fulvestrant

Exemestane

Time (months)

Potential predictive factors

Prognostic factors from Trials 0020 / 0021

WHO PS <1 (p=0.0004)

Positive receptor status (p<0.0001)

Prior endocrine response (p=0.0272)

AstraZeneca, data on file

Hormone responsive / resistant definition

Hormone responsive

– >2 years on adjuvant endocrine therapy

– CB (CR / PR / SD 24 weeks) on last endocrine treatment

Hormone resistant

– <2 years on adjuvant endocrine therapy

– PD in first-line setting

Pro

po

rtio

n o

f p

atie

nts

pro

gre

ssio

n-f

ree

Responsive

Resistant

Trials 0020 / 0021:TTP responsive vs resistant

268 130 70 42 26 8

160 53 34 24 12 7

1

2

At risk:ResponsiveResistant

0.0

0.2

0.4

0.6

0.8

1.0

Time (months)

0 3 6 9 12 15 18 24 30 36332721

279 108 61 40 23 12 1

144 66 34 20 12 5 0

0.0

0.2

0.4

0.6

0.8

1.0

Time (months)

0 3 6 9 12 15 18 24 30 36332721

Responsive

Resistant

Fulvestrant Anastrozole

Clinical trials in responsive patients

Study 004

19 confirmed hormone-responsive patients

– 69% of patients achieved CB

– versus ~40% of ER+ population in trials 20 / 21

Study 0-15-22

30 hormone-responsive Japanese patients

– 60% of patients achieved CB

Howell et al. Lancet 1995; 345: 29–30Watanabe et al. Anticancer Res 2004; 24: 1275–80

…and from a clinical experience programme

No CB on last therapy (N=99)

CB on last therapy (N=293)

No CB on fulvestrant

70.7%

CB onfulvestrant

29.3%

No CB onfulvestrant

61.8%

CB onfulvestrant

38.2%

Med duration on fulvestrant= 4 months

Med duration on fulvestrant= 5 months

392 Belgian patients receiving fulvestrant

Faslodex HD

720 postmenopausal women with HR+ advanced breast cancer after failure on one prior endocrine therapy

Progression Progression

3 monthly follow-up

Endpoints

TTP

ORR

CB

Safety

Faslodex AD

Randomisation 1:1

HD = fulvestrant 500 mg (IM) on Day 0, 500 mg (IM) on Day 14 and 28, and 500 mg/month (IM) thereafter

AD = fulvestrant 250 mg (IM) once-monthly

COmparisoN of Faslodex In Recurrent or Metastatic breast cancer

Potential predictive factors for long-term disease control with fulvestrant

Prognostic factors from Trials 0020 / 0021

– WHO PS <1 (p=0.0004)

– positive receptor status (p<0.0001)

– prior endocrine response (p=0.0272)

Line of treatment

Fulvestrant: the earlier the better

Fulvestrant as line of endocrine therapy in clinical trials

0251st-line ABC

0020/00212nd-line

186/428

170/313

CB rate (%)

0

80

70

60

50

40

30

20

10

EFECT3rd/2nd-line

87/270

0042nd-line

responsive

13/19

Clinical experience data: CB by line of endocrine therapy for advanced breast cancer

Fulvestrant as line of endocrine therapy in clinical practice

1st (n=22)

2nd (n=125)

3rd

(n=105)4th

(n=58)5th

(n=22)6th

(n=5)

Steger et al. Can Treat Rev 2005; 31: S10–S16

0

10

20

30

40

50CB rate (%)

Summary

Fulvestrant provides an effective and well-tolerated treatment option post-tamoxifen and post-AI for postmenopausal women with advanced breast cancer

Fulvestrant offers a durable response, explained in part by a different mode of action

Careful consideration of prognostic factors such as prior response, and use of fulvestrant earlier in the treatment sequence, may offer a better chance of achieving improved outcomes and lasting disease control