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Fulvestrant (FASLODEX ® ): an emerging story providing an increasing role William Gradishar Robert 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) dimerisation E E AF1 + AF2 active Oestradiol ER PARTIALLY INACTIVATED TRANSCRIPTION (reduced rate of tumour cell division) dimerisation AF1 active AF2 inactive Tamoxifen TT ER AF1 +AF2 inactive F Fulvestrant 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

Pre-treatment (n=29) 4–6 weeks (n=26) 6 months (n=20) PD (n=8) Time on treatment Mean ER H-score p=0.01 p=0.001 Gutteridge et al. Breast Cancer Res Treat 2004; 86, abs 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

Coactivator AF1 Accelerated tumour growth HER2 EGFR TGF  KK ER AKT MAPK AF2 E E Phosphorylation RNA POL II Cross-talk between GFR and ER is involved in the development of endocrine resistance

Coactivator AF1 Accelerated tumour growth HER2 EGFR TGF  KK ER AKT MAPK AF2 E E Phosphorylation X Fulvestrant X RNA POL II Fulvestrant may delay the onset of resistance resulting in a sustained duration of response

Median follow-up 22.1 months Proportion of patients responding Time (months) Fulvestrant 250 mg Anastrozole 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: Fulvestrant Exemestane Proportion of patients responding Fulvestrant Exemestane 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: Fulvestrant Exemestane HR = 0.963, 95% CI (0.819, 1.133), p= Cox analysis, p= Fulvestrant Exemestane Fulvestrant 3.7 Exemestane 3.7Median (months) EFECT: TTP (overall population) Chia et al. J Clin Oncol 2007; submitted

Proportion of patients progression- free 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: Fulvestrant Exemestane 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

Proportion of patients progression-free Responsive Resistant Trials 0020 / 0021: TTP responsive vs resistant At risk: Responsive Resistant Time (months) Time (months) Responsive Resistant FulvestrantAnastrozole

Clinical trials in responsive patients Study confirmed hormone-responsive patients –69% of patients achieved CB –versus ~ 40% of ER+ population in trials 20 / 21 Study hormone-responsive Japanese patients –60% of patients achieved CB Howell et al. Lancet 1995; 345: 29–30 Watanabe 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 on fulvestrant 29.3% No CB on fulvestrant 61.8% CB on fulvestrant 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 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 st -line ABC 0020/ nd -line 186/ /313 CB rate (%) EFECT 3 rd /2 nd -line 87/ nd -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 1 st (n=22) 2 nd (n=125) 3 rd (n=105) 4 th (n=58) 5 th (n=22) 6 th (n=5) Steger et al. Can Treat Rev 2005; 31: S10–S CB 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