1. De beste aromataseremmer? Natuurlijk exemestaan! J.W.R.Nortier 4e jaarlijks mammacarcinoom symposium 29 juni 2005

2. AROMATASE INHIBITION androstenedione testosterone estrone estradiol NADPH NADP catalytic site "steroidal inhibitor" "non-steroidal inhibitor"

3. Molecule structure aromatase inhibitors steroidal / aromatase- inactivator non-steroidal / aromatase- inhibitors androsteendion exemestane anastrozol letrozol

6. Lecture Outline Sequential studies Sequential vs upfront studies Safety

7. Postmenopausal HR+ breast cancer: Studies of adjuvant aromatase inhibition HR+: hormone receptor-positive Primary randomisation trials Switching trialsExtension trials ATACITAMA-17 BIG 1-98 (FEMTA)ABCSG/ARNO IES

8. ITA: Design RANDOMISERANDOMISE A: anastrazole; DFS: disease-free survival; HR: hazard ratio; T: tamoxifen T (2–3 years) A (2–3 years) n=440 DFS: HR 0.40, p=0.0002 in favour of anastrozole Serious adverse events more common in women continued on tamoxifen (29 vs 14) Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003.

9. No. and distribution of events TAM n=45ANA n=17 Local-regional (includes ipsilateral breast recurrences, relapses in local- regional nodes) 13 2 Distant metastases (with or without local-regional recurrences) 1910 Second primaries contra lateral breast endometrium other 10 2 5 3 5 1 3 Deaths Breast cancer related Deaths without relapse 7 3 4-4- Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003.

10. Event-free survival ANA Years % Surviving N° pts. Obs p= TAM 225 45 ANA 223 17 0.0002 TAM Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003.

11. Postmenopausal HR+ breast cancer: Studies of adjuvant aromatase inhibition HR+: hormone receptor-positive Primary randomisation trials Switching trialsExtension trials ATACITAMA-17 BIG 1-98 (FEMTA)ABCSG/ARNO IES

12. ABCSG/ARNO: Design RANDOMISERANDOMISE T (2 years) T (3 years) (n=1,606) A (3 years) (n=3,224) Median follow-up 28 m No preceding CT Tumour size <2 cm: 70%; grade 1/2: 95% LN–: 75% HR+: 100%; ER+/PgR+: 81%; ER–/PgR+: 0.6%; ER+ /PR–: 18.3% n=3,224 (T=1,606 and A=1,618) A: anastrazole; DFS: disease-free survival; HR: hazard ratio; T: tamoxifen Jakesz R. et al. San Antonio Breast Cancer Symposium 2004.

13. Event-free survival *Zero point = 2 years after surgery 0 75 80 85 90 95 100 012345 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: 1606343176 TAM ANA 1618 1217 1243 858 874 593 623 375 178 Jakesz R. et al. San Antonio Breast Cancer Symposium 2004.

14. Total TAM ANA n=3,224n=1,606 n=1,618 Events 177 110 67 Locoregional 44 24 20 Contralateral BC 28 16 12 Distant recurrences 121 75 46 Localization of events events occuring simultaneously are included twice Jakesz R. et al. San Antonio Breast Cancer Symposium, December 2004.

15. ABCSG/ARNO: Summary Efficacy results favour switch to anastrozole EFS: HR 0.60 (95% CI: 0.44, 0.81); p=0.0009 with: 20% fewer locoregional recurrences 20% less contralateral breast cancer Distant RFS: HR 0.61 Regardless of nodal stage or age Switch especially beneficial in ER+/PgR–  Serious adverse events more common in women continued on tamoxifen (29 vs 14) CI: confidence interval; EFS: event-free survival; RFS: recurrence-free survival Jakesz R. et al. San Antonio Breast Cancer Symposium, December 2004.

16. Postmenopausal HR+ breast cancer: Studies of adjuvant aromatase inhibition HR+: hormone receptor-positive Primary randomisation trials Switching trialsExtension trials ATACITAMA-17 BIG 1-98 (FEMTA)ABCSG/ARNO IES

17. Diagnosis and initial treatment of early breast cancer Tamoxifen therapy for 2-3 years IES: Design RANDOMISATIONRANDOMISATION * Intent to treat population Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092. Tamoxifen 2-3 y 20 mg po qd (n=2,372)* Exemestane 2-3 y 25 mg po qd (n=2,352)* 5 Years Total Hormone Treatment

18. IES: demographics Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.

19. IES: DFS Years from randomisation DFS (%) 01234 0 25 50 75 100 Hazard ratio: 0.73 (95% CI: 0.62, 0.86) Log-rank test: p=0.0001 Exemestane (262 events) Tamoxifen (353 events) No. events/at risk Exemestane 0 / 2,35257 / 2,23365 / 2,08175 / 1,41341+24† / 661 Tamoxifen 0 / 2,37282 / 2,243105 / 2,06296 / 1,35947+23† / 650 † Events occurring more than 4 years after randomisation Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.

20. IES: Subgroup analysis Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.

21. IES: Overall survival Years from randomisation ‘women alive’ (%) 01234 0 25 50 75 100 Hazard ratio: 0.83 (95% CI: 0.67, 1.02) Log-rank test: p=0.08 Exemestane (152 deaths) Tamoxifen (187 deaths) No. events/at risk Exemestane0 / 2,35218 / 2,27041 / 2,13741 / 1,46937+15† / 690 Tamoxifen0 / 2,37223 / 2,30053 / 2,16549 / 1,46541+21† / 701 † Events occurring more than 4 years after randomisation Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.

22. ExemestaneTamoxifenTotal Total number of deaths152187339 Breast cancer deaths Inc. other COD in patients with recurrence/CLB 95 11 124 12 219 23 Intercurrent (without recurrence/CLB) Vascular Cardiac Other cancer Other Unknown 57 15 13 11 5 63 7 12 22 14 8 120 22 25 35 25 13 IES: Causes of death CLB: contralateral breast cancer; COD: cause of death. Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.

23. IES: Safety profile – CV events and MI p-values not statistically significant; Coombes et al. San Antonio Breast Cancer Symposium 2004. Exemestane n (%) Tamoxifen n (%) Cardiovascular medical history775 (32.9)729 (30.7) All myocardial infarction20 (0.9)8 (0.4) Myocardial infarction on treatment14 (0.7)7 (0.3) Cardiac deaths on study13 (0.5)12 (0.6)

24. IES: Comparison of adverse events Difference between statistically significant adverse events (%) In favour of exemestane In favour of tamoxifen Thromboembolic disease Cramps Diarrhoea Arthralgia Gynaecologic symptoms Pain in limb Presentation of events where the difference between treatment groups (in either incident case analysis or treatment emergent analysis) p<0.01; Coombes et al. San Antonio Breast Cancer Symposium;2004. -3.5 6.7 -1.4 2.5 2.3 -2.1 -6-4-202468

25. IES: Efficacy conclusions Switching to exemestane reduces the risk of: Distant metastases by 34% (p=0.0001) Contralateral breast cancer by 50% (p=0.04) Switching to exemestane reduces the chances of dying (p=0.08) but, although more convincing than the March 2004 analysis (p=0.41), is not yet significant at the 0.05 level Coombes et al. San Antonio Breast Cancer Symposium;2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.

26. IES: Safety conclusions No excess of intercurrent deaths Endocrine effects similar to tamoxifen Musculoskeletal side effects more common in exemestane arm No significant difference in the incidence of fractures: Exemestane 3.1%, tamoxifen 2.3% p=0.08 Cardiovascular – more data are required but serious events are very rare Exemestane associated with a reduction in gynaecological and thromboembolic side effects Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.

27. Summary SWITCH studies AIs vs tamoxifen StudyAI Number of patients Design Number of countries Patient population IES-031Exemestane4712 Double-blind, randomised 37 N: +, - CT: +, - ITAAnastrozole426randomised1 N: + only CT: +, - ARNO/ ABCSG Anastrozole3224Retrospective, pooled analysis 2N: +, - (neg: 74%) CT: not allowed

28. Switch vs. Upfront - level A2 evidence studies IES: ATAC: BIG 1-98: 2-3 yr tamoxifen3-2 yr exemestane 5 yr tamoxifen 5 yr anastrozole 5 yr tamoxifen & anastrozole 5 yr tamoxifen 5 yr letrozole 2 yr letrozole3 yr tamoxifen 3 yr letrozole2 yr tamoxifen

29. Disease Free Survival (DFS) Parameter UPFRONTSWITCH BIG 1-98 (F vs.T) ATAC* (A vs. T) IES (E vs. T) DFS – relative risk reduction HR 0.81 (P=0.003)HR 0.83 (P=0.005) HR 0.73 (p=0.0001) DFS – absolute risk reduction 2.6%3.3% 30,6 months: 4,7%** 37,4 months: NA Distant Recurrences HR 0.73 (P=0.006) HR 0.84 (P=0.06) E: N= 150 T: N= 208 *** Contralateral BC0.4% vs 0.7% (p=0.125) HR 0.47 (P=0.001) HR 0.50 (p=0.04) ATAC: mediane FU: 68 months; only HR+ population ** FU: 37.4 months (NEJM) *** HR not reported

30. Retrospective analysis of time to recurrence for ER/PgR subgroups (Howell T et al, ATAC, SABCS 2004) At risk: A451435417400390347124 T42941237535332727696 Follow-up time (years) 25 0 5 10 15 20 0123456 Anastrozole (A) Tamoxifen (T) Patients (%) Patient group HR+ ER+PgR+ ER+PgR- Hazard ratio 0.79 0.84 0.43 ER+/PgR-

31. Smoothed hazard rates for recurrence HR+ patients 0.5 1.0 1.5 2.0 2.5 3.0 0123456 Follow-up time (years) Anastrozole Tamoxifen 0 Annual hazard rates (%) Which patients are these? HER2neu+++? Should have been treated with CT? ER+PgR-? Howell T. et al., ATAC trial, San Antonio Breast Cancer Symposium 2004.

32. Overall Survival UPFRONTSWITCH BIG I-98 (F vs.T) ATAC (A vs. T) IES (E vs. T) Mediane FU: 26 months Mediane FU: 68 months Mediane FU*: 37,4 months HR 0.86 (NS; p=?) HR 0.97 (p=0.7) HR 0.83 (p=0.08) * after randomisation after Tam

33. IES: Model effect addition AI after 3 years Tam in PR+ % recurrence -free 02468101214 1,0 0,9 0,8 0,7 Presentation of K. Osborne, St. Gallen Conference January 2005 jaar tamoxifen AI

34. Safety

35. Upfront and Switch - Summary of fracture risk

36.  Objective: To compare the effects of a steroidal or a nonsteroidal aromatase inhibitor on serum biomarkers of bone resorption and bone formation  Study subjects were randomized at two investigative sites in Germany to one of four single-blind treatment groups (target enrollment = 80)  Treated for 24 weeks  Re-assessed at 36 weeks Primary Endpoint:  Percent change from baseline in bone turnover markers at assessment week Secondary Endpoints:  Baseline-adjusted area under the curve (AUC) for 0-12 weeks and 0-24 weeks of treatment calculated for all bone turnover markers,  Percent change from baseline in bone turnover makers at assessment weeks 12 and 36,  Percent change from baseline in lipid profiles at assessment weeks 12, 24 and 36,  Percent of baseline estrogen concentrations at assessment weeks 12, 24 and 36 and safety Healthy Postmenopausal Volunteers Anastrozole 1 mg po qd Exemestane 25 mg po qd Letrozole 2.5 mg po qd Placebo po qd Subar M. et al. Oral presentation ASCO 2004, abstract # 8038

37. -10.00 0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 AnastrozoleExemestaneLetrozolePlacebo Treatment *p = 0.182 *Difference across active treatment groups Bone Resorption Marker: % Change Week 24 from Baseline serum CTX-I Median with 95% CI Subar M. et al. Oral presentation ASCO 2004, abstract # 8038

38. Bone Formation Marker: %Change Week 24 from Baseline Serum PINP Median with 95% CI -10.00 -5.00 0.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 AnastrozoleExemestaneLetrozolePlacebo Treatment *p = 0.093 *Difference across active treatment groups Subar M. et al. Oral presentation ASCO 2004, abstract # 8038

39. A total of 128 BMD-evaluable postmenopausal women with early breast cancer at low risk of relapse not given adjuvant therapy routinely during inclusion period or DCIS Exemestane 25 mg po daily for 24 months Placebo po daily for 24 months Patients were followed up for a total of 36 months for BMD and 5 years for DFS. The study data were reviewed yearly by a Data Monitoring Committee. Primary endpoint: Mean annual BMD loss Secondary endpoints: lipid metabolism parameters / cardiovascular risk parameters, bone metabolism markers, coagulation parameters, sex hormones profile, DFS BMD, bone markers, hormones, lipids, coagulation markers were measured at 0, 6, 12, 18, 24 and 36 months (follow-up) 027: Study design Lonning PE et al. ASCO 2004:Abstract 518.

40. 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 Months Lumbar spine Femoral neck Placebo Exemestane 062412 BMD (g/cm 2 ) 027: BMD Lonning PE et al. ASCO 2004:Abstract 518.

41. 027: T-score mean changes from baseline at 2 years Lonning PE et al. ASCO 2004:Abstract 518. Exemestane n=62 Placebo n=66 Difference Lumbar spine–0.30–0.210.09 Femoral neck–0.21–0.110.10 4 fractures in exemestane group; 5 fractures in placebo group

42. 027: 1-yr follow-up Lonning PE et al. ASCO 2005: poster # 531

43. 027: Conclusions Exemestane moderately increases bone loss in the lumbar spine (non-significant) and the femoral neck. No patient with normal BMD at baseline became osteoporotic on either treatment. There was no difference in the frequency of osteopenic patients becoming osteoporotic. “We conclude that pharmacodynamic effects of exemestane therapy on bone are mostly reversible within one year after treatment withdrawal. This suggests exemestane adjuvant therapy should not have long-term detrimental effects on bone metabolism.” Lonning PE et al. ASCO 2004: Abstract 518. Lonning PE et al. ASCO 2005: poster # 531

44. Molecule structure aromatase inhibitors The metabolite of exemestane is weak androgenic. steroidal / aromatase- inactivator non-steroidal / aromatase- inhibitors androsteendion exemestane anastrozol letrozol

45. Effect of Estrogen Concentration on Androgen Sensitivity in Bone

46. ASCO assessment of aromatase inhibitors (Journal of Clinical Oncology, 20 Jan 2005) “Optimal adjuvant hormonal therapy for a postmenopausal woman with hormone receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen.” AIs: Consensus guidelines

47. St. Gallen consensus panel (January 2005) Tamoxifen 2–3 years AI 2–3 years72% Tamoxifen 5 years AI in high risk93% AI irrespective of risk50% Upfront tamoxifen58% ER+, PR+ upfront tamoxifen65% ER+, PR– upfront tamoxifen14% HER2 overexpression upfront tamoxifen10%

48. Final conclusions Exemestane is superior in the sequential studies after tamoxifen. Exemestane has the most favourable tolerability profile, in particular on the skeleton. The TEAM trial will answer the question whether 5 years of exemestane is superior to the sequence tamoxifen followed by exemestane.

49. Back up slides