Aromatase inhibitors in the era of Evidence Based Medicine dr. Vivianne Tjan-Heijnen UMC St Radboud NKI symposium 29 j

1. Aromatase inhibitors in the era ofEvidence Based Medicinedr. Vivianne Tjan-Heijnen UMC St RadboudNKI symposium 29 juni 2005

2. Aromatase inhibitors in the era ofEvidence Based Medicine Evidence or believe That is the question

3. What does a patient expect when receiving a treatment? • That the treatment • is proven to be effective • has no unnecessary side-effects • has no unpleasant surprises The patient wants some certainty

4. N N N N N N NC CN CN NC H3C CH3 H3C CH3 O CH3 CH3 O CH2 All aromatase inhibitors are equal,but some are more equal than others Non-steroidal (Type II) Letrozole Anastrozole Steroidal (Type I) Exemestane

5. Clinical pharmacology of newer-generation AIs Anastrozole Letrozole Exemestane Class of AI Type II Type II Type I Daily clinical dose 1mg 2.5mg 25mg Androgenic metabolites No No Yes Yes No Effects on corticosteroids No 41 hours 2–4 days 27 hours Half-life Time to steady stateplasmalevels 60 days 7 days 7 days** % of E2 suppression 84-85 88 62-65 Adapted from: Buzdar A et al. Cancer 2002; 95: 2006–16

6. Anastrozole versus Exemestane in patients with visceral metastases Cameron et al. Proc ASCO 2004; abs 628

7. Anastrozole versus Letrozole 2nd lineTime to progression Rose et al. EJC 2003

8. BIG 1-98 • 3215 4003 • 3116 4007 ATAC Anastrozole IES ARNO/ABCSG ITA Letrozole 1618 2362 208 2372 218 100 100 Exemestane 1606 MA17 ABCSG 2575 387 2582 469 90 % RFS 80 64 63 64 61 62 Age 63 62 26 49 39 100 42 % node +ve 31 50 70 100 100 82 84 % ER/PR+ve 100 97 98 Follow up 37 52 26 28 60 68 29 0.83* 0.79 0.68 HR RFS 0.43 0.59 0.64 0.57 7.5 7 0 1 2 3 4 5 6 years *ER+ population

9. Aromatase inhibitors in early breast cancer Anastrozole1 Letrozole2 Exemestane3 Initial adjuvant therapy Efficacy vs tamoxifen Tolerability Full risk:benefit profile Switching from tamoxifen Efficacy vs tamoxifen Tolerability Extended adjuvant setting Efficacy vs placebo ? Tolerability 1) ATAC trialists’ Lancet 2005; Boccardo et al. ASCO 2005; Jakesz et al. SABCS 2004; Jakesz et al. ASCO 2005 2) Thurlimann St. Gallen 2005; Goss et al. NEJM 2003 3) Coombes et al. NEJM 2004

10. Neoadjuvant Anastrozole (OR%)Mastectomy / inoperable at baseline (n=344) Calliper Ultrasound 47% 50 50 40 40 36% 35% 30 30 26% ORR (%) ORR (%) 20 20 10 10 88/188 55/156 68/188 41/156 0 0 A T A T Statistically significant difference in favour of anastrozole A vs T: OR 1.65 (CI 1.06, 2.56) p=0.026 A vs T: OR 1.60 (CI 1.00, 2.55) p=0.048

11. Indirect comparison with letrozole trialObjective response rate (%) OR (%) L T L vs T A T A vs T Ultrasound 35 25 p=0.042 36 26 p=0.048 Eiermann et al. Ann Oncol 2001; 12: 1527–1532.

12. EfficacyConclusions • Head to head studies in advanced breast cancer demonstrate similar efficacy of aromatase inhibitors • There are no direct comparisons of aromatase inhibitors in early breast cancer • Indirect comparisons in primary endpoints show similar efficacy Differences in pharmacology do not seem to translate into differences in clinical efficacy

13. ASCO technology assessment 2004 In breast cancer therapy, ASCO currently recommends the use of the AI ‘that has been studied in the setting most closely approximating any individual patient’s clinical circumstance’ Winer et al. JCO 2005

14. Anno 2005: Evidence is what matters

15. Safety • Differences in pharmacology do not seem to translate into differences in clinical efficacy • Do these differences translate into different side effect profiles ? Focus on bone and cardio vascular effects

16. Interactions with the cytochrome P450 system Anastrozole Letrozole Exemestane Inhibits CYP1A2,CYP2C9 at relatively highconcentration No activity onCYP2A6 orCYP2D6 Metabolised byN-dealkylation,hydroxylation andglucuronidisation Strongly inhibitsCYP2A6 Moderatelyinhibits CYP2C19 Metabolised byCYP3A4 andCYP2A6 No inhibition ofCYP1A2, CYP2C9,CYP2D6, CYP2E1 orCYP3A4 Metabolised by CYP3A4and aldoketoreductase Adapted from: Buzdar A et al. Cancer 2002; 95: 2006–16

17. Cortisol Aldosterone 1200 1200 1000 1000 800 800 nmol/L nmol/L 600 600 400 400 Screening Day 28 200 200 Day 115 0 0 Baseline 30min 60min 60min 30min Baseline Time after ACTH stimulation Time after ACTH stimulation Anastrozole 10mg: ACTH stimulation cortisol and aldosterone Adapted from: Plourde et al. J Ster Biochem Mol Biol 1995; 53: 175–9; Esparza-Guerra, Buzdar. Proc ASCO 2001; 20 (Pt 2): 52b, Abstr 1954

18. Cortisol Aldosterone 1000 1000 800 800 p=0.015 600 600 nmol/L nmol/L p=0.04 400 400 Baseline 1 month (2.5mg LET) 200 200 3 months (2.5mg LET) 0 0 Baseline 30min 60min 60min 30min Baseline Time after ACTH stimulation Time after ACTH stimulation Letrozole: ACTH stimulation cortisol and aldosterone LET = letrozole Adapted from: Bajetta E et al. Eur J Cancer 1999; 35: 208–13

19. Safety ATAC vs. BIG 1-98 vs. IES Upfront • Anastrozole in favour of tamoxifen (ATAC): hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, ischemic cerebrovascular events and venous thromboembolic events. • Letrozole in favour of tamoxifen (BIG 1-98): hot flashes, vaginal bleeding and thromboembolic events. Switch • Exemestane in favour of tamoxifen (IES): vaginal bleeding, cramps and venous thromboembolic events. 1) ATAC trialists’ Lancet 2002,2005; 2) Thurlimann St. Gallen 2005; 3) Coombes et al. NEJM 2004

20. BIG 1-98 ATAC (1st analysis) ATAC (2nd analysis) Cardiac death 26 L, 13 T 19 A, 20 T 49 A, 46 T Cerebrovascular death 7 L, 1 T 3 A, 13 T 14 A, 21 T Safety ATAC vs. BIG 1-98 vs. IES IES Myocardial infarct: 20 exemestane; 8 tamoxifen Cardiac death / cerebrovascular death: to be reported 1) ATAC trialists’ Lancet 2002, 2005; 2) Thurlimann St. Gallen 2005; 3) Coombes et al. SABCS 2004

21. SafetyBone • In all adjuvant trials aromatase inhibitors lead to more fractures than tamoxifen • both in upfront and switching trials1-3 • Effects on bone do not seem to increase over time1 1) ATAC trialists’ Lancet 2005; 2) Thurlimann St. Gallen 2005; 3) Coombes et al. SABCS 2004

22. Estimated change (95% CI) in lumbar spine BMD over time Estimated % changes from baseline lumbar spine BMD 4 1 year 2 year 3 2 1 0 -1 -2 -3 -4 -5 -6 Anastrozole Tamoxifen Exe Tam Let Plac 122 104 101 105 71 58 69 64 Coleman EBCC 2004 abs 289, Coleman SA 2004 Abs 401 , Perez Abs 404

23. Fracturen

24. SafetyConclusions • Differences in potency and pharmacology do seem to translate into differences in side effect profiles • Longer follow up is needed to confirm this • With 68 months of follow up in ATAC anastrozole has the most robuust safety data

25. My patients with breast cancer expect me to be sure of what I am doing Evidence or believeIt is not a question !

27. VOOR DE DISCUSSIE

29. Conclusions about AIs • Upfront AI is clearly more effective/better tolerated than upfront TAM. AIs reduce events from the beginning. This is a fact. • Crossover from TAM to an AI after 2-5 years of TAM is clearly effective. However, 1.5-3.8%/year of TAM-treated pts develop treatment failure before crossover. The superiority of crossover regimens over AI upfront is a hypothesis only. • Until proven otherwise an AI upfront should be the preferred strategy. Hortobagyi ASCO 2005