1. Aromatase inhibitors in the era of Evidence Based Medicine dr
Aromatase inhibitors in the era of Evidence Based Medicine dr. Vivianne Tjan-Heijnen UMC St Radboud NKI symposium 29 juni 2005

2. Aromatase inhibitors in the era of Evidence 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. All aromatase inhibitors are equal, but some are more equal than othersNC CN N
Non-steroidal
(Type II)
CH3
H3C NC CN N
Letrozole
Anastrozole O
CH2
CH3
Steroidal
(Type I)
Key Points
AIs are a class of compounds that inhibit the synthesis of oestrogen from androgens in postmenopausal women. Anastrozole, which first became available in 1995, is a potent, orally active, highly selective, non-steroidal, third-generation AI that markedly reduces both circulating and intratumoural oestrogen levels in postmenopausal women with breast cancer
Anastrozole and letrozole are both triazole derivatives, non-steroidal in structure, compared with exemestane, which is steroidal
Anastrozole has no oestrogenic, progestogenic or androgenic effects
No androgenic, oestrogenic or progestogenic activity has been observed in over 800,000 patient-years of clinical experience with anastrozole
References
Geisler J, King N, Dowsett M et al. Influence of anastrozole ('Arimidex'), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in post-menopausal women with breast cancer. Br J Cancer 1996; 74: 1286–91.
Dukes M, Edwards PN, Large M et al. The preclinical pharmacology of 'Arimidex' (anastrozole; ZD1033) — a potent, selective aromatase inhibitor. J Ster Biochem Mol Biol 1996; 58: 439–45.
Plourde PV, Dyroff M, Dukes M. 'Arimidex': A potent and selective fourth-generation aromatase inhibitor. Breast Cancer Res Treat 1994; 30: 103–11.
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
Effects on corticosteroids No
Yes No
Half-life
41 hours
2–4 days
27 hours
Time to steady state plasmalevels
Key Points
There are a number of differences in clinical pharmacokinetic and pharmacological profiles between the three newer AIs, including:
Time to steady-state plasma levels
Terminal half-life
Time to maximal oestradiol (E2) suppression
Intratumoural activity
Although the clinical relevance has yet to be established, the different properties of these newer AIs may lead to differing safety profiles with long-term use, particularly in the adjuvant setting
Based on the observed pharmacological profiles, it cannot be assumed that each of the AIs will display the same tolerability and safety profiles when they are given for extended periods of time in the adjuvant setting
There appears to be an oestrogen threshold, beyond which no further improvements in clinical efficacy can be gained
References
Buzdar A et al. Cancer 2002; 95: 2006–16.
Buzdar A, Howell A. Clin Cancer Res 2001; 7: 2620–35.
Sainsbury R. Increased aromatase inhibitor potency: Correlation with clinical efficacy? Breast 2003; 12: S31–S32, Abstr P59.
7 days
60 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
In de open label studie van onze concurrent met een kleine 700 patienten kon t.a.v het primaire eindpunt tijd tot progressie geen verschil worden aangetoond tussen letrzole en Arimidex.
Ongeveer de helft van de patienten in de studie had een bekende positieve hormoonstatus. De tweede set gegevens kijkt naar deze meest relevante subpopulatie. De tijd tot progressie voor Arimidex was hier 6,4 maanden en voor letro 5,8 maanden.
(Desgevraagd: Op 6 van de 7 andere eindpunten is ook geen verschil gevonden tussen Arimidex en letrozole. Het verschil in respons tussen Arimidex en letrozole valt weg wanneer alleen wordt gekeken naar de relevante hormoongevoelige populatie. Aangezien dit een open label studie betreft is juist respons overigens een eindpunt dat zeer gevoelig is voor subjectiviteit)
Al met al tonen de studies bij gemetastaseerd mammacarcinoom aan dat Arimidex en letrozole redelijk vergelijkbaar zijn in effectiviteit. Verschillen in aromataseremming en oestrogeensuppressie tussen deze middelen lijken daarom niet relevant voor de effectiviteit.
Wanneer ik nu weer even mijn Arimidex pet opzet, wil ik nog wel even zeggen dat als er al verschillen lijken te zijn Arimidex er steeds zeer goed uitspringt.
Hoe kijkt u daar tegenaan ?
Graag wil ik nu de belangrijke punten van Arimidex nog eens op een rij zetten.
Cameron et al. Proc ASCO 2004; abs 628

7. Anastrozole versus Letrozole 2nd line Time to progression
In de open label studie van onze concurrent met een kleine 700 patienten kon t.a.v het primaire eindpunt tijd tot progressie geen verschil worden aangetoond tussen letrzole en Arimidex.
Ongeveer de helft van de patienten in de studie had een bekende positieve hormoonstatus. De tweede set gegevens kijkt naar deze meest relevante subpopulatie. De tijd tot progressie voor Arimidex was hier 6,4 maanden en voor letro 5,8 maanden.
(Desgevraagd: Op 6 van de 7 andere eindpunten is ook geen verschil gevonden tussen Arimidex en letrozole. Het verschil in respons tussen Arimidex en letrozole valt weg wanneer alleen wordt gekeken naar de relevante hormoongevoelige populatie. Aangezien dit een open label studie betreft is juist respons overigens een eindpunt dat zeer gevoelig is voor subjectiviteit)
Al met al tonen de studies bij gemetastaseerd mammacarcinoom aan dat Arimidex en letrozole redelijk vergelijkbaar zijn in effectiviteit. Verschillen in aromataseremming en oestrogeensuppressie tussen deze middelen lijken daarom niet relevant voor de effectiviteit.
Wanneer ik nu weer even mijn Arimidex pet opzet, wil ik nog wel even zeggen dat als er al verschillen lijken te zijn Arimidex er steeds zeer goed uitspringt.
Hoe kijkt u daar tegenaan ?
Graag wil ik nu de belangrijke punten van Arimidex nog eens op een rij zetten.
Rose et al. EJC 2003

8. ITA ARNO/ABCSG ABCSG ATAC 3215 4003 3116 4007 BIG 1-98 IES 2362 208
BIG 1-98
Anastrozole
IES
ITA
ARNO/ABCSG
Letrozole
1618
100
100
Exemestane
1606
MA17
ABCSG 90 %
RFS 80 64 61 64 63 63 62 62
Age 39 42 49
100 26 50 31
% node +ve 70 84
100 82
100
100 98 97
% ER/PR+ve 68 26 37 52 28 29 60
Follow up
Key Points
An indirect comparison of data from women aged >50 years with ER-positive, early breast cancer demonstrates that tamoxifen exhibited similar efficacy in both the ATAC trial and the EBCTCG overview
This comparison reveals that the tamoxifen group in the ATAC trial is continuing to perform as expected in the adjuvant setting, and that the better outcome seen with anastrozole cannot be explained by a poor performance of tamoxifen; although it should be noted that no adjustment was made for the difference in the nodal status between the EBCTCG overview and ATAC trial
The 4-year recurrence-free estimate in the hormone receptor-positive group of patients of the ATAC trial treated with tamoxifen (89.6%) was similar to the rate seen in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 1995 overview for tamoxifen (87.0%)1. In contrast, the 4-year recurrence-free rate in the hormone receptor-positive group of patients treated with anastrozole in the ATAC trial was 92.2%2
Reference
1. EBCTCG. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351:
2. The ATAC Trialists’ Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359:
0.83*
0.79
0.68
0.43
0.59
0.57
0.64
HR RFS 1 2 3 4 5 6 7
7.5
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. Statistically significant difference in favour of anastrozole
Neoadjuvant Anastrozole (OR%) Mastectomy / inoperable at baseline (n=344)
Calliper
Ultrasound 50
47% 50 40 40
36%
35% 30 30
26%
ORR (%)
ORR (%) 20 20 10 10
In the mastectomy/inoperable at baseline group, OR for both calliper and ultrasound data were statistically significant in favour of anastrozole.
88/188
55/156
68/188
41/156 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 trial Objective response rate (%)
OR (%) L T L vs T A T A vs T
Ultrasound p= p=0.048
Patient numbers were comparable:
n = 324 in the letrozole study
n = 262 in PROACT
Eiermann et al. Ann Oncol 2001; 12: 1527–1532.

12. Efficacy Conclusions
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 high concentration
No activity on CYP2A6 or CYP2D6
Metabolised by N-dealkylation, hydroxylation and glucuronidisation
Strongly inhibits CYP2A6
Moderately inhibits CYP2C19
Metabolised by CYP3A4 and CYP2A6
No inhibition of CYP1A2, CYP2C9, CYP2D6, CYP2E1 or CYP3A4
Metabolised by CYP3A4 and aldoketoreductase
Key Points
Anastrozole is the most selective AI in the clinical setting
Differences in selectivity, doses, pharmacology and pharmacokinetics between the third-generation AIs have the potential to produce clinically relevant effects when administered long-term, i.e. in the adjuvant setting
Anastrozole has shown no clinically significant drug interaction.* Caution should be used in the concomitant administration of drugs such as letrozole, whose disposition is mainly dependent on cytochrome P450 enzymes 2A6 and 2C19 and whose therapeutic index is narrow. CYP2C19 is responsible for the metabolism of a range of drugs, including: proton pump inhibitors (omeprazole, lansoprazole); anti-epileptics (phenytoin, phenobarbitone, diazepam); some antidepressants (citalopram, imipramine), cyclophosphamide and propranolol
Caution should be used with drugs such as exemestane that are metabolised via CYP3A4 and have a narrow therapeutic window. Drugs that are metabolised by CYP3A4 include: anti-arrhythmics (quinidine), calcium channel blockers (verapamil, diltiazem, amlodipine) and some statins (simvastatin, atorvastatin)
* (Tamoxifen and/or other therapies containing oestrogen should not be co-administered with anastrozole, as they may diminish its pharmacological action)
References
Buzdar A et al. Cancer 2002; 95: 2006–16.
Buzdar A, Howell A. Clin Cancer Res 2001; 7: 2620–35.
Adapted from: Buzdar A et al. Cancer 2002; 95: 2006–16

17. Anastrozole 10mg: ACTH stimulation cortisol and aldosterone
Baseline
30min
60min
nmol/L
Aldosterone
Time after ACTH stimulation
200
400
600
800
1000
1200
Cortisol
Screening
Day 28
Day 115
Key Points
Anastrozole is highly selective for the aromatase enzyme and therefore does not have any clinically relevant effect on adrenal function
In postmenopausal women with advanced breast cancer, anastrozole at 10 times the clinically recommended dose (i.e. 10mg daily) had no significant effect on basal or ACTH-stimulated adrenal function at baseline or after 115 days of treatment. This reduces the potential for toxicity and disturbance to steroid synthesis
Letrozole has been shown to have a statistically significant impact on adrenal function when given to women with advanced breast cancer at the standard clinical dose for 3 months
References
Plourde P et al. J Ster Biochem Mol Biol 1995; 53: 175–9.
Esparza-Guerra L, Buzdar A. Proc ASCO 2001; 20 (Pt 2): 52b, Abstr 1954.
Bajetta E, Zilembo N, Dowsett M et al. Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses in postmenopausal breast cancer patients. Eur J Cancer 1999; 35: 208–13.
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. Letrozole: ACTH stimulation cortisol and aldosterone
800
600
400
200
1000
p=0.04
p=0.015
Baseline
30min
60min
Time after ACTH stimulation
nmol/L
1 month (2.5mg LET)
3 months (2.5mg LET)
Aldosterone
Cortisol
Key Points
Letrozole has been shown to have a statistically significant impact on adrenal function when given to women with advanced breast cancer at the standard clinical dose for 3 months
In a study in postmenopausal women with advanced breast cancer, treatment with letrozole 2.5mg daily significantly inhibited ACTH-stimulated cortisol and aldosterone
Reference
Bajetta E, Zilembo N, Dowsett M et al. Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses in postmenopausal breast cancer patients. Eur J Cancer 1999; 35: 208–13.
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. Safety ATAC vs. BIG 1-98 vs. IES
BIG 1-98
ATAC
(1st analysis)
(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
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. Safety Bone
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 -1 -2 -3 -4
Changes from baseline were significantly different in lumbar spine bone marrow density (p<0.0001) for tamoxifen alone compared to anastrozole alone at year 1 and year 2.
No significant differences were observed at year 1 and year 2 for tamoxifen alone compared to combination treatment. -5 -6
Anastrozole
Tamoxifen
Exe Tam
Let Plac 71 58 69 64
101
105
122
104
Coleman EBCC 2004 abs 289,
Coleman SA 2004 Abs 401 , Perez Abs 404

23. Lumbar Spine (% change)
BMD after 1 year AI
Lumbar Spine (% change)
Total Hip (% change)
Year 1
Ari
(n=71)
-2.6
(-3.3 to –1.8)
-1.7
(-2.3 to –1.0)
Tam
(n=69)
1.2
(0.4 to 2.0)
0.8
(0.1 to 1.6)
Exe
(n=101)
-2.9
(-3.6 to -2.1)
-2.1
(-2.7 to –1.6)
(n=105)
0.02
(-0.7 to 0.7)
0.5
(0.0 to 1.0)
Eastell R, et al. ASMBR 2003 abstract
Coleman RE et al. SABCS 2004 abstract 401

24. Fracturen UPFRONT SEQUENTIEEL ATAC anastrozol vs tam BIG 1-98
letrozol vs tam
IES-031
exemestanevs tam
ABCSG8/ARNO95
FU: 36 mnd
5.9% vs 3.7%
(p< )
FU: 26 mnd
5.8% vs 4.1% (P=0.0006)
FU: 37,4 mnd
3.9% vs 2.9% (p=0.06)
FU: 28.0 mnd
2.4% vs 1.2% (significant)

25. Safety Conclusions
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

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

28. VOOR DE DISCUSSIE

30. 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, %/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