Aromatase inhibitors in the era ofAromatase inhibitors in the era ofEvidence Based MedicineEvidence Based Medicine

dr. Vivianne Tjan-Heijnen dr. Vivianne Tjan-Heijnen UMC St RadboudUMC St RadboudNKI symposium NKI symposium

29 juni 200529 juni 2005

Aromatase inhibitors in the era ofAromatase inhibitors in the era ofEvidence Based MedicineEvidence Based Medicine

Evidence or believe

That is the question

What does a patient expect when What does a patient expect when receiving a treatment?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

Letrozole

Non-steroidal(Type II)

Steroidal(Type I)

Anastrozole

NC CN

NN

N

ExemestaneO

CH2

OCH3

CH3

CH3 H3C

NC CN

NN

N

H3C CH3

All aromatase inhibitors are equal,All aromatase inhibitors are equal,but some are more equal than othersbut some are more equal than others

Clinical pharmacology of Clinical pharmacology of newer-generation AIsnewer-generation AIs

Anastrozole Letrozole Exemestane

Daily clinical dose 1mg 2.5mg 25mg

Effects on corticosteroids No Yes No

Half-life 41 hours 2–4 days 27 hours

Time to steady stateplasmalevels 7 days 60 days 7 days**

Androgenic metabolites No No Yes

Class of AI Type II Type II Type I

% of E2 suppression 84-85 88 62-65

Adapted from: Buzdar A et al. Cancer 2002; 95: 2006–16

Anastrozole versus Exemestane Anastrozole versus Exemestane in patients with visceral metastasesin patients with visceral metastases

Cameron et al. Proc ASCO 2004; abs 628

0

1

2

3

4

5

ve

rsc

hil

in T

TP

(m

aa

nd

en

)

Anastrozole versus Letrozole 2Anastrozole versus Letrozole 2ndnd line lineTime to progressionTime to progression

0

1

2

3

4

5

6

7

maa

nd

en

overall HR+

Arimidex

letrozol

Rose et al. EJC 2003

%RFS

100

80

0 1 2 3 4 5

years

90

70

100

3215 40033116 4007

2362 208 2372 218

2575 3872582 469

% node +ve39 49Age64

50% ER/PR+ve82

62

9884

64

6 7 7.5

2663

100

IESIES

1606

42100

61

HR RFS0.83* 0.79 0.68 0.59 0.57

ATACATAC BIG 1-98BIG 1-98

1618

ITAITA ARNO/ABCSGARNO/ABCSG

MA17MA17

Anastrozole

Letrozole

Exemestane

63100

100

0.43

ABCSGABCSG

6231

97

0.64Follow up29 6037 52 282668

*ER+ population

Aromatase inhibitors in early breast cancerAromatase inhibitors in early breast cancer

Anastrozole1 Letrozole2 Exemestane3

Initial adjuvant therapy

Efficacy vs tamoxifen

Tolerability

Switching from tamoxifen

Efficacy vs tamoxifen

Tolerability

Extended adjuvant setting

Efficacy vs placebo

Tolerability

Full risk:benefit profile

?

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

Neoadjuvant Anastrozole (OR%)Neoadjuvant Anastrozole (OR%)Mastectomy / inoperable at baseline (n=344)Mastectomy / inoperable at baseline (n=344)

47%

35%

0

10

20

30

40

50

A T

OR

R (

%)

36%

26%

0

10

20

30

40

50

A T

OR

R (

%)

Calliper Ultrasound

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

68/18888/188 55/156 41/156

Statistically significant difference in favour of anastrozole

Indirect comparison with letrozole trialIndirect comparison with letrozole trialObjective response rate (%)Objective 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.

EfficacyEfficacyConclusionsConclusions

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

ASCO technology assessment 2004ASCO 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

Anno 2005:

Evidence is what matters

SafetySafety

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

Interactions with the Interactions with the cytochrome P450 systemcytochrome 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

Anastrozole 10mg: ACTH stimulation Anastrozole 10mg: ACTH stimulation cortisol cortisol and aldosteroneand 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

Baseline 30min 60min

nm

ol/

Ln

mo

l/L

AldosteroneAldosterone

Time after ACTH stimulation

0

200

400

600

800

1000

1200

Baseline 30min 60min

nm

ol/

Ln

mo

l/L

CortisolCortisol

Time after ACTH stimulation

0

200

400

600

800

1000

1200

Screening

Day 28

Day 115

Adapted from: Bajetta E et al. Eur J Cancer 1999; 35: 208–13

Letrozole: ACTH stimulation Letrozole: ACTH stimulation cortisol and aldosteronecortisol and aldosterone

LET = letrozole

800

600

400

200

0

1000

p=0.04

p=0.015

Baseline 30min 60min

Time after ACTH stimulation

nm

ol/

Ln

mo

l/L

nm

ol/

Ln

mo

l/L

800

600

400

200

0

1000

Baseline 30min 60min

Time after ACTH stimulation

Baseline

1 month (2.5mg LET)

3 months (2.5mg LET)

AldosteroneAldosteroneCortisolCortisol

SafetySafety ATAC vs. BIG 1-98 vs. IES 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

SafetySafety ATAC vs. BIG 1-98 vs. IES ATAC vs. BIG 1-98 vs. IES

  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

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

SafetySafetyBoneBone

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

Estimated change (95% CI) in lumbar Estimated change (95% CI) in lumbar spine BMD over timespine BMD over time

Estimated % changes from baseline lumbar spine BMD

4

Anastrozole

71 58

Tamoxifen

69 64

1 year2 year3

2

1

0

-1

-2

-3

-4

-5

-6

101 105

Exe Tam

122 104

Let Plac

Coleman EBCC 2004 abs 289, Coleman SA 2004 Abs 401 , Perez Abs 404

FracturenFracturen

UPFRONT SEQUENTIEEL

ATAC

anastrozol vs tam

BIG 1-98

letrozol vs tam

IES-031

exemestanevs tam

ABCSG8/ARNO95

anastrozol vs tam

FU: 36 mnd

5.9% vs 3.7%

(p< 0.0001)

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)

SafetySafetyConclusionsConclusions

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

Evidence or believeIt is not a question !

My patients with breast cancer expect My patients with breast cancer expect me to be sure of what I am doingme to be sure of what I am doing

VOOR DE DISCUSSIE

Hortobagyi ASCO 2005

Conclusions about AIsConclusions 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.