The Role of Aromatase Inhibitors in the Treatment of Breast Cancer'

1
The Role of Aromatase Inhibitors in the Treatment
of Breast Cancer.

• Carsten Rose, MDDirector, Department of
  OncologyLund University HospitalLund, Sweden

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The majority of men are subjective towards
themselves and objective towards all others, but
the real task is in fact to be objective towards
oneself and subjective towards all others.
Soren Kierkegaard
3
Inhibition ofEstrogen-Dependent Growth
Estrogen biosynthesis
Nucleus
Tumor cell
4
Anti-estrogens Toremifene Raloxifene Droloxifene
Idoxifene
Hormones Estrogens Androgens
Tamoxifen
Aromatase Inhibitors Aminoglutethimide Formestan
e Fadrozole
Gestagens Medroxy-Prog acetate Megestrol acetate
5
The Gold Standard in MBC
Aromatase Inhibitors Anastrozle Letrozole Exemest
ane
Tamoxifen
6
Pharmacologic Profile of AIs

• Inhibition of aromatase activity in vitro, in
  vivo, and in humans
• Selectivity for aromatase
• Minimal or no activity against other P450 enzymes
  involved in steroidogenesis
• Efficacy of estrogen deprivation
• Endocrine effect
• Antitumor effect
• Minimal or no side effects

7
Structure of AIs
Steroidal Inhibitors
Androgen Substrate
Androstenedione
Nonsteroidal Inhibitors
8
Development of Aromatase Inhibitors
Toxicity
Selectivity
Potency
Aminoglutethimide
First generation
Fadrozole 4-OHA, Formestane
Second generation
Anastrozole Exemestane Letrozole
Third generation
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Inhibition of Aromatization
14
Androstenedione
Androstenedione
A R O M A T A S E
A R O M A T A S E
Nucleus
Breast Tumor
Peripheral Tissues
TOTAL BODY AROMATIZATION
10
Peripheral Aromatase Inhibition Postmenopausal
Women
Inhibition
Residual
Aminoglutethimid Formestane (i.m.) Anastrozole
Exemestane Letrozole
90.6 91.9 96.7 97.9 98.9
9.4 8.1 3.3 2.1 1.1
Lonning et al. Breast 199652028.Clin Cancer
Res. 19984208993.
11
From 1995 Introduction of Third-Generation AIs
in Advanced Breast Cancerin Postmenopausal Women

• Second-line endocrine treatment vs
  aminoglutethimide or megestrol acetate
• First-line endocrine treatment vs tamoxifen

12
Second Line Endocrine Therapy of MBC AIs vs
Megace
Fadrozole (2)
Formestane (2)
Vorozole
Megace
Letrozole (2)
Anastrozole (2)
Exemestane
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Third generation aromatase inhibitors /
inactivators - MA
Let - MA Let - MA Vor - MA AN - MA
Ex - MA RR yes no no
no no Bene no no
no no no TTP no
no no no yes TTF
yes no - no
yes Surv no no no
yes yes Kaufmann et al. J Clin Oncol
2000 Buzdar et al. Cancer 1998 Dombernowsky et
al. J Clin Oncol 1998 Goss et al. J Clin Oncol
1999 Buzdar et al. JCO 2001
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Third-Generation AIs in First-Line Studies
Tamoxifen 20 mg
RANDOMIZE

• Third-generation AIs
• Anastrozole 1 mg, or
• Letrozole 2.5 mg, or
• Exemestane 25 mg

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Exemestane vs Tamoxifen
No. of Patients ()
Exemestane
Tamoxifen
n (ITT) 61 (100) 59 (100) Response
rate 25 (44.6) 8 (14.3) Clinical benefit
rate 31 (55.3) 22 (39.3)
Dirix et al. Proc Am Soc Clin Oncol. 200120114.
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Anastrozole vs Tamoxifen Trials
030 (n353) 027 (n668)
Retrospective analysis P0.0098 P0.005
Nabholtz et al. J Clin Oncol. 2000183758.
Bonneterre et al. J Clin Oncol.
2000183748.www.fda.gov/cder/foi/nda/2000/20-541
S006_Arimidex.htm
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Anastrozole vs TamoxifenTrials 0030 and 0027
Combined
Anastrozole 1 mg Tamoxifen 20 mg P value
(n511) (n510)
TTP (months) 8.5 7.0 NS Response
() 29 27 NS Clinical benefit () 57 52 NS Median
Survival (mo) 39 40 NS
Bonneterre et al. J Clin Oncol.
2001192247. Bonneterre et al. Ann Onc.
20021547.
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Anastrozole vs Tamoxifen Trials 0030 and 0027
Combined Subgroup Analyses of TTP
All patients 0.103 Receptor status Known to be
ve 0.022 Not known to be ve 0.826 Prev
hormonal treatment No 0.075 Yes 0.982 Visceral
lesions No 0.081 Yes 0.957 Liver
lesions No 0.141 Yes 0.917 Bone lesions
only No 0.264 Yes 0.308 Age ?65 y 0.277 gt65
y 0.223
0.60
0.80
1.00
1.25
1.50
1.75
Hazard ratio (TAMANA)
Tamoxifen superior
Anastrozole superior
2-sided P values (based on retrospective
analysis).
Bonneterre et al. Cancer. 2001922247.
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Letrozole vs Tamoxifen Trial (025)
Letrozolen453
Tamoxifenn454
P Value
Response (CR PR) 32 21 0.0002 Clinical
Benefit 50 38 0.0004 Median TTP (mo) 9.4 mo
6.0 mo lt0.0001 Median Survival (mo) 34 mo 30
mo 0.5303
Significant early (2 yrs) survival benefit
Mouridsen et al. J Clin Oncol. 2001192596.
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Letrozole vs. Tamoxifen TTP by Baseline
Covariates
Letrozole Better
Tamoxifen Better
Subgroup
All pts. (ITT)
Adjuvant tamoxifen
No adjuvant tamoxifen
Receptor positive
Receptor unknown
Soft tissue
Bone
Viscera
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Hazard Ratios and 95 Confidence Intervals
21
Median Time to Progression According to Receptor
Status
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Median Time to Progression According to Adjuvant
Antiestrogen Therapy
Prior Adjuvant Antiestrogen Therapy
No Prior Adjuvant Antiestrogen Therapy
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Median Time to Progression According to Site of
Disease
Non-visceral disease
Visceral, non-liver
TTP Letro 11.9 M TAM 6.1 M P0.0017
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Overall Survival Analysis
1.0
0.9
0.8
Median overall survivalLetrozole 34
moTamoxifen 30 mo
0.7
0.6
0.5
Kaplan-Meier estimate
0.4
0.3
P0.5303 (log-rank test)
0.2
0.1
0.0
0
12
18
24
30
36
42
48
54
60
6
Months
Mouridsen et al. San Antonio Breast Cancer
Symposium, 2001.
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Exploratory Analysis First-Line Survival (Data
Censored at Crossover)
Letrozole n453, median 42 mo (95 CI, 38-gt56 mo)
1.0
0.9
0.8
0.7
0.6
0.5
Kaplan-Meier estimate
0.4
Tamoxifen n454, median 30 mo (95 CI, 27-36 mo)
0.3
0.2
0.1
0.0
0
12
18
24
30
36
42
48
54
60
6
Months
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Exploratory Analysis First-Line Survival (Data
Censored at Crossover)
Letrozole n453, median 42 mo (95 CI, 38-gt56 mo)
1.0
0.9
0.8
0.7
0.6
0.5
Kaplan-Meier estimate
0.4
Tamoxifen n454, median 30 mo (95 CI, 27-36 mo)
0.3
0.2
0.1
0.0
0
12
18
24
30
36
42
48
54
60
6
Months
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Third-Generation AIs vs Tamoxifen for First-Line
Treatment of Advanced Breast Cancer Conclusion

• Anastrozole and letrozole have been approved for
  first-line treatment based on the data from the
  Phase III trials
• Compared with tamoxifen
• Anastrozole has demonstrated equivalence
• Letrozole has demonstrated superiority
• Data related to exemestane not yet available

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Rationale for FEM-INT-01
Aromatase Inhibition
PRECLINICAL
CLINICAL
Endocrine Effects
Endocrine Effects
1. Aromatase inhibition 2. Uterine atrophy
1. In vivo aromatization 2. Serum estrogens
Anti-tumor Effects
Animals
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Second Line Endocrine Therapy of MBC Comparative
Efficacy of AIs
Letrozole
AG
Vorozole
Anastrozole
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Comparison between different aromatase inhibitors
/ inactivators (second-line)
Let AG Let Fadr Vor AG AN - Let
RR no yes
no yes Bene no yes
yes - TTP yes
no no no
TTF yes - yes
no Surv yes - no
no Gershanovic et al Ann Oncol 1998
Tominaga et al (Abstr) Ann Oncol 2000 Bergh et
al ASCO abstr 1997 Rose et al ASCO abstr
2002 AG 500 mg daily
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Letrozole vs Anastrozole FEM-INT-01 Trial

• Open-label, randomized, multicenter,
  multinational trial
• Postmenopausal women with hormone
  receptorpositive or unknown metastatic breast
  cancer after tamoxifen therapy failure

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Inclusion CriteriaPrior Hormonal Therapy

• Patients eligible who either
• Relapsed while on adjuvant antiestrogen therapy ?
  6 months
• Relapsed after completing at least 6 months of
  adjuvant antiestrogen therapy and within12
  months of stopping
• 713 patients enrolled in 105 centers in 19
  countries between December 1997 and November 1999
• Progressed while on first-line antiestrogen
  therapy

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Letrozole vs Anastrozole in Second-Line Treatment
of MBC FEM-INT-01

• Enrollment
• Recruited from 105 centers in 19 countries
• 713 patients entered the trial
• Anastrozole n357
• Letrozole n356
• Data collection stopped at visit 12 (30 months)

End Points TTP ORR Response Duration Survival
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Patient DemographicsBaseline Characteristics
Between Groups

Letrozole Anastrozole No. of
patients 356
357 Age (y) 63.5 (32-92) 63
(27-88) Hormone receptor status ER and PgR 102
(29) 104 (29) ER or PgR 71 (20) 63
(18) Unknown 183 (51) 189 (53) Dominant site
of disease Soft tissue 85 (24) 84
(24) Bone 85 (24) 87 (24) Viscera 185
(52) 186 (52)
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FEM-INT-01Patients Treated With Tamoxifen

• Letrozole Anastrozole (n356) (n357)
• Relapsed on 163 (46) 185 (52) adjuvant
  therapy
• Received first-line 192 (52) 171 (48)
  tamoxifen

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Letrozole vs AnastrozoleTime Events

• ITT
  Population P value
• Letrozole Anastrozole
  (n356) (n357)
• Median TTP (mo) 5.7 5.7 0.92090
  CI 5.1-6.0 4.6-6.1
• Median TTF (mo) 5.6 5.6 0.76190
  CI 4.4-5.8 4.0-6.0
• Median OS (mo) 22.0 20.3 0.62490
  CI 19.6-24.6 18.0-23.1

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Letrozole vs AnastrozoleResponse Rate
Letrozole 19.1

Anastrozole 12.3
ORR
P0.013
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Independent Peer Review (contd)

• Blinded independent peer review performed on 112
  responders
• Adequate documentation was available to assess 84
  of the 122 responders (75)
• Concordance 83
• Statistical signficance retained
• The 83 concordance was similar to results from
  the prospective peer review performed in the
  second-line trials AR/BC2 (79), AR/BC3 (84)

retrospective review in 2 centers, each with 2
reviewers
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Response Rates in Phase IIISecond-Line Trials
ORR
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Overall Tumor Response by Predefined Covariates
ITT Population

• No. of CR PR/Total No.
  Pts ()
• Baseline Covariate Letrozole
  Anastrozole P Value
• Receptor status 0.014
• ER and/or PgR 30/173 (17.3)
  28/167 (16.8)Unknown 38/183 (20.8)
  16/190 (8.4)
• Dominant site 0.012
• Soft tissue
  31/85 (36.5) 16/84 (19.0)Bone
  11/85 (12.9)
  10/87 (11.5)Viscera
  26/185 (14.1) 18/186 (9.7)

Analysis based on Cochran-Mantel-Haenszel.
41
Letrozole has previously proven efficacious in an
ER/PR-unknown collective of patients
- not analysed -
0.60
0.80
1.00
1.25
1.50
1.75
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Hazard Ratio (Tam Anastrozole)
Hazard ratio
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FEM-INT-01Summary and Conclusions

• Letrozole produced significantly superior
  response rates compared with anastrozole
• 50 more patients responded to letrozole vs
  anastrozole(19.1 vs 12.3 P0.013)
• A retrospective independent blinded peer
  reviewin responders determined a concordance of
  83statistical significance persisted

• No significant differences in TTP, TTF, OS,
  clinical benefit rate,duration of response, or
  duration of clinical benefit

• Adverse events were comparable in both groups

• The significant difference in response rates for
  letrozole is consistent with pre-clinical and in
  vivo data demonstrating higher efficacy

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Rationale for FEM-INT-01
Aromatase Inhibition
PRECLINICAL
CLINICAL
Endocrine Effects
Endocrine Effects
1. Aromatase inhibition 2. Uterine atrophy
1. In vivo aromatization 2. Serum estrogens
Anti-tumor Effects
Animals
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Clinical Conclusion

• In direct comparison with Anastrozole, Letrozole
• leads to stronger estrogen suppression
• induces clinical remissions more frequently
• is preferred by patients due to better quality of
  life

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Aromataseinhibitors in Metastatic Breast Cancer
Patients Conclusion

• AIs are first-line ET treatment for patients with
  MBC
• AIs are more efficient and less toxic than MA or
  AG in second-line ET of MBC
• Experimental, clinical and QoL data indicate
  higher activity for letrozole in comparision with
  aminoglutethimide and anastrozole

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The Gold Standard
Tamoxifen
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Tamoxifen
Advantages
Disadvantages

• Established efficacy Breast cancer treatment/
  prevention
• Bone and lipid/CVD benefits

• EFFICACY
• Antagonist / Agonist
• Resistance/dependence
• TOXICITIES
• Endometrial cancer
• Thromboembolism
• Hot flushes
• Vaginal/urinary symptoms

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Rationale for Adjuvant Therapy With Aromatase
Inhibitors

• 2/3 of at-risk ER pts. die despite adjuvant
  tamoxifen
• Relapses continue for 15 years
• New SERMs have not replaced tamoxifen
• Aromatase inhibitors
• Effective after tamoxifen
• Better than tamoxifen first line
• Distinct mechanism of estrogen suppression
• May not have tamoxifen-like resistance
• Not likely to cause thrombo-embolism or
  endometrial cancer
• Well tolerated

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Aromatase InhibitorsEnd-Organ Effects

• Reduction of estrogen
• Decrease breast cancer
• Decrease endometrial cancer
• Decrease venous thromboembolism
• Menopausal symptomatology
• Bone metabolism
• Lipid metabolism

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Trial Strategies in Adjuvant Therapy Aromatase
Inhibitors
TAMOXIFEN
ANASTROZOLE
ATAC
LETROZOLE
EXEMESTANE
ARNO
PLACEBO
MA-17
BIG 1-98(BIG FEMTA)

ICCG Study 96
NSABP B33
TEAM
EXEM 027

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ATAC Trial Disease-Free Survival (ITT)
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ATAC Trial Significant DifferenceIn Predefined
Adverse Events
First events
Anastrozole (n3125)
Tamoxifen (n3116)
Combination (n3125)
Total (n9366)
Local recurrence Distant recurrence Contralat.
breast cancer invasive Ductal carcinoma
i.s. Deaths before recurrence Total
67 158 14 9 5 78 317 (10.1)
83 182 33 30 3 81 379 (12.2)
81 204 28 23 5 70 383 (12.3)
231 544 75 62 13 229 1079 (11.5)
Including 5 deaths (2 on anastrozole, 1 on
tamoxifen, and 2 on the combination) which were
attributed to breast cancer without prior
information about recurrence.
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Questions NOT Answered byCurrent AI Adjuvant
Trials

• Optimal duration of AI treatment in EBC
• Optimal sequencing of endocrine therapy in
  EBCover 10 years
• Should AI be started simultaneously or
  postchemotherapy?
• Optimal use of tamoxifen with AIs
• Is there a way to overcome toxicities?
• Is there a way of selecting patients for therapy?

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ATAC Trial Significant DifferenceIn Predefined
Adverse Events
Anastrozole (n3092)
Tamoxifen (n3094)
P
Hot flushes MSK disorders Vaginal
discharge Vaginal Bleeding Endometrial
cancer Fractures ICARVE ICERVE Any VTE DVT PE
34.9 27.8 2.8 4.5 0.1 5.9 2.5 1.0 2.1 1.0

39.7 21.3 11.4 8.2 0.5 3.7 1.9 2.1 3.5 1.
7
lt0.0001 lt0.0001 lt0.0001 lt0.0001 0.02 lt0.0001 0.14
0.0006 0.0006 0.02
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Ongoing Adjuvant Trials With AIs BIG 1.98
(Letrozole)
RANDOMIZE
Tamoxifen 20 mg od
Surgery Completetumorresection
Letrozole 2.5 mg od
DFS/OS
Tamoxifen 20 mg od
Tamoxifen 20 mg od
Letrozole 2.5 mg od
Letrozole 2.5 mg od
2 years
3 years

• Companion Studies
• Lipid metabolism
• Bone metabolism

Milestones Activated March 1999 Planned
accrual 7900 Accrual to date 7900
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Implications of Adjuvant Studies to Clinical Care

• How will we judge the results of AI trials ??
• Efficacy DFS/OS 5, 10, 15 yrs
• Contralateral breast cancer
• Common toxicities vasomotor/ urogenital
• Serious toxicities uterine cancer / DVTPE
• End organ effects bone/ lipid/ cognitive/ other
• Incidence of other cancers colon/uterus

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Aromatase Inhibitors in Breast Cancer - Status

• 1st and 2nd line ET for MBC
• Pre-operative therapy for SR tumors
• Cross-sensitivity and non-cross resistance
  toother ET
• HER2 predictor of response to AIs in ER
  tumors?
• Awaiting results in the adjuvant setting of
  combined and sequential use of AIs several
  large trials ongoing. Tamoxifen still first
  choice.
• Few trials in DCIS

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Backup Slides
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Inhibition of Aromatase in Cell Systems in Vitro
Anastrozole
Letrozole
40
30
30
Relative potency
18
20
14
12
10
2
1
1
1
1
1
0
Hamster ovary cells
Human breast fibroblasts
Human MCF-7Ca cancer cells
Human JEG-3 cancer cells
Placental aromatase cell-free
Bhatnagar et al. J Steroid Biochem Mol Biol.
2001.199-202.
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Letrozole vs. Anastrozole Time to Progression

• Letrozole Anastrozole (n356) (n357)
• Median TTP (mo) 5.7 5.790 CI 5.1-6.0 4.6-6.1
• Hazard ratio (adjusted) 1.0190 CI 0.88-1.16P
  value 0.920

Note A hazard ratio of lt1 denotes a lower risk
of progression with letrozole,while a hazard
ratio gt1 denotes a lower risk of progression
with anastrozole. Adjusted on baseline covariates
of receptor status and dominant site of disease.
Analysis based on Cox proportional hazards
regression model.
66
Letrozole vs AnastrozoleResponse Rate
Note An odds ratio gt1 favors letrozole, while an
odds ratio lt1 favors anastrozole. Adjusted
analysis based on baseline covariates of receptor
status and dominant site of disease. Analysis
based on logistic regression model.
67
Independent Peer Review

• A blinded independent peer review was performed
  retrospectively in 2 centers, each with 2
  reviewers
• University of Tübingen (Tübingen, Germany)
• Jens Huober, MD
• Katja Siegmann, MD
• Mount Vernon Hospital (London, UK)
• Andreas Makris, MD
• Anwar Padhani, MB, MRCP, FRCR

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FEM-INT-01 Summary of Adverse Events
No. of Patients ()
Letrozole Anastrozole
(n356) (n356) A.E. gt2 Bone
pain 53 (15) 47 (13) Dyspnea 37 (10) 40 (11) Nau
sea 28 (8) 39 (11) Vomiting 23 (7)
19 (5) Abdominal pain 15 (4) 20 (6) Any
serious A.E. 68 (19) 63 (18) Discontinuations
due to A.E.s 28 (8) 28 (8)
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Budzar et al. Cancer. 199779730.
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Demissies. J Clin Oncol. 200119322.
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Holli et al. J Clin Oncol. 2000183487.
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Nabholtz et al. J Clin Oncol. 2000183758.
Mouridsen et al. J Clin Oncol. 2001192596.
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Strongly agree Agree Neither Disagree 30
(51) 24 (41) 5 (8) 0 (0) SAA versus
ND Plt0.00001
84
Summary
Aminoglutethimide Progestogens Tamoxifen
SERMs Exemestane Anastrozole Letrozole