Transcript Clinical trial work from the Austrian Breast & Colorectal Cancer

Anastrozole (‘Arimidex’):
a new standard of care?
Professor Gershon Y. Locker
Northwestern University Feinberg
School of Medicine, Evanston, IL, USA
ASCO technology assessment 2004
 Recommended a fundamental change in standard
clinical practice
 Five years’ tamoxifen should no longer be the
standard treatment choice for patients with EBC
 “Adjuvant hormonal therapy for postmenopausal
women with HR+ve breast cancer should include
an AI in order to lower the risk of tumour
recurrence”
– “Neither MA.17 or IES trials addressed the use of an AI as
initial therapy” nor the option of planning at the time of initial
diagnosis to switch to, or sequence, an AI after tamoxifen
ASCO = American Society of Clinical Oncology;
EBC = early breast cancer; HR = hormone receptor;
AI = aromatase inhibitor
Winer EP et al. J Clin Oncol 2005; 23, in press
Data covered in the ASCO
technology assessment 2004
 ATAC
– 47 month update, 2002 analysis
 ITA
 IES
 MA.17
ASCO = American Society of Clinical Oncology
Winer EP et al. J Clin Oncol 2005; 23, in press
New data not addressed in the ASCO
technology assessment 2004
ATAC completed treatment analysis
(68 month, 2004 analysis)
BIG 1-98
ABCSG 8/ARNO 95
ASCO = American Society of Clinical Oncology
Winer EP et al. J Clin Oncol 2005; 23, in press
ATAC Trialists’ Group. Lancet 2005; 365: 60–62
Key unresolved questions from the
ASCO technology assessment 2004
Include:
– are the AIs most effective:
 if used as initial therapy?
 or after exposure to tamoxifen?
– what are the long-term toxicities and
risks associated with AIs?
ASCO = American Society of Clinical Oncology
Winer EP et al. J Clin Oncol 2005; 23, in press
What have we learned from the ATAC
completed treatment analysis?
 Anastrozole demonstrates significant and
consistent long-term efficacy benefits over
tamoxifen in the adjuvant treatment of
postmenopausal women with EBC
– significantly reduced risk of local and distant recurrence
 Anastrozole has a significantly better and
consistent long-term tolerability profile than
tamoxifen
 Anastrozole is the most effective adjuvant
treatment for EBC
– anastrozole has a known risk-benefit profile over the full
5 years’ treatment
EBC = early breast cancer
The ATAC Trialists’ Group. Lancet 2005; 365: 60–62
Efficacy analysis: ITT and HR+ populations
Disease-free survival
Time to recurrence
ITT population
HR+ population
Time to distant recurrence
Overall survival
Time to breast cancer death
Contralateral breast cancer
0.2
0.4
0.6 0.8 1.0 1.2 1.5 2.0
Hazard ratio (A:T) and 95% CI
Anastrozole (A) better
ITT = intent-to-treat
HR+ = hormone receptor-positive
Tamoxifen (T) better
ATAC Trialists’ Group. Lancet 2005; 365: 60–62;
Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1
Analysis of time to
recurrence for subgroups
Nodal status
+ve
-ve
Tumour size
≤ 2 cm
>2 cm
Receptor
status
+ve
-ve
unknown
Previous
chemotherapy
yes
no
All patients
0.40
Hazard ratio (A:T) and 95% CI
*HR+=hormone receptor positive
0.60
0.80 1.00
Anastrozole better
1.25 1.501.75
Tamoxifen better
Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1
ATAC: summary of efficacy endpoints
 In the overall ITT population, compared
with tamoxifen, anastrozole significantly
reduced risk of:
– all events: 13% (p=0.01)
– recurrence: 21% (p=0.0005)
– distant recurrence: 14% (p=0.04)
– contralateral recurrence: 42% (p=0.01)
Anastrozole demonstrates superior
efficacy to tamoxifen
 Anastrozole is more effective than tamoxifen in
reducing the risk of recurrence, distant
recurrence and contralateral breast cancer
 The absolute difference between anastrozole and
tamoxifen continues to increase over time, and
extends beyond completion of treatment
 As expected for this population, overall survival
is similar for both treatments, with a trend in
favour of anastrozole for breast cancer death
 There are no significant subgroup interactions
ATAC Trialists’ Group. Lancet 2005; 365: 60–62;
Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1
Added benefit versus tamoxifen
EBCTCG
ATAC
Benefit for
tamoxifen vs
placebo
Additional benefit
of anastrozole vs
tamoxifen
Reduction in risk of
recurrence
50%
26%
Reduction in risk of breast
cancer mortality
28%
13%
Reduction in risk of
contralateral breast cancer
47%*
53%
Hormone receptor-positive
population
*hormone receptor-positive and -negative patients
EBCTCG = Early Breast Cancer Trialists’ Collaborative Group
Added benefit versus tamoxifen
38% risk of recurrence with no adjuvant treatment
50% risk reduction with tamoxifen
Further 26% risk
reduction with
anastrozole
Overview of adverse events*
Anastrozole (%) Tamoxifen (%)
(n=3092)
(n=3094)
p-value
All adverse events
93.9
94.6
0.2
Adverse events leading to
withdrawal
11.1
14.3
0.0002
6.5
8.9
0.0005
33.3
36.0
0.03
Serious adverse events
leading to withdrawal
4.7
5.9
0.04
Serious adverse events
leading to death
3.3
3.6
0.6
Drug-related serious adverse
events leading to death
0.2
0.3
0.5
Drug-related adverse events
leading to withdrawal
All serious adverse events
*Adverse events on treatment or within 14 days of discontinuation
Pre-defined adverse events*
Hot flushes
Joint disorders
Vaginal bleeding
Vaginal discharge
Endometrial cancer**
Fractures***
Ischaemic cerebrovascular event
Venous thromboembolic events
Deep venous thromboembolic events
0.2
0.4
0.6
In favour of anastrozole
0.8 1.0
1.5
2.0
In favour of tamoxifen
Odds ratio (anastrozole / tamoxifen)
*Adverse events on treatment or within 14 days of discontinuation; **Excludes patients with prior
hysterectomy and includes on- and off-therapy AEs; ***Fractures occurring at anytime prior to
recurrence (includes patients no longer receiving treatment)
ATAC Trialists’ Group. Lancet 2005; 365: 60–62
ATAC: tolerability and safety summary
 Compared with tamoxifen, anastrozole is associated with
significantly fewer:
– SAEs, treatment-related AEs and withdrawals due to SAEs or AEs
– potentially life-threatening AEs such as endometrial cancer,
thromboembolic, and cerebrovascular events
 No new safety concerns have emerged with long-term followup
 Anastrozole now has a known, predictable and manageable
safety profile
Only anastrozole has a tolerability profile of this
robustness and maturity, as it covers more than
5-years’ follow-up from 3 analyses
AEs = adverse events;
SAEs = serious AEs
The ATAC Trialists’ Group. Lancet 2005; 365: 60–62;
Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1
ABCSG 8/ARNO 95:
summary of efficacy endpoints
 Switching from tamoxifen to anastrozole at
2 years is superior to continuing on tamoxifen in
terms of:
– EFS (HR=0.60; p=0.0009)
– DRFS (HR=0.61; p=0.0067)
– Data are not yet sufficiently mature to show a
significant difference in OS
 The benefits of switching to anastrozole are seen
regardless of baseline prognostic factors
EFS = event free survival
DRFS = distant recurrence free survival
When to treat?
 Recurrence rates in EBC are highest in
the first 5 years after surgery, with a peak
at 2 years, regardless of baseline
prognostic factors
 Tamoxifen is associated with higher rates
of recurrence, AEs and withdrawals than
anastrozole
 Substantial benefit with anastrozole in the
first 3 years justifies offering the most
effective therapy at the earliest
opportunity
EBC = early breast cancer; AEs = adverse events
Annual hazard of recurrence
Hazard of 25
recurrence
by yearly
20
interval
15
10
5
0
0.5
1.5
2.5
3.5
4.5
5.5
6.5
7.5
8.5
9.5
10.5
Year
Saphner et al. J Clin Oncol 1996; 14: 2738–2746
Smoothed hazard rates for recurrence
(ITT population)
Annual
hazard
rates
(%)
3.0
2.5
2.0
1.5
1.0
Anastrozole
Tamoxifen
0.5
0
0
ITT = intent-to-treat
1
2
3
4
Follow-up time (years)
5
6
ATAC Trialists’ Group. Lancet 2005; 365: 60–62;
Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1
Use the best drug first
Estimated
100
proportion of
receptor-positive
patients without 90
recurrence (%)
ATAC
ATAC
switching
from
tamoxifen
80
EBCTCG
after 5 years’
tamoxifen
Control (EBCTCG)
Tamoxifen (EBCTCG)
70
EBCTCG
Anastrozole (ATAC)
Tamoxifen (ATAC)
0
0
1
2
3
4
5
Years
Comparison with Early Breast
Cancer Trialists’ Collaborative
Group (EBCTCG): receptor-positive
patients >50 years
ATAC Trialists’ Group. Lancet 2005; 365: 60–62;
EBCTCG. Lancet 1998; 351: 1451–1467
Summary
 5 years of tamoxifen alone is no longer the
optimum treatment choice for EBC1
 ATAC completed treatment analysis confirms the
benefits of anastrozole as initial adjuvant
therapy2
 For patients already receiving initial adjuvant
tamoxifen switching studies3,4 and extended
adjuvant studies5 suggest it is reasonable to
switch these patient to an AI after 2–3 or 5 years
1. Winer EP et al. J Clin Oncol 2005; 23, in press;
2. ATAC Trialists’ Group. Lancet 2005; 365: 60–62;
3. Boccardo et al. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6;
4. Coombes et al. NEJM 2004; 350: 1081–1092;
5. Goss et al. NEJM 2003; 349: 1793–1802
Conclusion
 Higher rates of recurrence, increased
AEs and treatment withdrawals with
tamoxifen support the use of the best
treatment first
 5 years of anastrozole should now be
considered as the preferred initial
adjuvant endocrine treatment for
postmenopausal women with hormone
receptor-sensitive EBC