Transcript ATAC issues

The ‘Arimidex’, Tamoxifen
Alone or in Combination
(ATAC) trial: Completed
Treatment Analysis
Questions & Answers /
Issues Management
Survival and
distant recurrence
Q1: If ‘Arimidex’ is a superior drug compared
with tamoxifen, why did it not show a survival advantage
in this ‘definitive’ 5-year analysis?
Q1: If ‘Arimidex’ is a superior drug compared
with tamoxifen, why did it not show a survival advantage
in this ‘definitive’ 5-year analysis?
 ‘Arimidex’ maintains the considerable survival
benefit already established for tamoxifen in this
setting
 Primary endpoints of ATAC, DFS and
tolerability, were both significantly in favour of
‘Arimidex’
– Overall survival was a secondary endpoint
– Trial was not statistically powered for survival
– Non-inferiority was clearly demonstrated for
‘Arimidex’ based on upper CI < 1.25
Q1: If ‘Arimidex’ is a superior drug compared
with tamoxifen, why did it not show a survival advantage
in this ‘definitive’ 5-year analysis?
 Absence of a benefit at this point is not
unexpected !
 Large randomised studies versus placebo take a
long time to detect a significant advantage in
overall survival
– in the early 1980s it was widely but mistakenly believed
that adjuvant tamoxifen did not affect survival
– NSABP P14 (n=2644) took 7 years to detect a significant
survival advantage for tamoxifen over placebo*
*Fisher
et al. J Nat Cancer Inst 2001; 93: 684-690
Q1: If ‘Arimidex’ is a superior drug compared
with tamoxifen, why did it not show a survival advantage
in this ‘definitive’ 5-year analysis?
 ATAC compares 2 active treatments, therefore it
is likely to take even longer to detect a
meaningful difference
 Prognostic factors are also important
– many patients in ATAC had good prognoses
 61% of patients were lymph node negative
 64% of patients had tumours  2 cm
 It is therefore still too early to expect a significant
survival difference between treatment arms at
this time
Time to recurrence or death in the
first 10 years after surgery*
Recurrence
Patients 100
(%)
80
Node positive
Node negative
Death
100
80
60
60
40
40
20
20
0
0
0–5 years 5–10 years
Node positive
Node negative
0–5 years 5–10 years
 Most recurrences occur during the first 5 years after surgery,
but most deaths occur during the second 5 years after surgery
*EBCTCG. Lancet 1998; 351: 1451–1467
Why did ‘Arimidex’ not show a
survival advantage over tamoxifen in
ATAC trial?
64% of
In the NSABP B141 (n=2644) it took 7 years
to patients
detect had
tumours
a survival advantage for tamoxifen over
placebo<2 cm in diameter
61% of patients were
lymph node-negative
It is too
early to see a
survival
advantage!
There was no difference in survival
The ATAC
trial population had
between ‘Arimidex’
and tamoxifen
a at
relatively
good prognosis
in the ATAC trial
68 months
0
1
2
3
4
Follow-up time (years)
1Fisher
5
6
7
B et al. J Natl Cancer Inst 1996;88:1529-1542
Q1: If ‘Arimidex’ is a superior drug compared
with tamoxifen, why did it not show a survival advantage
in this ‘definitive’ 5-year analysis?
 There is already a non-significant trend for
reduction in breast cancer mortality with
‘Arimidex’
 This together with the significant
reductions in DFS and TTDR strongly
suggest a benefit in breast cancer survival
will be observed with time
Q2: If the HR+ve population is more clinically relevant than
the ITT population, why isn’t the difference for TTDR
significantly in favour of ‘Arimidex’ for these patients?
Q2: If the HR+ve population is more clinically relevant than
the ITT population, why isn’t the difference for TTDR
significantly in favour of ‘Arimidex’ for these patients?
 The difference in TTDR between treatment arms
was not significant in the HR+ve population in the
ATAC trial (p=0.06)
 TTDR data depends on distant recurrence events
– As expected, the HR+ve population respond better to
treatment and therefore there are fewer recurrences
in these patients (~ 100 fewer events per arm)
– The HR+ve population is also smaller than the
ITT population
– Therefore there are currently insufficient events to detect a
significant difference
HR+ve=hormone receptor-positive; ITT=intent-to-treat;
TTDR=time to distant recurrence
Recurrence events by patient population
Endpoint
ITT population
HR+ve population
‘Arimidex’ (A) n=3125;
Tamoxifen (T) n=3116
‘Arimidex’ (A) n=2618;
Tamoxifen (T) n=2598
Events
A vs T
HR
A vs T
p-value
Events
A vs T
Recurrence
or death
575 vs 651
0.87
0.01
424 vs 497
0.83
0.005
Recurrence
402 vs 498
0.79
0.0005
282 vs 370
0.74
0.0002
Distant
recurrence
324 vs 375
0.86
0.04
226 vs 265
0.84
0.06
35 vs 59
0.58
0.01
26 vs 54
0.47
0.001
Contralateral
breast cancer
p-value
HR
A vs T
 The HR for TTDR is more in favour of ‘Arimidex’ in the
HR+ve population (0.84) than the ITT population (0.86)
 This difference is expected to reach significance over time
as more events are observed
HR=hazard ratio; HR+ve=hormone receptor-positive; ITT=intent-to-treat
Subgroup analyses
Q3: There are certain subgroups of patients who appear to
derive little or no benefit from ‘Arimidex’ over that seen with
tamoxifen – should I limit my prescribing accordingly?
Q3: There are certain subgroups of patients who appear to
derive little or no benefit from ‘Arimidex’ over that seen with
tamoxifen – should I limit my prescribing accordingly?
Time-to-recurrence by subgroup
Nodal status
+ve
-ve
 ‘Arimidex’ is indicated for
all postmenopausal
patients with hormonesensitive disease
unknown
Tumour size
 There is no subset of
women in the ATAC trial in
which tamoxifen confers
greater benefit
? 2 cm
>2 cm
unknown*
Receptor status
+ve
-ve
unknown
Previous
chemotherapy
yes
no
All patients
Intent-to-treat population
Hazard ratio (A:T) and 95% CI
0.40
*confidence limit extends beyond plot
0.60
0.80
‘Arimidex’ (A) better
1.00
1.25 1.50 1.75
Tamoxifen (T) better
 The treatment effect is
consistent across baseline
prognostic factors, with no
heterogeneity for any
subgroup
Q3: There are certain subgroups of patients who appear to
derive little or no benefit from ‘Arimidex’ over that seen with
tamoxifen – should I limit my prescribing accordingly?
 ATAC was NOT powered to detect differences in
subgroups
 All subgroup analyses such as these are
exploratory
– Findings should not be over-interpreted or influence
patient selection unless they are clearly contradictory of
the overall conclusion
 It should be the overall result of ATAC which
influences clinical practice not a retrospective,
exploratory subgroup analysis
Q4: Did patients who received adjuvant chemotherapy
receive the same benefits as those who did not? Early
results suggested that ‘Arimidex’ conferred no
additional benefit over tamoxifen in this subgroup
Q4: Did patients who received adjuvant chemotherapy
receive the same benefits as those who did not? Early
results suggested that ‘Arimidex’ conferred no
additional benefit over tamoxifen in this subgroup
 Approximately 20% of patients in the ATAC trial received
prior chemotherapy
 The first analysis (33 months) revealed a potential
difference in outcomes based on prior chemotherapy
 The updated analysis (47 months) detected a detrimental
HR only for patients who had received CMF (suboptimal?), but not for those receiving anthracyclines or
taxanes
 The ATAC completed treatment analysis (68 months)
found no interaction between ‘Arimidex’ and prior
chemotherapy
Time-to-recurrence by chemotherapy usage
2001
Overall
Chemotherapy no
Chemotherapy yes
2002
Overall
Chemotherapy no
Chemotherapy yes
2004
Overall
Chemotherapy no
Chemotherapy yes
Intent-to-treat population
Hazard ratio (A:T) and 95% CI
0.6
0.8
1.0
‘Arimidex’ (A) better
1.2
1.4
1.6
Tamoxifen (T) better
The efficacy of ‘Arimidex’ is superior to
that of tamoxifen regardless of any
baseline prognostic factor or prior
adjuvant treatment
Nodal status, PgR status or prior
adjuvant chemotherapy is not a
reason for denying patients
‘Arimidex’ !
Long-term safety data
Q5: Why were there more non-breast cancer-related deaths
with ‘Arimidex’ compared with tamoxifen?
Q5: Why were there more non-breast cancer-related deaths
with ‘Arimidex’ compared with tamoxifen?
 There were a total of 831 deaths at the time of this
analysis
– 500 (60%) breast cancer deaths
– 331 (40%) non-breast cancer deaths
 Overall survival was similar in both treatment arms
 Numerically, more deaths overall were seen in the
tamoxifen group.
 However, there were more deaths before
recurrence (non-breast cancer deaths) in the
‘Arimidex’ group
Q5: Why were there more non-breast cancer-related deaths
with ‘Arimidex’ compared with tamoxifen?
 The difference in the number of non-BC deaths
between ‘Arimidex’ and tamoxifen is small and does
NOT represent a safety concern
 Review of the data shows that these deaths before
recurrence were spread across a variety of
apparently causes and no link to ‘Arimidex’ was
found
– There is no increase in any one particular cause of death
– The majority were not considered related to study therapy
and occurred after patients had completed or discontinued
treatment
– There is no increase in the number of deaths with longer
drug exposure
Q5: Why were there more non-breast cancer-related deaths
with ‘Arimidex’ compared with tamoxifen?
 The imbalance is not unexpected!
 Due to the significantly reduced number of
withdrawals due to adverse events and
disease recurrence compared with tamoxifen,
more patients stay on ‘Arimidex’ for longer
 These patients therefore become at higher
risk of death from other causes!
Q6: What are the risks of experiencing bone fractures on
‘Arimidex’ compared with tamoxifen?
Q6: What are the risks of experiencing bone fractures on
‘Arimidex’ compared with tamoxifen?
 Fracture risk increases with postmenopausal status
and increasing age
– in postmenopausal women, fractures due to osteoporosis
typically occur in the spine, hip and wrist
– fractures of the hip have a high morbidity and mortality
 Tamoxifen is known to have ‘bone-protecting’ effects,
due to its partial oestrogen-agonist mode of action
 Important to establish the risk:benefit ratio for
‘Arimidex’ vs tamoxifen as adjuvant therapy in
postmenopausal women
Q6: What are the risks of experiencing bone fractures on
‘Arimidex’ compared with tamoxifen?
 The fracture risk with ‘Arimidex’ is predictable and
manageable
 The RR of fracture remains steady, stabilising after
2 years, and shows no evidence of worsening
over time
– the ATAC Completed Treatment Analysis shows that the OR of
fracture was 1.49; the RR was 1.60 in previous analyses
– importantly, there is no significant difference between ‘Arimidex’
and tamoxifen for fractures of the wrist, or even hip
– spinal fractures were more frequent with ‘Arimidex’ but these are
vertebral compression fractures
OR=odds ratio; RR=relative risk
Stability of fracture rates over time
6-monthly
1.8
fracture rates/ 1.6
100 patients
1.4
‘Arimidex’ 1 mg od
Tamoxifen 20 mg od
1.2
Wrist, spine and hip fracture rates
measured at 6-monthly intervals
1.0
0.8
0.6
0.4
0.2
0
6
12
18
24
30
Months
36
42
48
 Fracture rates stabilise after 2 years of treatment and
relative risk remains constant
Locker, Eastell. Proc ASCO 2003; Abs 98
Indirect fracture rate comparison
 Fracture rates in the ATAC trial fall within the broad range of
fracture rates in other large trials or surveys, indicating that
any increase associated with ‘Arimidex’ is modest
Clinical
study
Setting
Average age (years)
Fracture rate/1000
patient years
ATAC
(n=6186)
Early breast cancer (adjuvant)
Age = 64 (mean)
‘Arimidex’ = 22.6
Tamoxifen = 15.6
PI
(n=13,175)
Breast cancer prevention
Age = 35-49 (39%), >50 (61%)
Tamoxifen = 18.05
Placebo = 18.40
WHI
(n=16,608)
Healthy women
Age = 63 (45% 50-69)
HRT (total) = 14.75
Placebo (total) = 19.10
ATAC Trialists’ Group, 2004; Fisher et al. J Natl Cancer Inst 1998; 90:
1371–1388; Women's Health Initiative Writing Group. JAMA 2002; 288: 321–333
Standard care for all postmenopausal
women: osteoporosis guidelines
 Recommend healthy lifestyle changes
– smoking cessation
– moderating caffeine and alcohol intake
– regular weight-bearing exercise
– calcium and vitamin D supplements
 Screen for osteoporosis risk factors
 DXA scan on all patients with risk factors
 Bone health is manageable
2002 clinical practice guidelines for the diagnosis and management
of osteoporosis in Canada, CMAJ 2002; 167
ASCO Tech Assessment 2004:
“Aromatase inhibitor–associated bone loss may
represent a preventable and treatable condition”
 Clinical trial evidence indicates that bisphosphonates are
effective in maintaining bone density in breast cancer patients
on hormonal therapy
 In otherwise healthy women, a strong body of evidence
supports early detection and therapy of osteoporosis
 The ASCO bisphosphonate guideline identifies
postmenopausal breast cancer patients on AIs to be at high
risk for osteoporosis and recommends baseline BMD
evaluation.
 It is hoped that implementation of these guidelines will reduce
fracture rates associated with adjuvant AI use
 Based on recent results and ongoing studies, adjuvant
bisphosphonates may become a more standard component of
the treatment of women with early-stage breast cancer