Transcript Clinical trial work from the Austrian Breast & Colorectal

Start or Switch?:
Latest data from ABCSG/ARNO
Adjuvant endocrine therapy for
early breast cancer
 Recent trial data has challenged tamoxifen’s
position as the gold standard adjuvant therapy1
 The ATAC trial has shown that anastrozole
provides a new standard of care for newlydiagnosed postmenopausal women
 Anastrozole significantly decreases the risk of
recurrence, distant recurrence and contralateral
breast cancer and has a significantly better
tolerability profile
1ATAC
Trialists’ Group Lancet 2005; 365: 60–62
Unanswered questions in adjuvant
therapy for early breast cancer
 Would postmenopausal patients already
receiving tamoxifen benefit from switching
to AI therapy?
 Are AIs more effective if used as initial
treatment or sequential to tamoxifen?
 Could premenopausal women with breast
cancer also benefit from AI therapy?
Switching trials: evidence from
8,414 postmenopausal women
Italian Tamoxifen Anastrozole (ITA) trial
International Exemestane Study (IES)
ABCSG 8/ARNO 95 combined analysis
ITA: study design
 All women were:
– postmenopausal
– hormone receptor positive
– node positive
Surgery
± RT
± Chemo
Tamoxifen (n=448)
2–3 years
Tamoxifen (n=225)
Therapy blinded at
randomization to A or T
Anastrozole (n=223)
3–2 years
 Women were regularly followed until they reached a major trial endpoint
that included any of the following:
– disease recurrence
– second primary tumour (including a second breast tumour)
– death (from any cause)
Boccardo F et al. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6–S7 (abs 3)
ITA: disease-free survival
Proportion
disease-free
1.0
0.8
0.6
0.4
Anastrozole
Tamoxifen
0.2
No. of pts
223
225
Obs
17
45
p-value
0.0002
0.0
0
1
2
3
Years
4
5
6
Boccardo F et al. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6–S7 (abs 3)
IES: trial design
Diagnosis of breast cancer and
treatment for primary disease
2–3 years’ tamoxifen
Years from
randomisation
0
2
RANDOMISED
n=4742
3
2–3 years’
tamoxifen
n=2380
2-3
Years from start
of tamoxifen
0
2–3 years’
exemestane
n=2362
Patients followed-up
5
Coombes RC et al. N Engl J Med. 2004; 350: 1081–1092
IES: disease-free survival
100
Proportion
disease-free (%)
75
Hazard ratio = 0.68 (95% CI: 0.56–0.82)
Log rank test: p-value < 0.001
50
25
Exemestane
Tamoxifen
0
0
No. of events/at risk:
Exemestane
0/2362
Tamoxifen
0/2380
†events
1
2
3
Years from randomisation
52/2168
78/2173
60/1696
90/1682
44/757
76/730
4
20+6†/201
18+4†/185
occurring more than 4 years after randomisation
Coombes RC et al. N Engl J Med. 2004; 350: 1081–1092
ABCSG 8/ARNO 95 combined analysis
 Aim: to prospectively assess whether
switching from tamoxifen to anastrozole
after 2 years is more effective than
continuing on tamoxifen
 Pre-planned combined analysis of ABCSG 8
(Austria) and ARNO 95 (Germany)
 Patients: postmenopausal women with
hormone receptor-positive EBC
 Median 28 months’ follow-up
ABCSG 8/ARNO 95:
Combined analysis trial structure
Primary
surgery
+/- RTx
+ TAM
2 years
Total
patients
n=3224
TAM 3 years
n=1606
ABCSG 8
n=2262
+
ARNO 95
n=962
ANA 3 years
n=1618
Patient demographics
TAM
n=1606
%
ANA
n=1618
%
T1
69.7
70.2
Node negative
74.0
74.2
Breast conservation
77.3
76.4
G1,2,x
93.7
95.2
39.9
38.6
81.1
81.3
18.3
18.1
0.6
0.6
Age < 60 yrs
ER+/PgR+
ER+/PgRER-/PgR+
Gx = lobular carcinoma
Event-free survival
Event- 100
free
survival 95
(%)
ANA
90
TAM
85
80
ANA vs TAM
p=0.0009 HR 0.60 [95% CI 0.44–0.81]
75
0
0
1
At risk:
1606
1217
TAM
1618
1243
ANA
Zero point = 2 years after surgery
2
3
EFS time in years*
858
593
874
623
4
5
343
375
176
178
Localisation of events
Events
Locoregional
Contralateral BC
Distant recurrences
Total
n=3224
TAM
n=1606
ANA
n=1618
177
44
28
121
110
24
16
75
67
20
12
46
Events occuring simultaneously are included twice
Distant recurrence-free survival
100
Distant
recurrencefree survival 96
(%)
ANA
92
TAM
88
ANA vs TAM
p=0.0067 HR 0.60 [95% CI 0.42–0.88]
84
0
0
At risk:
TAM
ANA
1606
1618
1
1224
1247
Zero point = 2 years after surgery
2
3
DRFS time in years
869
879
600
631
4
5
351
382
181
181
Subgroup analysis of EFS*
3224
All patients
Nodal status
Grading
Age
Receptor (ER / PR)
n
-ve
+ve
2389
G1, G2, Gx
G3
3044
<60 years
>60 years
1265
+ve / +ve
+ve / -ve
2519
*Events: locoregional, metastatic
and contralateral recurrences
833
167
1959
564
ANA better TAM better
Hazard ratio (ANA vs TAM)
Tolerability data from ABCSG 8
 Both treatments were well tolerated
 The incidence of prespecified side effects was
low in both groups
 As expected, there were significantly more
fractures in patients switching to anastrozole:
27 (2.4%) vs 14 (1.2%) for tamoxifen
 No significant difference between treatments was
seen in gynaecological side effects because – as
seen in ATAC – these generally occur soon after
starting tamoxifen
ABCSG 8/ARNO 95: Summary
 These data confirm results from ITA and IES
 Switching from TAM to ANA at 2 years is
superior to continuing on TAM in terms of:
– EFS (HR=0.60)
– DRFS (HR=0.61)
– Data are not yet sufficiently mature to show a
significant difference in OS
 The benefits of switching to ANA are seen
regardless of baseline prognostic factors
 Both treatments are well tolerated
Conclusions
ATAC: initial adjuvant therapy with
anastrozole is superior to tamoxifen
ABCSG/ARNO: switching to
anastrozole after 2 years is superior
to remaining on tamoxifen
Which of these treatment strategies is
more effective?
Can these benefits of anastrozole in
postmenopausal women be translated
into the premenopausal setting?
What do we know to date?
 Premenopausal women:
– Benefit from adjuvant tamoxifen alone or in
combination with goserelin
– Combining an LHRHa and tamoxifen confers better
efficacy than LHRHa alone in advanced disease
If a patient is rendered postmenopausal, could she
also be eligible from the added benefit of
anastrozole?
Jakesz et al JCO 2002;20:4621-4627
Klijn et al. JCO 2001; 343–353
Klijn et al. JNCI 2000; 92: 903–911
Bonneterre et al. Cancer 2001; 92: 2247–2258
ATAC Trialists Group. Lancet 2005; 365: 60–62
Goserelin plus anastrozole
in 2nd line ABC
• Patients deriving clinical benefit from goserelin plus
Mean serum oestradiol (pmol/L)
tamoxifen received goserelin plus anastrozole on progression
250
p<0.0001
200
150
100
p<0.0001
50
0
Baseline
Goserelin + Goserelin +
Tamoxifen Anastrozole
Forward DP et al. Br J Cancer 2004; 90: 590–594
Clinical benefit
N=16
n (%)
Partial response [PR]
1 (6)
Stable disease [SD] 6 months
9 (56)
Biochemical response [BR]*
2 (13)
Clinical benefit (CB; PR + SD 6 months + BR) rate
75%
*no evidence of progression beyond 6 months with decreasing blood tumour markers
 Median duration of clinical benefit 17 months (range 6-47)
Forward DP et al. Br J Cancer 2004; 90: 590–594
Goserelin plus anastrozole
in 1st line ABC
 Phase II trial of 22 patients whose E2 was decreased
to postmenopausal levels with goserelin and then
received anastrozole
Objective response
Complete response
Partial response
Stable disease 6 months
Clinical benefit
Patients (%)
28
6
22
44
72
 To date median TTP = ~10 months
Carlson R et al. Breast Cancer Res Treat 2004; 88 (Suppl 1):S237–238, abs 6052
ABCSG 12: trial structure
• 3 years adjuvant endocrine treatment +/- bisphosphonate
therapy
• premenopausal HR-positive patients
Anastrozole 1 mg/d
OP
Random
1:1:1:1
Anastrozole 1 mg/d
Zoledronic acid 4 mg/d q 6 Mo
Goserelin
3.6 mg q 4W
Tamoxifen 20 mg/d
Tamoxifen 20 mg/d
Zoledronic acid 4 mg/d q 6 Mo
Accruals
Target:
Status:
1800 (450/arm)
1372 (Jan. 11, 2005)
Conclusions
 4 trials have reported data suggesting that
postmenopausal women receiving adjuvant
tamoxifen should switch to an AI after 2–5
years
 Postmenopausal women currently receiving
tamoxifen are 40% less likely to relapse if
switched to anastrozole after 2 years
compared with continuing on tamoxifen
 For premenopausal women with hormonesensitive EBC, the combination of goserelin
and anastrozole is a promising treatment and
warrants further research