Dr Gnant - ESMO Oral Presentation 08

Zoledronic Acid Improves DFS and RFS in
Premenopausal Women With Early Breast Cancer:
Multivariate Analysis of Efficacy Data From ABCSG-12
Richard Greil, MD
Paracelsus Medical University Salzburg
Salzburg, Austria
1

Questions to Be Answered
• When based on a Goserelin backbone, can
aromatase inhibitors improve clinical outcome
compared with tamoxifen?
• Can bisphosphonates added to endocrine
therapy further improve outcome?
2

Rationale for Investigating AIs for Premenopausal
Endocrine-Responsive Breast Cancer
• Aromatase inhibitors (AIs) have superior efficacy
compared with tamoxifen for postmenopausal
endocrine-responsive breast cancer 1-7
– Significantly prolong disease-free survival (DFS)
– Significantly reduce distant recurrence
• ANA plus goserelin significantly reduced mean
estrogen levels in premenopausal women who
experienced disease progression during treatment
with goserelin plus TAM (P < .0001) 8
– TAM + goserelin reduced estrogen by 89%
– ANA + goserelin further reduced estrogen by an additional 76%
ANA = Anastrozole; TAM = Tamoxifen.
1. Howell A, et al. Lancet. 2005;365:60-62; 2. Thurlimann B, et al. N Engl J Med. 2005;353:2747-2757; 3. Coates A, et al. J Clin
Oncol. 2007;25:486-492; 4. Coombes RC, et al. N Engl J Med. 2004;350:1081-1092; 5. Coombes RC, et al. Lancet.
2007;369:559-570; 6. Jakesz R, et al. Lancet. 2005;366:455-462; 7. Goss P, et al. J Natl Cancer Inst. 2005;97:1262-1271;
8. Forward DP, et al. Br J Cancer. 2004;90:590-594.
3

Zoledronic Acid Can Inhibit the Process of
Metastasis at Several Key Steps
Primary tumor
Synergy with
anticancer drugs
Inhibits
angiogenesis
Angiogenesis
Metastases Micrometastases
Adhesion &
extravasation
Adapted from Mundy GR, et al. Nature Reviews Cancer. 2002;2:584-593.
Direct antitumor effect Indirect antitumor effect
Induces
tumor cell
apoptosis
Stimulates immune
surveillance
Invasion
Decreases
matrix invasion
Decreases
adhesion to bone
Arrest in distant
capillary
4

ABCSG-12 Trial Design
• Accrual 1999-2006
• 1,803 premenopausal breast cancer pts
• Endocrine-responsive (ER + and/or PgR + )
• Stage I and II, < 10 positive nodes
• No chemotherapy except neoadjuvant
• Treatment duration: 3 years
Surgery
(+ RT)
Goserelin
3.6 mg q 28 d
DFS = Disease-free survival; RFS = Relapse-free survival;
OS = Overall survival; BMFS = Bone metastasis-free survival;
TAM = Tamoxifen; ANA = Anastrozole; ZOL = Zoledronic acid.
Randomize
1 : 1 : 1: 1
2 Key Comparisons:
TAM vs ANA
ZOL vs no ZOL
TAM 20 mg/d
TAM 20 mg/d
+ ZOL 4 mg q 6 mo
ANA 1 mg/d
ANA 1 mg/d
+ ZOL 4 mg q 6 mo
5

Study Endpoints (TAM vs ANA; ZOL vs No ZOL)
• Primary endpoint
– Disease-free survival (DFS)
– DFS events: local recurrence, contralateral breast cancer,
distant metastasis, secondary carcinoma, death
• Secondary endpoints
– Recurrence-free survival (RFS): local recurrence,
contralateral breast cancer, distant metastasis,
secondary carcinoma
– Overall survival
– Safety
• Exploratory endpoint
– Bone-metastases–free survival
6

Baseline Demographics and
Disease Characteristics
n, (%)
TAM
(n = 451)
TAM + ZOL
(n = 449)
ANA
(n = 453)
ANA + ZOL
(n = 450)
Median age, years 45.5 45.3 45.0 44.5
≥ T1
T2
338 (75.1) 335 (74.6) 348 (77.0) 339 (75.5)
99 (22.0) 98 (21.8) 93 (20.6) 97 (21.6)
Node negative 301 (66.9) 295 (65.7) 303 (67.0) 302 (67.3)
Node positive 136 (30.2) 138 (30.7) 139 (30.8) 135 (30.1)
ER + / 2+ 217 (48.1) 210 (46.8) 221 (48.8) 211 (46.9)
ER 3+ 204 (45.2) 204 (45.4) 206 (45.5) 210 (46.7)
PgR + / 2+ 212 (47.0) 206 (45.9) 217 (47.9) 190 (42.2)
PgR 3+ 185 (41.0) 195 (43.4) 200 (44.2) 212 (47.1)
Histologic Grade 3 93 (20.7) 89 (19.0) 97 (21.5) 98 (21.0)
Neoadj. Chemo 24 (5.3) 23 (5.1) 24 (5.3) 26 (5.8)
TAM = Tamoxifen; ZOL = Zoledronic acid; ANA = Anastrozole; ER = Estrogen receptor; PgR = Progesterone receptor.
Update of Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4.
7

Trial Status
• 1,803 patients recruited from 1999 to 2006
– Baseline demographics and disease characteristics well
balanced between study arms
• Median follow-up: 48 months
• 137 first DFS events, 42 deaths recorded
– 30 locoregional relapse events
– 70 distant relapse events
• 39 bone metastasis events
– 16 contralateral breast cancer events
– 19 new nonbreast primaries
• Overall: 4-year DFS = 92.4%; 4-year OS = 97.7%
8

ANA Does Not Improve DFS vs TAM
Disease-free survival, %
No. at risk
TAM
ANA
100
90
80
70
60
50
40
30
20
10
No. of Hazard ratio (95% CI)
events vs TAM P value
ANA 72 1.096 (0.78 to 1.53) .593
TAM 65
0 0 12 24 36 48 60 72 84
Time since randomization, months
900 834 718 552 411 243 129 50
903 844 725 540 411 255 139 51
Median follow-up = 48 months.
DFS = Disease-free survival; CI = Confidence interval; ZOL = Zoledronic acid.
Update of Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4.
9

ZOL Significantly Improves DFS Compared
With Endocrine Therapy Alone
Disease-free survival, %
100
90
80
70
60
50
40
30
20
10
0
No. of Hazard ratio (95% CI)
events vs No ZOL P value
ZOL 54 0.643 (0.46, 0.91) .012
No ZOL 83
0 12 24 36 48 60 72 84
Time since randomization, months
No. at risk
No ZOL 904 832 713 537 407 241 145 47
ZOL 899 846 730 555 414 257 123 54
Median follow-up = 48 months.
DFS = Disease-free survival; CI = Confidence interval; ZOL = Zoledronic acid.
Update of Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4.
10

ZOL Significantly Improves RFS Compared
With Endocrine Therapy Alone
Recurrence-free survival, %
100
90
80
70
60
50
40
30
20
10
0
No. of Hazard ratio (95% CI)
events vs No ZOL P value
ZOL 54 0.653 (0.46, 0.92) .014
No ZOL 82
0 12 24 36 48 60 72 84
Time since randomization, months
No. at risk
No ZOL 904 832 713 537 407 241 145 47
ZOL 899 846 730 555 414 257 123 54
Median follow-up = 48 months.
RFS = Recurrence-free survival; CI = Confidence interval; ZOL = Zoledronic acid.
Update of Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4.
11

ZOL-Treated Patients Showed a
Nonsignificant Trend Toward Improved OS
Overall survival, %
100
90
80
70
60
50
40
30
20
10
0
No. of Hazard ratio (95% CI)
events vs No ZOL P value
ZOL 16 0.595 (0.32, 1.11) .101
No ZOL 26
0 12 24 36 48 60 72 84
Time since randomization, months
No. at risk
No ZOL 904 838 735 565 441 265 161 60
ZOL 899 851 744 573 434 270 131 59
Median follow-up = 48 months.
OS = Overall survival; CI = Confidence interval; ZOL = Zoledronic acid.
Update of Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4.
12

Incidence of Bone Metastases Was Reduced
in Patients Receiving ZOL
BMF survival, %
100
99
98
97
96
95
94
93
92
Hazard ratio (95% CI)
Events, n vs No ZOL P value
ZOL 16 0.676 (0.359, 1.272) .224
No ZOL 24
0 12 24 36 48 60 72 84
Time since randomization, months
Median follow-up = 48 months.
BMF = Bone metastases-free; CI = Confidence interval; ZOL = Zoledronic acid.
13

ZOL Reduced Recurrence at All Sites
First event per patient, n
90
80
70
60
50
40
30
20
10
0
2
10
10
41
20
No ZOL vs ZOL
No ZOL ZOL
(n = 904) (n = 899)
DFS = Disease-free survival; ITT = Intent-to-treat; ZOL = Zoledronic acid.
Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4.
0
9
6
29
10
Death without prior recurrence
Secondary malignancy
Contralateral breast cancer
Distant recurrence
Locoregional recurrence
14

ZOL Is Associated With Better DFS and RFS
in a Multivariate Analysis
Therapy
No ZOL vs ZOL
Tumor stage
(T1 vs T2)
Tumor grade
(1/2 vs 3)
Lymph node status
(Negative vs positive)
Progesterone receptor
(neg, +, 2+ vs 3+)*
Disease-free survival
Recurrence-free survival
0 0.25 0.5 0.75 1.0 1.25 1.5 1.75 2.0 2.25 2.5 2.75 3.0
Hazard ratio
Decreased risk Increased risk
Median follow-up = 48 months
DFS = Disease-free survival; RFS = Recurrence-free survival; ZOL = Zoledronic acid.
*Reiner score for staining: + = 10 to 30%; ++ = 31 to 70%; +++ = 71 to 100%
P value
.022
.028
.023
.036
< .001
< .001
< .001
< .001
.001
.001
15

Selected Adverse/Serious Adverse Events*
AE, n (%)
TAM
(n = 435)
TAM + ZOL
(n = 434)
ANA
(n = 436)
ANA + ZOL
(n = 439)
P value
4-group comparison,
Fisher’s exact test
Arthralgia 52 (11.5) 65 (14.5) 112 (24.7) 150 (33.3) < .0001
Bone pain 94 (20.8) 132 (29.4) 128 (28.3) 185 (41.1) < .0001
Fever 9 (2.0) 34 (7.6) 11 (2.4) 46 (10.2) < .0001
Periodontal disease* 5 (1.1) 3 (0.7) 0 (0.0) 6 (1.3) .054
SAE, n (%)
Arthralgia 0 (0.0) 1 (0.2) 0 (0.0) 1 (0.2) .374
Bone pain 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.2) .499
Fever 1 (0.2) 1 (0.2) 1 (0.2) 2 (0.4) .882
Fracture 6 (1.3) 4 (0.9) 4 (0.9) 7 (1.6) .747
Thrombosis 3 (0.7) 5 (1.1) 0 (0.0) 0 (0.0) .012
Uterine polyp 40 (8.9) 51 (11.4) 7 (1.6) 5 (1.1) < .0001
Periodontal disease* 0 (0.0) 1 (0.2) 0 (0.0) 1 (0.2) .374
AE = Adverse event; SAE = Serious adverse event; TAM = Tamoxifen; ANA = Anastrozole; ZOL = Zoledronic acid.
*No confirmed cases of osteonecrosis of the jaw. No case of renal toxicity observed
Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4.
16

Summary
• In multivariate analyses:
– ZOL treatment and high PgR expression associated with
improved DFS and RFS
– Lymph node involvement, high tumor grade, and large
tumors associated with poor DFS and RFS
• ZOL significantly improves clinical outcomes beyond
those achieved with endocrine therapy alone
–� Risk of DFS events by 36% (HR = 0.64; P = .012)
–� Risk of RFS events by 35% (HR = 0.65; P = .014)
–� improved OS (HR = 0.60; P = .10)
–� Risk for bone metastases (HR = 0.68; P = .224)
17

Zoledronic Acid-Mediated Mechanisms
Contributing to Improved Disease-Free Survival
�Bone mets
recurrence
Direct
antitumor
activity
�Non-bone
mets recurrence
�Contralateral
recurrence
�Disease-free survival
Immune
activation
�Locoregional
recurrence
18

Acknowledgments
• Patients who contribute to this and other ABCSG trials
• ABCSG-12 investigators and study nurses
• Trial center staff
• ABCSG statistical team: P. Wohlmuth,
E. Ruecklinger, M. Mittlboeck, and P. Bauer
• Members of the IDMC and IAB
• AstraZeneca and Novartis for supporting this
academic trial
19

Acknowledgments II
Members of the Austrian Breast and Colorectal Cancer Study Group participating in Trial 12 included the following: M. Gnant, R. Jakesz, P. Dubsky, F. Fitzal, G. Steger, S.
Taucher, T. Bachleitner-Hofmann, S. Schoppmann, M. Rudas, U. Pluschnig, D. Hussian, U. Sevelda, R. Bartsch, G. Locker, and C. Wenzel (Departments of Surgery and Internal
Medicine, Vienna University, Vienna); Ch. Dadak and R. Obwegeser (Department of Gynecology and Obstetrics, Vienna University, Vienna); R. Greil, C. Menzel, B. Mlineritsch,
P. Mayer, M. Moik, C. Rass, R. Reitsamer, and G. Russ (Third Medical Department and Department of Special Gynecology, Salzburg Hospital, Salzburg); H. Samonigg, W.
Schippinger, T. Bauernhofer, A.-K. Kasparek, P. Wagner, U. Langsenlehner, P. Krippl, M. Balic, E. Andritsch, R. Schaberl-Moser, B. Lileg, W. Weitzer, G. Hofmann, H.-J.
Mischinger, F. Ploner, M. Smola, and H. Stöger (Departments of Internal Medicine and Surgery, Graz University, and Second Department of Surgery, Graz Hospital, Graz); E.
Kubista, M. Seifert, E. Asseryanis, and R. Möslinger-Gehmayr (Department of Special Gynecology, Vienna University, Vienna); W. Kwasny, D. Depisch, A. Lenauer, K. Haider,
and T. Payrits (Department of Surgery, Wiener Neustadt Hospital, Wiener Neustadt); M. Fridrik, R. Greul, G. Hochreiner, and G. Wahl (Department of Oncology, Linz Hospital,
Linz); J. Tschmelitsch and A. Reichenauer (Department of Surgery, Sankt Veit Hospital, Sankt Veit); V. Wette (Department of Surgery, Friesach Hospital, Friesach); M. Stierer,
U. Selim, S. Artner, H. Matzinger, A. Galid, J. Baumann, and M. Medl (Department of Surgery, Hanusch Hospital, Vienna); U. Schmidbauer and M. Wunderlich (Department of
Surgery, BHS Hospital, Vienna); F. Hofbauer and M. Lang (Department of Surgery, Oberpullendorf Hospital, Oberpullendorf); W. Horvath, I. Luisser, and G. Fandl (Department
of Surgery, Güssing Hospital, Güssing); M. Prager and E. Klug (Department of Surgery, Oberwart Hospital, Oberwart); P. Kier and K. Renner (Second Medical Department and
Department of Surgery, SMZ Ost Hospital, Vienna); M. Pichler, M. Weigert, F. Sevelda, P. Sevelda, U. Denison, Ch. Peters-Engl, and N. Veneziano (Department of Gynecology
and Obstetrics, Lainz Hospital, Vienna); R. Kocher and F. Stangl (Department of Surgery, Leoben Hospital, Leoben); G. Luschin-Ebengreuth, V. Bjelic-Radisic, R. Winter
(Department of Gynecology, Graz University, Graz); P. Sandbichler, W. Schennach, and M. Mühlthaler (Department of Surgery, Zams Hospital, Zams); P. Anderl, B. Mitterdorfer,
U. Draxler, and B. Volgger (Department of Gynecology, Lienz Hospital, Lienz); S. Poestlberger, C. Tausch, R. Helfgott, C. Schmidhammer, D. Heck, F. Kugler, M. Aufschnaiter,
G. Michlmayr, and R. Schildberger (Departments of Surgery and Internal Medicine, BHS Hospital, Linz); E. Hanzal and C. Sam (Department of Gynecology and Obstetrics,
Vienna University, Vienna); A. Haid and R. Köberle-Wührer (Department of Surgery, Feldkirch Hospital, Feldkirch); W. Döller and E. Melbinger (Department of Surgery,
Wolfsberg Hospital, Wolfsberg); J. Berger and R. Lenzhofer (Medical Department, Schwarzach Hospital, Schwarzach); W. Zeilmann, B. Medek, and S. Schäfer (Department of
Gynecology and Obstetrics, Schwarzach Hospital, Schwarzach); H. Stephan and FX Schmid (Medical Department, Bregenz Hospital, Bregenz); H. Ludwig and P. Sagaster (First
Medical Department, Wilhelminenspital, Vienna); G. Reiner and D. Semmler (Department of Surgery, Mistelbach Hospital, Mistelbach); A. Kretschmer (Department of Internal
Medicine, Waldviertel Hospital, Waidhofen/Thaya); H. Trapl and R. Tichatschek (Department of Surgery, Thermenklinikum Baden); P. Magg (Department of Surgery, Hospital
Mostviertel, Scheibbs); C. Bosse (Medical Department, Klosterneuburg Hospital, Klosterneuburg); G. Weissinger and B. Labuda (Department of Surgery, Melk Hospital, Melk);
B. Hartmann and A. Bernhaus (Department of Gynecology, Neunkirchen Hospital, Neunkirchen); P. Lechner and B. Zeh (Department of Surgery, Hospital Donauklinikum, Tulln);
B. Beer, W. Simma, and B. Pichler-Gebhard (Department of Surgery, Vöcklabruck Hospital, Vöcklabruck); L. Schiller, K. Wilthoner, and F. Haslbauer (Medical Department,
Vöcklabruck Hospital, Vöcklabruck); J. Thaler, V. Trommet, S. Pillichshammer, C. Baldinger, P. Oppitz, T. Kühr, L. Wimmer, and R. Koplmüller (Department of Oncology,
Clinical Centre Wels-Grieskrichen); Ch. Tausch (Department of Oncology, Linz Hospital, Linz and Private Ordination Linz); S. A. Wenzl-Eybl (Department of Surgery, Ried
Hospital, Ried); H. Haberfellner (Department of Surgery, Schärding Hospital, Schärding); R. Függer and W. Havlicek (Department of Surgery, Hospital Elisabethinen, Linz); C.
Hinterbuchinger, W. Aschauer, and G Grenzfurtner (Department of Surgery and Gynecology, Kirchdorf Hospital, Kirchdorf); J. Omann, A. Urbania, and K. Holzmüller
(Department of Surgery, Klagenfurt Hospital, Klagenfurt); H. Hofmann and Ch. Radl (Department of Gynecology and Obstetrics, Feldbach Hospital, Feldbach); W. Neunteufel, C.
Poyssl, and K. Bischofberger (Department of Gynecology, Dornbirn Hospital, Dornbirn); C. Marth, M. Hubalek, M. Widschwendtner, A. Bergant, A. Zeimet, H. Müller, B. Volgger,
and A. Ramoni (Division of Gynecology and Obstetrics, Medical University Innsbruck); B. Spechtenhauser, Ch. Felgel-Farnholz, and S. Alicke (Department of Surgery, Kufstein
Hospital, Kufstein); K. Matthä and A. Bachmann (Department of Gynecology, Hospital Hall in Tirol); E. Hartner and H. L. Seewann (Department of Internal Medicine, Fürstenfeld
Hospital, Fürstenfeld); J. Keckstein, F. Tuttlies, and D. Pacher (Department of Gynecology and Obstetrics,Villach Hospital, Villach); and K. Unterrieder (Department of
Gynecology and Obstetrics, Villach Hospital and Private Hospital Villach).
In addition, the sponsor for Germany, the University of Kiel, represented by W. Jonat and the following German Investigators participated in Trial 12: W. Jonat, H. Eidtmann
(Department of Gynecology, University Hospital Kiel, Kiel); W. Eiermann, J. Seitz, M. Sanchez, C. Hanusch, R. Lorch, U. Jessat, M. Stehle (Department of Gynecology,
Frauenklinikum vom Roten Kreuz, Munich); L. Sommer, M. Franz (Department of Gynecology, University Hospital Munich, Munich); B. Conrad, G. Hopf, A. Balwanz, E. Stitz
(Department of Breast-Center, Elisabeth Hospital Kassel, Kassel); K.P. Hellriegel, S. Shim (Department of Hämatology and Oncology, Vivantes Klinikum am Urban, Berlin); T.
Dewitz (Department of Gynecology, Hospital Gifhorn, Gifhorn); S. Vietoris, M. Beha (Department of Gynecology and Obstetrics, Hospital St. Marien Amberg, Amberg); N.
Marschner (Department of Oncology, Hospital for Tumorbiology, Freiburg); B. Otremba,D. Reschke (Internal - Hämatological Practice Oldenburg, Oldenburg).
20

Safety of Zoledronic Acid Treatment
• Zoledronic acid has a well-established safety profile
and is generally well tolerated
• The combination of adjuvant endocrine therapy and
zoledronic acid was well tolerated
– Side effects were as expected
– Zoledronic acid therapy was not significantly associated
with serious adverse events
– No confirmed cases of ONJ
– No renal toxicity
21

Efficacy: ZOL vs No ZOL
• Adding zoledronic acid to endocrine therapy
significantly prolonged DFS and RFS vs endocrine
therapy alone
–� Risk of DFS events by 36% (HR = 0.64; P = .012)
–� Risk of RFS events by 35% (HR = 0.65; P = .014)
• Zoledronic acid produced a trend toward improved
OS (HR = 0.60; P = .10)
• Trend towards a reduction in bone metastases with
zoledronic acid
– 16 ZOL vs 23 No ZOL (HR = 0.68; P = .224)
22