Zoledronic acid in early stage breast cancer

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Zoledronic acid in early stage breast cancer

• Rama Suresh, M. D.

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BONE METASTASIS
Adherence
Bonemetastases
Zoledronic acid inhibits osteoclastic bone
resorption
Guise Mundy, Endocr Rev, 1998
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Zoledronic Acid Inhibits Multiple Steps in the
Metastatic Cascade from a Primary Neoplasm
Guise Mundy, Endocr Rev, 1998
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Piccart-Gebhart ASCO 2008
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Prenylation of Signaling proteins
Zoledronic Acid
X
FPP synthase
X FTI
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Piccart-Gebhart ASCO 2008
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Piccart-Gebhart ASCO 2008
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Effect of Zoledronic Acid on Bone Marrow
Micrometastases in Women Undergoing Neoadjuvant
Chemotherapy for Breast Cancer

• Objective Randomized phase II study of
  zoledronic acid on disseminated tumor cells
  (early stage breast cancer)
• Study design
• 120 women with clinical stage II/III breast
  cancer
• Randomized to receive zoledronic acid (4 mg q3w)
  for one year or no bisphosphonate
• All patients received 4 cycles of neoadjuvant
  epirubicin/docetaxel (75 mg/m2) with pegylated
  G-CSF support followed by surgery and 2
  additional cycles of epirubicin/docetaxel
• Bone marrow biopsies taken prior to therapy, at
  time of surgery, and 1 year from diagnosis.

Aft, ASCO 2008, abstract 1021
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RESULTS

• Tumor cells in the bone marrow after three months
• No drug 36
• Zol 23

Aft, ASCO 2008, abstract 1021
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BONE RESORPTION MARKER PREDICTS BREAST CANCER
BONE METASTASIS

• Beta C-terminal telopeptide to predict Br Ca
  relapse
• Higher pretreatment B-CTx predicts decreased RFS
  for bone-only metastasis.

Lipton A, et al. ASCO 2008. Abstract 591 poster
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Piccart-Gebhart ASCO 2008
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TRIALS IN EARLY STAGE BREAST CANCER

• ABCSG-12
• Z-FAST
• ZO-FAST
• AZURE
• SWOG S0307
• NaTaN

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Original Article Endocrine Therapy plus
Zoledronic Acid in Premenopausal Breast Cancer
Michael Gnant, M.D., Brigitte Mlineritsch, M.D.,
Walter Schippinger, M.D., Gero Luschin-Ebengreuth,
M.D., Sabine Pöstlberger, M.D., Christian
Menzel, M.D., Raimund Jakesz, M.D., Michael
Seifert, M.D., Michael Hubalek, M.D., Vesna
Bjelic-Radisic, M.D., Hellmut Samonigg, M.D.,
Christoph Tausch, M.D., Holger Eidtmann, M.D.,
Günther Steger, M.D., Werner Kwasny, M.D., Peter
Dubsky, M.D., Michael Fridrik, M.D., Florian
Fitzal, M.D., Michael Stierer, M.D., Ernst
Rücklinger, Ph.D., Richard Greil, M.D., for the
ABCSG-12 Trial Investigators
N Engl J Med Volume 360(7)679-691 February 12,
2009
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ABCSG-12 Austrian Br CRC Study Group
RANDOMIZE
Zol 4 mg q 6 mos
TAMOXIFEN Goserelin
RANDOMIZE
No Zol
RANDOMIZE
Zol 4 mg q 6 mo
ANASTROZOLE Goserelin
No Zol

• Patient Population Treatment x 3 yrs
• BrCa Stage I/II Enrollment complete, N 1,803
• Premenopausal Adjuvant chemo not allowed but
  neoadjuvnat chemo was allowed
• lt 10 axillary lymph nodes affected
• ER and/or PR

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ABCSG-12 Key Study Objectives

• Primary Objectives
• DFS after 5 yrs in pre-menopausal women with
  stage I/II, HR BC (all pts received goserelin)
• Tamoxifen vs Anastrozole
• Zol vs No Zol
• Secondary Objectives
• RFS and OS _at_ 5 yrs
• BMD measurement
• Exploratory Endpoint
• Bone-metastases-free survival

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KEY STUDY POPULATION INFO

• 1803 patients enrolled
• 75 had T1 stage
• 30 had node positive
• 85 had ER/PR scores indicative of highly
  endocrine responsive cancer
• 5.4 had neoadjuvant chemo

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Events in the Intention-to-Treat Population
Gnant M et al. N Engl J Med 2009360679-691
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ABCSG-12 Study Results
Safety Treatment was generally well tolerated
and consistent with known safety profiles of the
drugs
DFS Disease Free Survival RFS Recurrence
Free Survival OS Overall Survival BMFS Bone
Metastases Free Survival
Gnant M, et al. NEJM 360679-91, 2009
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(No Transcript)
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Results of Multivariate Analyses of Independent
Variables for Disease-free Survival and
Recurrence-free Survival
Gnant M et al. N Engl J Med 2009360679-691
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LUMBAR SPINE
A Tam B TamZol
C Ana DAnaZol
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TROCH
A Tam B TamZol
CAna D AnaZol
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ABCSG-12 (5 year f/u) BMD Change in Lumbar
Spine
Gnant MF. Presented at SABCS 2007, Abstract 26
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Selected Adverse Events
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Gnant M, et al. NEJM 360679-91, 2009
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No confirmed cases of osteonecrosis of the jaw
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Gnant M, et al. NEJM 360 679-91,2009
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Piccart-Gebhart et al. ASCO 2008
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Z-FAST ZO-FAST Early Breast Cancer Patients
Receiving Adjuvant Letrozole
R A N DO M I Z E D
Zol 4 mg q 6 mo LET 2.5 mg q d (UP FRONT)
Z-FAST N 602 ZO-FAST N 1,066
Zol 4 mg q 6 mo LET 2.5 mg q d (DELAYED)
5 year study
Primary Endpoint Lumbar Spine BMD change at 12
mo Secondary Endpoint Change in TH BMD and serum
bone turnover markers at 12 mo

• Secondary Anti-tumor Analyses
• Disease Recurrence
• Time to Recurrence
• DFS

Z-FAST Brufsky A, et al. JCO 2007,25829-836,
and SABCS, 2007. Abstract 27ZO-FAST Bundred
N, et al. Cancer 2008,1121001-10 and De Boer,
et al. SABCS, 2007. Abstract 501
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Z-FAST (36mo) Effect of Zol on AIBL in
Postmenopausal Women w/ Early Br Ca
Upfront Zol (4 mg/6 months)
Delayed Zol (4 mg/6 months)
P lt .0001
P lt .0001
P lt .0001
P lt .0001
P lt .0001
P lt .0001
4
3
n189
n204
2
n251
n188
1
n199
n256
Mean (SEM) change BMD
0
1
n256
n251
2
n189
n206
n197
3
n187
4
Month 24
Month 12
Month 24
Month 12
Month 36
Month 36
Lumbar spine
Total hip
SEM Standard error of the mean P values
correspond to intergroup comparisons.Intragroup
comparisons from baseline to month 12 or 24 for
all treatment groups were significant (P lt .0001
for all).Adapted from Brufsky A, et al. SABCS,
2006 Abstr 5060 Brufsky A, et al. SABCS, 2007.
Abstr 27
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Z-FAST/ZO-FAST 36 mo data
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Z-FAST/ZO-FAST 36 mo data
Brufsky et
al. SABCS 2007 Abstr 27
Bundred et al. SABCS 2008 Abstr 44
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NTX and BSAP concentrations
Brufsky et al.The Oncologist, Vol. 13, No. 5,
503-514, May 2008
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Z-/ZO-FAST Safety Information

• Most common AEs occurring in gt 5 of pts
• Upfront Delayed
• Arthralgia 32 29
• Hot Flashes 24 25
• Fatigue 13 13
• Bone pain 12 6
• Pyrexia 12 1

Brufsky A, et al. The Oncologist 2008,13503-514
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AZURE (BIG01/04) Zoledronic Acid for the
Prevention of Bone Metastases in Adjuvant Breast
Cancer

• Patient Population Treatment x 5 yrs
• BrCa Stage II/III Enrollment complete, N
  3,360
• Pre- and post-menopausal
• Neoadjuvant/Adjuvant systemic therapy
• ER /-
• N/N-

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AZURE Study Endpoints

• Primary Endpoint
• DFS after 5 yrs of standard therapy adjuvant
  Zol vs standard therapy alone in women with
  high-risk localized breast cancer (stage II/III
  pre- or post-menopausal HR or HR-)
• Secondary Endpoints
• OS, Time to bone mets, SREs

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AZURE Safety Data 3,360 Patients

• Zolendronic Acid Chemotherapy is safe
• Safety profile (except for vomiting and fever)
• Dose reductions and duration of chemotherapy
• Renal Dysfunction
• 7 cases of ONJ

Coleman et al. Presented at SABCS 2006 Abstract
2080.
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Winter MC et. Al, SABCS 2008 Abstr 5101
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(No Transcript)
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SWOG 0307 Study Design
RANDOMIZE
Zoledronic acid 4 mg IV monthly for 6 mo then Q
3 mo for 30 mo
Clodronate 1600 mg orally QD x 36 mos
Ibandronate 50 mg orally QD x 36 mos
111
Treatment x 3 yrs Follow-up x 7 yrs 10 yrs
total
Patient Population N4500 BrCa stage
I/II/IIIa f/u 6 mo for recurrence
then Q yr Std adj systemic therapy X 10 yr for
survival
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SWOG 0307 Study Endpoints

• Primary Endpoints
• Disease-free survival, overall survival
• Secondary Endpoints
• Time to progression, tolerability, patients
  compliance, bone markers, dental substudy

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Zoledronic Acid Dosing in Adjuvant Br Ca Studies
Data anticipated later in 2008
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Summary Expanding Role of Zoledronic Acid

• Approved for hypercalcemia of malignancy and bone
  metastases (at 4 mg IV q 3-4 wks)
• Anti-tumor properties ( in vitro/in vivo)
• Prolongs DFS and RFS (vs endocrine therapy
  alone).
• Improves bone mineral density
• Optimal dosing ?

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SEED AND SOIL THEORY
the best work in pathology of cancer is done by
those who are studying the nature of the seed
the cancer cell, the observations of the
properties of the soil" the secondary organ
"may also be useful...
Lancet, Volume 133, Issue 3421, 23 March 1889,
Pages 571-573,