The Role Of Bisphosphonates In The High Risk Patient

1
The Role Of Bisphosphonates In The High Risk
Patient

• Prof. Dr. med. Dr. h.c. Manfred Wirth
• Klinik und Poliklinik fur Urologie
• Universitatsklinikum Carl Gustav Carus
• Dresden, Germany

2
AUA 2006 Risk Stratification Scheme

• Low Risk
• PSA ? 10mg/dl and Gleason score 6 or less and
  clinical stage T1c or T2a
• Intermediate Risk
• PSA 10mg/dl-20mg/dl or Gleason Score 7 or
  clinical stage T2b
• High Risk
• PSA gt 20mg/dl or Gleason score 8-10 orclinical
  stage T2c

3
AUA 2006 Treatment Recommendations

• Monotherapies (e.g. Prostatectomy, Radiation
  therapy, Cryosurgical ablation) may be associated
  with a lower risk of cancer recurrence and
  improved survival
• Recurrence rates are high after primary
  treatment, unimodality therapy represents
  undertreatment
• Monotherapy for the high risk patient has poor
  outcomes. This is an excellent group for clinical
  trials

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Multimodality Therapy1
Initial Therapy
Adjuvant Therapy
Hormone Therapy (consider conc. Chemotherapy)
Hormone Therapy (?. Chemotherapy? ?.
Bisphosphonates?)
Prostatectomy (consider neoadj. Chemotherapy)
High-Risk Patients
Hormone Therapy (?. Chemotherapy? ?.
Bisphosphonates?)
Radiation Therapy (consider neoadj. Hormone
therapy)
Hormone Therapy (?. Chemotherapy? ?.
Bisphosphonates?)
Cryoablation therapy
1. Masood et Partin Management of High-Risk
Population with Locally advanced Prostate
Cancer, The Oncologist 2003 8 259-269
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The Role of Bisphosphonates in the High Risk
Patient
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The Bone Marrow Micro-environment
Osteoblastic bone disease
Osteolytic bone disease
PTHrP
OPG
OPG
ET-1
Unknown GFs
TGF-?
Osteoblast
Osteoclast
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Rationale for Adjuvant Bisphosphonates
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Effects of Bisphosphonates on Tumour Cells in
Vitro
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Zoledronic Acid Inhibits Metastases in the Murine
4T1/luc Syngeneic Breast Cancer Model
Bone mets. (mm2 histo.)
Liver mets. ( luc)
( luc)
15
0.6
150
150
10
100
100
0.4


Zoledronic acid

5
0.2
50
50




0
0
0
0
Zoledronic acid, 250 µg/kg, 1x every 4 days, day
7-22
P lt 0.05, n 10
Hiraga et al, Clin Cancer Res, 2004
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Minodronate Inhibits Tumour Growth and Prolongs
Survival in Nude Mice Bearing Melanoma Xenografts
G361 melanoma cells (106) injected i.d.
Minodronate dose 5µg/mouse/day i.p.
Survival ()
Macrophagenumber
CD31 area
Tumour volume (mm3)
100
100
750
minodronate
500
50
50
250
0
0
0
40
70
100
20
30
40
Days
Days
control
minodronate
Yamagishi et al, Am J Pathol, 2004
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Can Bisphosphonates Prevent Metastasis In The
Clinic?
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Pilot Study (small sample size) Zoledronic Acid
for Bone Metastasis Prevention in Patients With
Recurrent Solid Tumors
Bone-metastasesfree interval (18-month analysis)
N 40
Median Zol. 12 mo Contr. 6 mo Log rank P lt
.0005
Mystakidou, et al. Medical Oncology.
200522195-201.
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Zoledronic Acid Eliminates Residual Isolated
Breast Cancer Cells in the Bone Marrow

• All patients in this study had persistent
  isolated tumor cells in bone marrow after at
  least 6 months of adjuvant therapy
• Associated with an increased risk of distant
  relapse and shorter survival1
• These persistent tumor cells may be in a dormant
  state and refractory to chemotherapy
• 14 Patients treated with zoledronic acid every
• 4 weeks for 6 months
• 14/14 (100) had no detectable tumor cells in
  bone marrow after 6 months

1Janni W, et al. Cancer, 20019246-53. Rack et
al. Proc Am Soc Clin Oncol, 2004Abstract 9515
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Adjuvant Studies with Zoledronic Acid

• Cancer
• Breast
• Prostate
• NSCLC

Study N
Purpose

• AZURE 3300
• Intergroup S0307 6000

• BMs prevention
• BMs prevention

• 5 trials 6370

• BMs prevention
• Combination studies

• BMs prevention / delay in Stage III A and
  III B NSCLC

• 3 trials 1438

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Adjuvant Trial in High-risk Prostate-Ca ZEUS

• Effectiveness of zoledronic acid treatment for
  the prevention of bone metastases in high-risk
  prostate cancer patients
• A randomized, open-label, multicenter study of
  the European Association of Urology (EAU) in
  Cooperation with the Scandinavian Prostate Cancer
  Group (SPCG) and the Arbeits-gemeinschaft
  Urologische Onkologie (AUO)

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Study Objectives

• Primary
• To show superiority of zoledronic acid as
  compared to control in the proportion of patients
  with at least 1 bone metastasis after 48 months
  of treatment
• Secondary
• To evaluate the effect of zoledronic acid on time
  to the first bone metastasis irrespective of
  whether symptomatic
• To evaluate the effect of zoledronic acid on
  overall survival
• To evaluate the effect of zoledronic acid on PSA
  doubling time
• To evaluate the effect of zoledronic acid on
  biochemical markers of bone turnover (selected
  centers only)

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Patient Study Population Standard Therapy

• Standard curative therapy
• Radical prostatectomy
• Radical radiotherapy
• Standard palliative therapy
• Watchful waiting
• Anti-androgen monotherapy
• Castration
• LHRH analogues
• Subcapsular Orchiectomy
• LHRH antagonists

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Patient Population Inclusion Criteria

• Patients gt 18 years old, ECOG status 0
• M0 prostate cancer patients who previously
  received curative treatment or no curative
  treatment
• At least 1 of the following
• Gleason score 8 to 10
• pN
• PSA ? 20 at diagnosis
• Patients receiving androgen deprivation therapy
  or no androgen deprivation therapy corresponding
  to standard medical management
• Life expectancy gt 6 months and informed consent
  given

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Patient Population - Main Exclusion Criteria

• Patients with known visceral metastasis or bone
  metastases
• Prior treatment with bisphosphonates
• Chemotherapy to treat prostate carcinoma
• Anti-androgen monotherapy
• Use of other investigational drugs (drugs not
  marketed for any indication) within 6 months
  before start of study
• Serum creatinine gt 3 mg/dL (265 ?mol/L)

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Study Design
48-month treatment period
Zoledronic acid 4 mg IV every 3 months
N 1,300
In case of bone metastasis, treatment with a
bisphosphonate every 4 weeks is recommended
(eg, zoledronic acid)
Prostate cancer
R
with no history
of bone disease
Control group
At randomization stratification for curative
treatment Y/N, hormonal treatment Y/N for each
participating center
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Timelines

• FPFV June 2004
• LPFV March 2007
• LPLV March 2011
• Interim analysis Expected March 2009
• Final analysis October 2011
• 1st Publication November 2011
• Review of safety data by an Independent Data
  Monitoring Committee (IDMC) at 12 months from
  study starting

FPFV First patient, first visit LPFV Last
patient, last visit LPLV Last patient, last
visit Interim analysis will be performed on the
primary end-point when 100 of the patients are
recruited and observed for 24 months on average
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Recruitment Status October 5th, 2006 1000
Patients
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Participating Countries
467
450
400
Germany
The Netherlands
350
Finland
300
Denmark
Sweden
250
Spain
No of patients
Norway
200
France
Italy
150
Switzerland
82
Belgium
100
54
66
51
44
49
Turkey
21
50
11
5
11
34
Greece
23
0
Country
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Patient Population May 2006 (n 802)
Patients, n () Patients, n () Patients, n () Patients, n ()
Zoledronic acid (n 402) Zoledronic acid (n 402) No zoledronic acid(n 400) No zoledronic acid(n 400)
1) PSA 20 230 (29) 223 (28)
2) Gleason 8-10 235 (29) 247 (31)
3) pN 116 (15) 84 (10)
1) 2) 97 (12) 98 (12)
1) 3) 47 (6) 38 (5)
2) 3) 54 (7) 43 (5)
1) 2) 3) 19 (2) 23 (3)
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Patient Population Previous Curative Therapy

• Previous curative therapy in zoledronic acid
  versus no zoledronic acid group
• Prev. Cur. Th. n 197 in zoledronic acid n
  200 in no zoledronic acid group

RAND 1 Zometa
RAND 2 No Zometa
curative treatment
curative treatment
no curative treatment
no curative treatment
PM Stratification at randomization for curative
treatment Y/N
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Conclusion

• Role of Chemotherapy in the neoadjuvant and
  adjuvant setting has to be elucidated (randomized
  Phase III trials are ongoing)
• In vitro and in vivo data support an antitumour
  effect of zoledronic acid
• Clinical studies in the adjuvant setting are
  ongoing with zoledronic acid