Targeting the Bone: Biphosphonates in the Treatment of Skeletal Complications of Malignancy

1
Targeting the BoneBiphosphonates in the
Treatment of Skeletal Complications of Malignancy

• ZOMERA

2
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• ZOMERA
• Targeting the Osteoclast

3
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4
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• ???????????? ?????, ???? ???? ????, ????? ?????
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• ???? ?? ?? ????? ????? ???? ?? ????? ????, ?????
  ????-???? ???, ????? ????? ??????, ????? ?????
  ????.

5
Bone metastasis in common tumors1-3
Breast Myeloma Prostate Lung Incidence ofbone
metastases 6575 95100 6575 3040 Progn
osis 5-yr survival 20 10 25 2 to 5
median survival 24 months 20 months 40 months lt6
months
1. Mundy GR. Mechanisms of bone metastasis.
Cancer. 1997801546-1556. 2. Coleman RE.
Skeletal complications of malignancy. Cancer.
1997801588-1594. 3. Ginsberg RJ, Vokes EE,
Rosenzweig K. Non-small cell lung cancer. In
DeVita VT Jr Hellman S, Rosenberg SA, eds.
Cancer Principles Practice of Oncology.
Philadelphia Lippincott Williams Wilkins6th
ed.2001925-983.
6
Complications Associated With Bone Metastases

• Pathologic fractures
• Spinal cord compression
• Bone pain
• Hypercalcemia
• Bone marrow failure
• Osteoporosis

7
Pathogenesis of Osteolytic/Osteoblastic Bone
Metastases1-4

• Underlying mechanisms

• Factors are released by tumor cells that
  stimulate both osteoclast and osteoblast
  activity
• Excessive new bone formation occurs around
  tumor-cell deposits, resulting in low bone
  strength and potential vertebral collapse
• Osteoclastic and osteoblastic activity
  releases growth factors that stimulate tumor-cell
  growth, perpetuating the cycle of bone resorption
  and abnormal bone growth

Tumor cell
1
2
2
TGF-?, BMPIGFs, FGF
3
1
5
PTHrP/IL-6
Unknown GFs
4
TGF-?
4
5
3
Osteoblast
Osteoclast
1. Goltzman D. Cancer. 1997801581-1587.2.
Adami S. Cancer. 1997801674-1679.3. Mundy GR.
Cancer. 1997801546-1556.4. Boyce B et al
Endocr Relat Cancer. 19996333-347.
8
Molecular mechanism of action of
nitrogen-containing bisphosphonates
HMG-CoA
mevalonate
geranyl diphosphate


farnesyl diphosphate (FPP)
geranylgeranyl diphosphate (GGPP)
9
Rationale for Using Bisphosphonates to Treat
Skeletal Complications of Bone Metastases

• Preferentially bind to bone surfaces undergoing
  active remodeling
• Inhibit osteoclast maturation and suppress
  osteoclast function
• Inhibit osteoclast recruitment to site of bone
  resorption
• Reduce bone-resorbing cytokine production
• May inhibit tumor-cell secretion of growth
  factors that stimulate osteoblasts
• Inhibit number and activity of osteoblasts

1. Berenson JR, Lipton A. Annu Rev Med.
199950237-248. 2. Evans CE, Braidman IP. Bone
Miner. 19942695-107. 3. Green JR, Müller K,
Jaeggi KA. J Bone Miner Res. 19949745-751. 4.
Derenne S et al. J Bone Miner Res.
1999142048-2056.
10
Relative potencies of bisphosphonates1
900
847
800
700
600
Potency relative to pamidronate disodium in vivo
(hypercalcemic rat), linear scale
500
400
300
200
100
43.60
35.90
7.44
2.77
0.05
1.00
0
clodronate
pamidronatedisodium
olpadronate
alendronate
risedronate
ibandronate
ZOMERA(zoledronic acid)
1. Green JR, Müller K, Jaeggi KA. Preclinical
pharmacology of CGP 42'446, a new, potent,
heterocyclic bisphosphonate compound. J Bone
Miner Res. 19949745-751.
11
Anti-Tumor Effects of ZOMERA

• Preclinical data show anti-tumor potential of
  ZOMERA
• Inhibits invasion of breast cancer cells through
  artificial extra cellular matrix more effectively
  than other bisphosphonates
• Anti-angiogenic effects
• Induces apoptosis in human endothelial cells
• Inhibits basic fibroblast growth factor-induced
  neovascularization in tissue chamber implants in
  mice
• Potential to reduce metastases in bone, soft
  tissue potentially prolong survival

12
Hypercalcemia of malignancy (HCM)
Mechanisms Factors involved Types Primary signs
and symptoms Diagnosis Overview of
treatment ZOMERA (zoledronic acid)
13

• Humoral HyperCalcemia of Malignancy (HCM)

Stimulation of osteoclastic resorption Inhib
ition of bone formation
Inhibition of Ca absorption
Ca
Increased Ca reabsorption Inhibition of Pi
reabsorption Increased cAMP excretion
Adapted with permission from Mundy GR.1
1. Mundy GR. In Mundy GR (ed). Calcium
Homeostasis Hypercalcemia and Hypocalcemia.
199069-99.
14
Parathyroid hormone-related protein (PTHrP)

• Produced by tumor cells1,2
• Stimulates vicious cycle of osteoclastic bone
  resorption contributing to HCM1,2
• Also stimulates increased renal tubular calcium
  resorption1,3

1. Goltzman D, Kremer R, Rabbani SA Abstract
   presented at the Second North American Symposium
   on Skeletal Complications of Malignancy. October
   1516, 1999 Montréal, Canada.
2. Guise TA. metastases. Abstract presented at
   the Second North American Symposium on Skeletal
   Complications of Malignancy. October 1516,1999
   Montréal, Canada.
3. Mundy GR (ed). Bone Remodeling and Its
   Disorders. London, England Martin Dunitz Ltd
   1989113-119.

15

• Local osteolytic HCM associated with bone
  metastases1-3

Metastatic tumor cells release factors (PTHrP,
prostaglandin E, growth factors, and
cytokines) that directly stimulate osteoclast
activity1,2 Osteoclastic activity releases
growth factors (ie, TGF-?) that stimulate
tumor-cell growth, perpetuating a vicious
cycle of bone resorption2 Bone resorption
releases calcium from the skeleton, increasing
the flow of calcium through the extracellular
space, resulting in elevated serum calcium1
1
2
3
Adapted with permission from Mundy GR, Guise TA,
Place N.
1. Guise TA, Mundy GR. Cancer and bone. Endocr
Rev. 19981918-54. 2. Mundy GR (ed). Cellular
mechanisms of bone resorption. In Bone
Remodeling and Its Disorders. 2nd ed. London,
England Martin Dunitz Ltd 199923-25. 3. Mundy
GR. Cancer. 199780 (suppl 8)1546-1556.
16
Bone-resorbing cytokines

• Four types exhibit potent bone-resorbing
  activity
• Transforming growth factors (TGF-? and TGF-?)1
• Tumor necrosis factors (TNF-? and TNF-?)2,3
• Colony-stimulating factors (CSFs)2
• Interleukins4

1. Todaro GJ, Fryling D, DeLarco JE. Proc Natl
Acad Sci USA. 1980775258-5262. 2. Mundy GR
(ed). Bone Remodeling and Its Disorders.
London, England Martin Dunitz Ltd 198945-82
113-119. 3. Mundy GR. Endocrinol Metab Clin
North Am. 198918795-806. 4. Kelly PJ, Eisman
JA. Cancer Metastasis Rev. 1989823-52.
17
Vitamin D

• Increased production by tumor cells leads to HCM
• Increased production leads to increased serum
  calcium levels via
• Recruitment of osteoclast precursors
• Production of osteoclast-stimulating factors from
  osteoblasts

1. Mundy GR. (ed). Bone Remodeling and Its
Disorders. 2nd ed. London, England Martin
Dunitz Ltd 19894582 113-119.
18
Primary signs and symptoms of HCM1

• Altered levels of consciousness
• Coma
• Nausea
• Vomiting
• Dehydration
• Constipation
• Polyuria
• Cardiac arrythmia

1. Morton AR, Lipton A. Clin Oncol.
1995527-542.
19
Diagnosis of HCM

• Consider HCM in any person with cancer showing
  symptomatic deterioration1
• Confirm hypercalcemia by measuring corrected
  serum calcium (CSC)2-4 CSC, mg/dL Serum Ca,
  mg/dL 0.8 (4.0 serum albumin, g/dL)
• Confirm HCM by measuring PTH level.

1. Ralston SH. In Body JJ (ed). Tumor Bone
Diseases and Osteoporosis in Cancer Patients. New
York, NY Marcel Dekker 2000393-407. 2. Iqbal
SJ, Giles M, Ledger S, Nanji N, Howl T. Lancet.
1988ii1477-1478. 3. Payne RB, Little AJ,
Williams RB, Milner JR. BMJ. 19734643. 4.
Morton AR, Hercz G. Dialysis Transplant.
199120661.
20
Treatment of HCM

• Treatment of mild HCM (CSC levels lt12.8mg/dL)
• ambulation
• avoid inactivity
• avoid salt restriction and dehydration
• force fluids
• antiresorptive drug therapy to inhibit
  osteoclastic bone resorption

21
Treatment of moderate HCM to severe HCM

• Rehydration with intravenous fluid therapy to
  promote urinary excretion of calcium1 (with
  isotonic saline depending on cardiac status)
• Confirm good urine flow
• Loop diuretic (?) , plus maintenance of volume
  expansion. monitor serum levels, and administer
  potassium and magnesium as necessary.
• Salmon calcitonin
• IV bisphosphonates

1. Barnett ML. Hypercalcemia. Semin Oncol Nurs.
199915(3)190-201.
22
Treatment of moderate-to-severe HCM by IV
bisphosphonates

• IV bisphosphonates The treatment of choice for
  reducing or inhibiting osteoclastic activity
• Available IV bisphosphonates for HCM
• Pamidronate disodium for injection 90 mg 4 hour
  infusion
• ZOMERA (zoledronic acid) 4 mg 15-minute infusion

23
ZOMERA vs pamidronate in HCMMajor P, et al. J
Clin Oncol. 200119558-567.
pamidronate 90 mg (N99)
ZOMERA 4 mg (N86)
ZOMERA 8 mg (N90)
Total (N275)
Sex Male 46 (53.5) 60 (66.7) 56 (56.6) 162
(58.9) Female 40 (46.5) 30 (33.3) 43 (43.4) 113
(41.1) Age Mean 60.0 58.7 59.0 59.0 Range 33
84 2184 2587 2187 Primary cancer site Lung
15 (17.4) 25 (27.8) 23 (23.2) 63
(22.9) Breast 22 (25.6) 14 (15.6) 15 (15.2)
51 (18.5) Multiple myeloma 9 (10.5) 5 (5.6)
9 (9.1) 23 (8.4) Head and neck 9 (10.5)
9 (10.0) 12 (12.1) 30 (10.9) Renal 9 (10.5)
10 (11.1) 11 (11.1) 30 (10.9) Unknown 2
(2.3) 1 (1.1) 4 (4.0) 7
(2.5) Hematologic 9 (10.5) 7 (7.8) 7
(7.1) 23 (8.4) Other 11 (12.8) 19 (21.1) 18
(18.2) 48 (17.5)
1. Major P, et al. J Clin Oncol. 2001 January
1519(2)558-567.
24

• Patient demographics (continued)

pamidronate disodium 90 mg (N99)
ZOMERA 4 mg (N86)
ZOMERA 8 mg (N90)
Total (N275)
Bone metastases No 37 (43.0) 40 (44.4) 54
(54.5) 131 (47.6) Yes 49 (57.0) 50 (55.6)
45 (45.5) 144 (52.4) Baseline PTHrP ? 2 pmol/L
62 (72.1) 59 (65.6) 65 (65.7) 186
(67.6) gt2 pmol/L 20 (23.3) 25 (27.8) 24
(24.2) 69 (25.1) Bisphosphonate use in past
year No 77 (89.5) 86 (95.6) 91 (91.9) 254
(92.4) Yes 9 (10.5) 4 (4.4) 8
(8.1) 21 (7.6)
25
Results 1

• Complete response rate
• Normalization of corrected serum calcium ?10.8
  mg/dL (?2.7 mmol/L)

100
P
.002
80
P
.005
60
Complete response,
40
ZOMERA 4 mg
20
pamidronate disodium 90 mg
0
0
4
7
10
Day
Denotes statistical significance vs pamidronate
disodium.
26
Results 2

• Median duration of remission of HCM

30
ZOMERA 4 mg (N86)
17
pamidronate disodium 90 mg (N99)
(P.001)
Days
27
Results 3
Time to relapse
1.0
ZOMERA 4 mg median 30 days
.8
pamidronate disodium 90 mg median 17 days
.6
Proportion of patients without relapse
.4
.2
0
0
7
14
21
28
35
42
49
56
63
Days since start of treatment ( Day 1)
Censored time

ZOMERA 4 mg vs pamidronate disodium 90 mg
P.001
28
Summary of the results

• ZOMERA 4 mg was more effective than pamidronate
  disodium 90 mg in the treatment of HCM1
• Significantly faster normalization of corrected
  serum calcium (P?.05)
• Significantly longer therapeutic effect (P.001)
• Significantly higher response rate (P.002)
• Well tolerated
• More rapid infusion than pamidronate disodium
• Recommended dose in HCM
• ZOMERA 4 mg via 15-minute infusion

29
Phase III Studies ZOMERA for Treatment of
Bone Metastases1-3
Protocol
Patient population
Trial design
010
Bone metastases in
Randomized, double-blind,
breast cancer and
12-month,
multicenter
multiple
myeloma,
vs
pamidronate disodium
N1,648
011
Bone metastases in lung
Randomized, double-blind,
and other cancers,
placebo-controlled,
multicenter
N773
039
Bone metastases in
Randomized, double-blind,
prostate cancer,
placebo-controlled,
multicenter
N643
Primary end points reduction or prevention of
skeletal-related events (SREs) in proportion of
patients

1. Rosen LS et al Cancer J. 20017377-387.
2. Rosen L et al Lung Cancer. 200134(suppl 1)67.
   Abstract.
3. Saad F et al JNCI. 2002941458.

30
Trial 10 Efficacy of zomera in breast cancer and
multiple myeloma
31
Rosen LS et al. Cancer J. 20017377-387.

• ZOMERA Pam 4 mg 90 mg
• Demographic factor N 561 N 555
• Mean age, yr 59.7 58.8
• Gender, female 81.5 83.5
• Race, Caucasian 87.9 87.1
• Performance status
• ECOG 0 - 1, 84.5 78.6
• Breast cancer
• Chemotherapy, n 178 181
• Hormonal therapy, n 200 207
• Multiple myeloma, n 183 167

31
Phase III trial 010 skeletal morbidity rate
ZOMERA Mean SMR by SRE (zoledronic acid) 4
mg pamidronate disodium
All SREs (HCM) 1.13 1.40 All SREs
(HCM) 1.13 1.47 Pathologic fracture 0.62 0.66 Ver
tebral fracture 0.27 0.27 Nonvertebral
fracture 0.41 0.45 Spinal cord compression 0.03 0.
09 Radiation to bone 0.47 0.71 Surgery to
bone 0.05 0.10 Hypercalcemia 0.02 0.06 P.018
for 4 mg of ZOMERA vs pamidronate disodium.
32
Trial 10 Efficacy of zomera in breast cancer and
multiple myelomaPatients with Skeletal-Related
Events (SREs)
Proportion With SRE
33
Phase III trial 010 overall conclusions

• Proven effective in the treatment of bone
  metastases in breast cancer and multiple myeloma
  with respect to primary end point.
• ZOMERA better then PAM with respect to reducing
  bone radiation.
• Well tolerated with a safety profile similar to
  pamidronate disodium 90 mg (including renal
  safety).
• Renal tolerability was similar for 4 mg via 15
  min.
• ZOMERA (zoledronic acid) is conveniently infused
  over 15 minutes, compared to 2 hours for
  pamidronate disodium

34
?????? ??????? ??? ??????? ????? 2002
????????? ???? ???

• Zomera ?????? ???????? (20) ?? ?????? ????
  ?????? ??????? (SRE) ????? Aredia ?????? ???? ??
  ????? ?????? ????? ??????.

35
A phase III trial of ZOMERA in the treatment of
bone metastases associated with advanced lung
cancer and other cancers (Protocol 011)
Rosen L et al Lung Cancer. 200134(suppl 1)67.
Abstract.
Patients, n
() zomera 4 mg Placebo Demographic Variable N
254 N 247
Primary site of cancer Lung 124 (48.8)
123 (49.8) Other Renal cell
carcinoma 27 (10.6) 19 (7.7) Unknown
primary 15 (5.9) 14 (5.7) Thyroid 2 (0.8) 4 (1.6
) Head and neck 6 (2.4) 4 (1.6) Other 80 (31.5
) 83 (33.6)
Non-small cell lung cancer and small cell lung
cancer.
36
Trial 11 Efficacy in solid tumours other than
breast and prostate cancerSignificant reduction
in proportion of patients with any SRE at 9
Months
37
Phase III trial 011 time to first pathologic
fracture1
100 90 80 70 60 50 40 30 20 10 0
Percent of patients without event
Median Time ZOMERA (zoledronic acid) 4 mg
N.R. Placebo N.R.
P.031
0 50 100 150 200 250 300 350 400 450 500 550
Time after start of therapy (days)
38
Phase III trial 011 overall conclusions

• ZOMERA
• Decreased proportion of patients with SRE and SMR
  (HCM)
• Delayed time to first SRE
• Significantly delayed time to the first fracture
• Decreased proportion of patients with fracture
  (data not shown)
• Well tolerated, with a safety profile comparable
  to other bisphosphonates

39
History of Bisphosphonate Therapy in Prostate
Cancer

• Etidronate
• No effect on pain
• Clodronate
• Minimal effect on pain
• No effect on progression of bone disease
• Pamidronate
• Minimal effect on pain
• No effect on incidence of SREs

40
Phase III trial 039 Study ObjectivesSaad et al
JNCI 2002191458
zomera 4 mg zomera 8/4 mg Placebo Demographic
variable (n 214) (n 218) (n 208)
Median age, years 72 72 73 Previous SRE, n
() Yes 66 (30.8) 70 (32.1) 78
(37.5) No 148 (69.2) 148 (67.9) 130
(62.5) Baseline serum creatinine Normal (lt 1.4
mg/dL) 173 (80.8) 168 (77.1) 170
(81.7) Abnormal (? 1.4 mg/dL) 41 (19.2) 47
(21.6) 33 (15.9) Missing 0 (0) 3 (1.4) 5
(2.4) BPI composite pain score N
193 198 191 Mean 2.0 ? 1.98 2.5 ? 2.10 2.1
? 2.04 Baseline PSA, ng/mLMedian 81.7 88.5 61.0

41
zomera in Prostate Cancer Reduced Proportion of
Patients with SRE and Mean SMR
42
Pathologic Fractures by Treatment
43
Zomera in Prostate Cancer Delayed Time to First
Pathological Fracture
44
Mean Change From Baseline of the CompositePain
Score by Treatment
P lt .05 versus placebo







Higher score means more pain
45
Disease-Related and Quality of Life Endpoints in
Protocol 039

• No significant difference was found between
  zomera and placebo in
• Time to progression of bone metastases
• Time to overall progression of disease
• Time to death
• Global quality of life (Fact-G, ECOG)

46
Efficacy Conclusions

• zomera (4 mg via 15-minute infusion) versus
  placebo
• Proportion of patients with an SRE and SMR were
  significantly decreased
• Significantly delayed time to first SRE
• Delayed time to first pathologic fracture
• Significantly reduced increases in pain
• No significant effects on bone lesion response,
  bone lesion progression, or overall disease
  progression

47
zomera phase III clinical trials - Safety
evaluation in 2,185 patients

• All treatment-related adverse events in gt15 of
  patients in phase II and phase III controlled
  bone metastases clinical trials
• zomera pamidronate placebo 4 mg disodium 90 mg
• Adverse events (n1,099) (n631) (n455)
• Bone pain 52.7 54.7 59.8
• Nausea 42.8 44.7 35.2
• Fatigue 35.9 37.2 27.5
• Vomiting 29.8 30.0 25.1
• Pyrexia 29.7 27.7 18.2
• Anemia 29.1 26.9 26.2
• Constipation 27.9 23.5 35.4
• Dyspnea 24.0 23.3 20.4
• Diarrhea 21.7 24.9 16.7
• Myalgia 21.1 23.5 14.9
• Weakness 21.1 16.3 23.1
• Anorexia 20.0 12.0 21.5
• Cough 19.3 20.9 12.5
• Edema, lower limb 18.5 18.2 16.7
• Arthralgia 17.7 17.3 13.2
• Headache 17.6 24.1 10.3

48
Safety Conclusions

• zomera is well tolerated, with an overall safety
  profile similar to that of other intravenous
  bisphosphonates
• Laboratory abnormalities (grade 3 and 4) were
  similar for zomera (4 mg) and placebo (anemia and
  hypocalcemia)
• zomera (4 mg) via 15-minute infusion has an
  acceptable renal safety profile

49
The Use of Zomera in Early and Metastatic Breast
Cancer
50
Zoledronic acid (Zomera)
C

• Third generation, nitrogen-containing
  bisphosphonate
• 100-850 times greater potency of pamidronate
• Decreases levels of serum VEGF

Green JR, et al. J Bone Miner Res.
19949745-751.Green JR, et al. Pharmacol
Toxicol. 199780225-230.
51
Zoledronic acid (Zomera)
C

• Given IV at a fixed dose of 4mg in 15 minutes
• Benefit in increasing BMD is seen with q4 weeks
  up to q12 months schedule
• Increase in BMD is seen in various solid tumor
  types with bone metastases
• Prostate
• Lung
• Renal Cell

52
Skeletal Issues in Breast Cancer

• Preserving normal Skeletal health
• Chemotherapy induced amenorrhea
• Ovarian ablation
• Estrogen deprivation by aromatase inhibitors
• Preventing bone metastases
• Adjuvant therapy with bisphosphonates
• Reducing skeletal morbidity rate in women with
  bone metastases
• Pain Narcotic use
• Pathological fractures
• XRT

53
Chemotherapy Induced Amenorrhea

• Ovarian failure after chemotherapy results in
  menopause 5-10 years earlier than usual
• CMF 63-85 of all patients
• CAF gt50 of all patients more age
  dependent, nearly 100 over age 40
• Taxanes No comprehensive data

54
Risedronate to Prevent Bone Loss in Women with
Chemotherapy-Induced Ovarian Failure Delmas et
al (1997) JCO 15955-962
Plt0.05 for each comparison
AP Spine
Femoral Neck
55
Hormonal Induced Amenorrhea

• Re-emergence of ovarian ablation as routine
  therapy of young women with hormone responsive
  disease post chemotherapy or as solitary hormonal
  therapy
• Increasing use of aromatase inhibitors in the
  adjuvant setting

56
Pre-specified Adverse Events All Fractures
Relative Risk
1.59
1.60
57
Prevention of bone loss induced by estrogen
depletion
Accrual 1999-2004 Premenopausal patients Stage
III, lt10pos nodes ER / PgR Treatment duration
3 years Preoperative CT allowed
Tamoxifen 20 mg/d
Tamoxifen 20 mg/d Zoledronic acid 4mg q6m
Surgery (RT)
Goserelin 3.6mg q28d
Randomize 1 1 1 1
Anastrozole 1 mg/d
Anastrozole 1 mg/d Zoledronic acid 4mg q6m
Gnant et al., SABCC 2002 and St. Gallen poster
P101
58
Skeletal Issues in Breast CancerPreserving
normal Skeletal health

• Adjuvant chemotherapy and hormonal therapy can
  lead to premature menopause and osteoporosis.
• The administration of bisphosphonates can
  ameliorate the decrease in BMD.
• Continuous oral therapy or frequent IV
  administrations are inconvenient and costly.
• Zomera offers greater efficacy, cost
  effectiveness and convenience.

59
Skeletal Issues in Breast Cancer

• Preserving normal Skeletal health
• Chemotherapy induced amenorrhea
• Ovarian ablation
• Estrogen deprivation by aromatase inhibitors
• Preventing bone metastases
• Adjuvant therapy with bisphosphonates
• Reducing skeletal morbidity rate in women with
  bone metastases
• Pain Narcotic use
• Pathological fractures
• XRT

60
Skeletal Issues in Breast Cancer

• Preserving normal Skeletal health
• Chemotherapy induced amenorrhea
• Ovarian ablation
• Estrogen deprivation by aromatase inhibitors
• Preventing bone metastases
• Adjuvant therapy with bisphosphonates
• Reducing skeletal morbidity rate in women with
  bone metastases

61
Bisphoaphonates in MBC

• Bisphosphonates made a major change in the
  management and morbidity of bone metastases in
  breast cancer
• Reduction of XRT use
• Reduction of pathological fractures
• Reduction of narcotic use

62
The influence of Pamidroante on SRE in MBC
Pamidronate trial 1990s Breast hormonal
Pamidronate trial 1990s Breast chemotherapy
63
Zoledronic Acid in Patients With Breast Cancer

• Pamidronate-Controlled Trial

64
Breast Cancer and Multiple MyelomaEntry Criteria

• Stage IV breast cancer with ? 1 bone metastases
• OR
• Durie-Salmon stage III multiple myeloma with? 1
  bone lesions
• Appropriate antineoplastic therapy at baseline
  and during the course of the trial
• ECOG performance status 0, 1, 2
• Serum creatinine ? 3.0 mg/dL (265 µmol/L)

65
Breast Cancer and Multiple Myeloma Trial Design
N564
R A N DO M I Z E D
Zoledronic acid 4 mg q 3 to 4 wk daily oral
vitamin D 400 IU and calcium 500 mg
N558
Pamidronate q 3 to 4 wk daily oral vitamin D
400 IU and calcium 500 mg
0
13 monthsCore analysis
25 months Final analysis

• Double-blind, double-dummy study designed to
  demonstrate noninferiority of zoledronic acid
  compared with pamidronate

66
Study Endpoints

• Primary endpoint
• Proportion or percentage of patients with a
  skeletal-related event (SRE)
• Secondary endpoints
• Time to first SRE
• Skeletal morbidity rate (SMR) mean annual
  incidence of events
• Multiple event analysisconsiders all events and
  time between events
• Pain/analgesic scores
• Bone lesion response
• Time to progression of disease
• Safety (including survival)

All skeletal events occurring within 21 days
counted as a single occurrence.
67
Skeletal-Related Events (SREs)

• SREs include the following skeletal complications
• Radiation for bone pain or to treat or prevent
  pathologic fractures or spinal cord compression
• Pathologic fracture
• Spinal cord compression
• Surgery to bone
• Hypercalcemia of malignancy (HCM)

68
Breast Cancer and Multiple Myeloma

• Zoledronic acid Pamidronate 4 mg 90 mg
• Stratum (n 561) (n 555)
• Breast cancer 378 388
• Chemotherapy 178 181
• Hormonal therapy 200 207
• Multiple myeloma 183 167

ITT population.
69
Breast Cancer Patients With an SRE

• Zoledronic acid 4 mg versus pamidronate 90 mg
  95 CI 10.5, 3.6. The noninferiority
  criterion, the upper boundary of the 95 CI, is lt
  8

Hypercalcemia of malignancy is excluded as an
SRE.
70
Breast Cancer Patients With SREs
Patients,
71
Breast Cancer Mean Skeletal Morbidity Rate
Hypercalcemia of malignancy is included as an
SRE.
72
Breast Cancer-Multiple Event Analysis

• Zoledronic acid decreased the risk of developing
  a skeletal complication by 20 compared with
  pamidronate

Hazardratio
P value
.025
.799
HCM
.042
.816
HCM
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Hazard ratio (zoledronic acid 4 mg versus pam)
In favor of zoledronic acid
In favor of Pamidronate
73
Breast CancerSecondary Endpoints

• No significant differences between zoledronic
  acid and pamidronate were seen for the following
  endpoints
• Time to overall progression of disease
• Time to progression of bone metastases
• Global quality of life
• ECOG performance status
• Pain and analgesic use
• Survival

74
Zoledronic Acid in Metastatic Breast Cancer

• Zoledronic acid (4 mg) is more effective than
  pamidronate (90 mg) in patients with breast
  cancer
• Significantly reduced the requirement for
  radiation therapy to bone
• Significantly reduced the risk of developing
  skeletal complications compared with pamidronate
• Zoledronic acid is as safe and well tolerated as
  pamidronate
• Zoledronic acid is more convenient than
  pamidronate
• 4 mg IV over 15 minutes

75
Bisphosphonates in Breast Cancer

• Skeletal health is a major issue in all phases of
  therapy in breast cancer.
• Awareness of the increased rate of osteoporosis
  and the morbidity of bone metastases is of
  paramount importance.
• Zomera offers potency, activity and ease of use.

76
Bisphosphonates in Prostate Cancer
77
Treatment of Bone Complications in Advanced
Prostate Cancer Rationale for bisphosphonate Use
and Results of a Phase III Trial With zoledronic
Acid

• Prostate cancer often metastasizes to bone
  during disease progression. Patients who develop
  bone metastases have a high risk of developing
  skeletal complications, including pathologic
  fractures, spinal cord compression, and severe
  bone pain. Bisphosphonate therapy is widely used
  for the prevention of skeletal complications in
  patients with bone lesions from multiple myeloma
  and breast cancer. Until recently, however, no
  bisphosphonate had ever shown objective clinical
  benefit in patients with prostate cancer and
  osteoblastic bone lesions.  

78
Treatment of Bone Complications in Advanced
Prostate Cancer Rationale for bisphosphonate Use
and Results of a Phase III Trial With zoledronic
Acid

• A recent multicenter, randomized,
  placebo-controlled trial found zoledronic acid (4
  mg) to be a safe and effective therapy in
  patients with bone metastases from
  hormone-refractory prostate cancer. Zoledronic
  acid significantly reduced the proportion of
  patients who experienced skeletal complications
  and extended the time to first skeletal
  complication. Further, zoledronic acid
  significantly reduced the risk of skeletal
  complications over this 15-month study and
  provided consistent reductions in bone pain that
  were significant at the 3- and 9-month time
  points compared with placebo.

79
Treatment of Bone Complications in Advanced
Prostate Cancer Rationale for bisphosphonate Use
and Results of a Phase III Trial With zoledronic
Acid

• These results suggest that zoledronic acid
  may become an important advancement in the care
  of patients with prostate cancer metastatic to
  bone. The role of zoledronic acid in the
  treatment of patients with prostate cancer
  continues to evolve.
• (Saad F. Semin Oncol. 2002 Dec29(6 Suppl
  21)19-27)