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ZOLEDRONIC ACID(ZOMETAR)

FOR BONE METASTASES OFSOLID TUMOURS

By Joan Fabbro

BSc Pharm

BCCA- Fraser Valley Center



Outline

•Bone metastases and cancer

•Bisphoshphonates in cancer

•Zoledronic acid

Hypercalcemia

Bone metastases

•Cost comparison

•Summary



Bone Remodelling in Healthy

vs. Cancer Patients osteoclast = bone resorbing cells => osteolysis

osteoblast = bone forming cells => osteogenesis

Healthy bone “remodelling”: osteoclast = osteoblast activity



Cancer Bone “remodelling”

Osteolytic

Osteoclast > Osteoblast Net bone resorbtion

Release of growth factors => tumour growth

Release mediators => stimulate osteoclast activity



Osteogenic

Osteoblast > Osteoclast

Net bone formation

Osteoclast activity

osteolysis



The Impact of Metastatic Bone Disease Advanced

Breast

Cancer

Multiple

Myeloma

Prostate

Cancer

Lung

Cancer

Renal

Cancer

%

Incidence

of Bone

Metastases

65 – 75 95 - 100 65 -75 30 - 40 25 - 30

5 yr

survival

median

survival

20%

24 months

10 %

20 months

25 %

40 months

<2%

to<5%

< 6 months

**

<9 months

ClassificationMixed

Osteolytic

>

Osteogenic

Mostly

Osteolytic

Mixed

Osteogenic

>>

Osteolytic

Mostly

Osteolytic

Mostly

Osteolytic



Bisphosphonates in cancer

1) hypercalcemia

2) bone metstreatment

prevention-mixed evidence

Available in Canada :

Clodronate(BonefosR )…oral/IV

Pamidronate(ArediaR

)…IV Alendronate(FosamaxR )..oral

Etidronate(DidronelR , DidrocalR )..oral

Risendronate(ActonelR )….oral

Zoledronic Acid(ZometaR )…IV



Bisphophonates - Mechanism of Action

•clinical benefit takes several days

vs. osteoclast:

•inhibit hyperactivity

•inhibit maturation

•inhibit attachment to bone site

•decrease cytokine production

vs. tumour activity:•inhibit tumour cell invasion, proliferation &

adhesion to bone

•induce apoptosis

•reduce tumour cell proliferation



Properties of bisphosphonates

Absorption

• Low oral bioavailability

• dose = side effects

• Food

Elimination

• renal

• bound to bone

Side Effects

• flu-like symptoms

• bone pain• GI complaints

• dyspnea

• lower limb edema



Zoledronic Acid

• New highly potent 3rd generation

bisphosphonate

• Heterocyclic nitrogen-containingmolecule with:

– A core bisphosphonate moiety

– An imidazole-ring side chaincontaining 2 critically positioned

nitrogen atoms

Green JR, et al. J Bone Miner Res . 1994;9:745-751.

Green JR, et al. Pharmacol Toxicol . 1997;80:225-230.

C



C

o m p l e t e r e s p o n d e r s ( % )

Efficacy in Hypercalcaemia of

Malignancy

0

20

40

60

80

100

Day 0 Day 4 Day 7 Day 10

Zoledronic Acid 4mg

Pamidronate 90 mg (n = 99)

87%P = .015*

82.6%P = .005*

45%

33%

64%70%

C

Major, P et al. JCO ,2001;19: 558-567



Phase III Trials With Zoledronic Acid in Patients With Metastatic

Bone Disease

•Zoledronic Acid4mg, 8mg or

placebo

•Prostate cancer with bonemetastases

stratification: Prostate Ca - no

mets; prostate Ca with mets

•Randomized, double-blind, placebo control

•Duration: 15 months

•039

•10 efficacy parameter: proportion of patients with at least one skeletal-related event (SRE)

• Adjustments: zoledronic acid infused over 15 min. 8mg dose => 4mg for renal complications

•Zoledronic Acid

4mg, 8mg or

placebo

•Lung and other cancers with bonemetastases

(excluding breast or prostate)

stratification: lung Ca; „other solid

tumours‟

•Randomized, double-

blind, placebo control


•011

•Zoledronic Acid

4mg, 8mg or

pamidronate 90mg

•Multiple myeloma or breast

cancer with bone metastases

stratification: myeloma;

breast Ca-chemo; breast Ca-hormonal

•Randomized, double-

blind, non-inferiority


•010

•Treatments•Patients•Design•Protocol



Protocol 010

Completed trial

N = 353

Efficacy analysis: 561Safety analysis: 561

Zoledronic Acid 4 mg

N = 564

Completed trial

N = 313


Zoledronic Acid 8/4 mg

N = 526

Completed trial

N = 338


Pamidronate 90 mg

N = 558

RandomizedN = 1648

Rosen L S, et al. Zoledronic Acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesiona of multiplemyeloma: a phase III, double-blind commparative trial. Cancer J.2001; 7: 377-387



Protocol 010

• Multicenter, double-blind, randomized, controlled,

phase III

• “inferiority” trial

• Zoledronic Acid 4mg, 8mg IV vs. pamidronate 90mg IV q 3-4 weeks x 12months

• multiple myeloma, breast Ca (chemo, hormonal)

• pamidronate 90 mg IV - standard• study objective: zoledronic acid non-inferior vs.

pamidronate preventing SRE

• 60% completed trial



Breast Cancer and Multiple Myeloma

proportion (%) of patients in protocol

010 With an SRE

44%46%

0

10

20

30

40

50

P e r

c e n t o f p a t i e n t s

Zoledronic Acid4mgPamidronate90 mg

N = 561 555

Zoledronic Acid 4 mg versus pamidronate 90 mg: 95% CI ( –7.9%, 3.7%). The noninferiority

criterion, the upper boundary of the 95% CI, is below 8%

p= 0.052

14



Protocol 010: Breast Cancer and

Multiple Myeloma time to first SRE

0

10

20

30

40

5060

70

80

90

100

0 60 120 180 240 300 360 420

Time after start of study drug, days

P e r c e n t w i t h o

u t e v e n t

Zoledronic Acid 4 mg 373

Pamidronate 90 mg 363

0 1 0 P T F 9 . 2 - 1 p 4 ; C S R 0

1 0 T 9 - 3

14

Median time,

days



Study 010 Comments (at 25 months)

• 12 month extension N=606 (<40%) and >50% completion

• % patients - one SRE (not HCM); Z4mg 47%;Pam90mg 51%

• median time to first SRE - Z4mg 376 days;Pam90mg 356 days

• confirmed long-term safety, efficacy - ZoledronicAcid 4mg;

Pamidronate 90 mg

• subset group (breast Ca-hormonal) - further trials



Protocol 011

Intent-to-treatN = 257

Zoledronic Acid 4 mgN = 257

Not included in analysis

Zoledronic Acid 8/4 mgN = 266

Intent-to -treatN = 250

PlaceboN = 250

Randomized

N = 773

Rosen L, Gordon D, Tchekmedyian S, et al. Zoledronic Acid versus placebo in the treatment of skeletal metastases in patients with lung

cancer and other solid tumours: A phase III, double-blind, randomized trial - the Zoledronic acid lung cancer and other solid tumours study group. JCO 21: 3150 - 3157, 2003.



Protocol 011

• Randomized, double-blind, multicenter, phase III

• placebo control trial

• zoledronic Acid 4mg, 8mg IV vs. placebo

q3weeks (daily calcium/vit D) x 9 months• bone metastases from solid tumours

• not breast or prostate

• study objective: efficacy- zoledronic acid+chemovs. chemo preventing SRE

• 25 % completed trial

12



Protocol 011: Solid tumors (not PC &BC)

proportion (%) of patients with an SRE

time to first SRE

38

44

30

40

50

P e r c e n t o f p a t i e n

t s

Zoledronic Acid

Placebo

N = 257 N = 250

12

P = .127

0

10

2030

405060

70

8090

100

0 30 60 90 120 150 180 210 240Time after start of study drug, days

P e r c e n t w i t h o

u t e v e n t

Median time,

days P -value

Zoledronic Acid 4 mg 230 .023

Placebo 163



Protocol 039

Completed Trial

N = 81

Efficacy analysis: 214

Safety analysis: 214

Zoledronic Acid 4mg

N = 214

Completed Trial

N = 62

Efficacy analysis : 221


Zoledronic Acid 8/4mg

N = 221

Completed Trial

N = 65

Efficacy analysis: 208


Placebo

N = 208

Randomized

N = 643

Saad F, et al. Journal of the National Cancer Institute. 2002; 94 : 1458 - 1468.



Protocol 039

• Randomized, double-blind, multicenter, phase III• placebo control trial

• zoledronic acid 4mg, 8mg IV vs. placebo q 3

weeks (daily calcium/vit D)• 15 months

• prostate cancer - metastatic, PSA, hormonal

treatment

• study objective: efficacy zoledronic acid+chemo

vs chemo preventing SRE

• 40 % completed trial



Proportion of protocol 039 patients

with skeletal-related events (SRE)

All patients

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

p = 0.021

P r o p o r t i o n o f p a

t i e n t s

Zoledronic Acid 4 mg

Placebo

Saad F, et al. Journal of the National Cancer Institute. 2002; 94 : 1458 - 1468.

33.2% 44.2%



Protocol 039: Time to first skeletal-

related event

100

90

80

7060

50

40

30

20

10

0

0 50 100 150 200 250 300 350 400 450 500

550

P e r c e n t o f p a t i e

n t s

w i t h o u t e v e n

t

Time after start of therapy (days)

NR = not reached

P-value = 0.011

Median Time:

Zoledronic Acid 4 mg=NR

Placebo = 321 days

Saad F, et al. Journal of the National Cancer Institute. 2002



Subset Analysis of Renal Cancer Patients from

Study 011

• N= 74 pt

• 10 endpoint - 74% placebo vs 37% Zoledronic Acid

• the time to SRE & morbidity rate - improved significantly

on the zoledronic acid 4mg arm.

• bone pain - placebo group

• subset group = lower numbers = lower power

• warrants investigation



Cost Comparison Pamidronate vs Zoledronic Acid

Pamidronate 90 mg (monthly cost) $307.35

Zoledronic Acid 4mg (monthly cost) $564.63

• chair time shorter for Zoledronic acid (15 min vs 1-2 hours

infusion )

•time/motion study in USA - adapted to Canada

•Zoledronic Acid $9 more expensive to administer

•IV zoledronic acid vs. IV pamidronate = 1 hr extra chair time

Dranitsaris, G et al. Zoledronic Acid versus pamidronate as palliative therapy in cancer patients: A Canadian time and motion analysis. J Oncol Pharm Practice 2001;7: 27 - 33

S



Summary

•cancer mets to bone => morbidity

• bisphosphonates provide clinical benefit

•Zoledronic Acid more effective than pamidronate in

hypercalcemia of malignancy and shorter infusion time

•study 010 suggests zoledronic acid 4mg IV effective in

patients with bone mets from breast cancer/multiple myeloma

•studies 011 and 039 support efficacy of zoledronic acid 4mg

IV vs. placebo in pts with bone mets from solid tumours

•renal subset analysis of study 011 numbers and power



BCCA - Benefit

Current:

•multiple myeloma - pamidronate

• breast Ca + mets - clodronate

Future:

(PEC proposal)

• prostate Ca + mets - zoledronic acid

•renal Ca - zoledronic acid



BCCA - Non benefit

Current:

•hypercalcemia - pamidronate

• palliative care - pamidronate- zoledronic acid

Future:

• prostate Ca osteoporosis

+ LHRH - zoledronic acid

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