Managing Skeletal Metastases

Alison Stopeck, M.D.

Professor of Medicine

Director, Breast Cancer Program

University of Arizona Cancer Center

Tucson, AZ

Disclosures: Consulting , research funding, and honoraria from Amgen

The Natural History of Bone Metastases in Breast Cancer

• Pathologic fracture is the most common SRE in

patients with breast cancer

• Median onset is 11 mos from initial diagnosis of

bone metastases

• ~ 20% develop hypercalcemia after a median of

14 mos

• ~ 10% develop cord compression after a median

of 17 mos

• Over 60% of patients develop SRE within 2 years

of diagnosis if untreated with a bone-modifying

agent Lipton A. Cancer. 2003;97:848-853.

Complications of Bone Metastases Skeletal Related Events

• Fracture

• Need for radiation to bone

– PAIN

• Need for surgery to bone

– Impending fracture

• Spinal cord compression

• Hypercalcemia

• Skeletal complications account

for 63% of hospital costs in

patients with advanced breast

cancer Coleman RE. Cancer. 1997;80:1588-1594.

Biermann WA, et al. Bone. 1991;12(suppl 1):S37-S42

RANK Ligand Is a Key Mediator in the “Vicious Cycle” of Bone Destruction

Bone RANK

RANKL

Bone

Resorption

Osteoclast

Cancer Cells in Bone

Growth Factors (TGF-b, IGFs, FGFs,

PDGFs, BMPs)

Cytokines and Growth

Factors (IL-6, IL-8, IL-1b,

PGE-2, TNF-, CSF-1, PTHrP)

Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.

RA

NK

L

Direct effects

on tumor?

Hypercalcemia

Bone

Metastasis

Fracture

Spinal cord

compression

Optimal Management of Patients with Bone Metastases: Treat the Disease and Prevent SREs

Bone pain

Primary

treatment Prevent the consequences

Patients with SREs have worse OS than

those with bone mets alone1,2 1 Yong M et al. Breast Cancer Res Treat 2011; 129(2): 495-503 2Sathiakum N et al. Prostate Cancer Prostatic Dis. 2011 14 (2): 177-83

Preventing Skeletal Related Events

FDA-Approved Agents for Prevention of

SREs in Patients with Solid Tumors

Both ASCO and NCCN recommend all 3 agents[1,2]

– No agent recommended over another

Agent Drug Class Recommended Dose and Schedule

Zoledronic acid Bisphosphonate 4 mg IV q3-4w

Pamidronate Bisphosphonate 90 mg IV q3-4w

Denosumab RANKL-targeted MAb 120 mg SQ q4w

1. Van Poznak CH, et al. J Clin Oncol. 2011;29:1221-1227. 2. NCCN. Clinical practice guidelines in

oncology: breast cancer. v.2.2011.

Agents

Approved

Outside US

Drug Class Recommended Dose and Schedule

Clodronate Bisphosphonate 600-900mg IV or 1000 – 2400 mg po

daily

Ibandronate Bisphosphonate 6mg IV or 50mg po daily

Differences in Bone-Modifying Agents

Efficacy

Toxicity

Administration

Cost

Risks Benefits

Patient

Characteristics

and

Preferences

Bisphosphonates Reduce Skeletal Related Events in Breast Cancer

% pts with SRE

Placebo 65% 24 months 1

Pamidronate 46%

Pamidronate 49% 24 months 2

Zoledronic Acid 46% (p = ns)

Placebo 50% 12 months 3

Zoledronic Acid 30%

1 Lipton A et al, Cancer, 2000; 2 Rosen LS et al, Cancer, 2003; 3 Kohno N et al, J Clin

Oncol 23, 2005

Zoledronic Acid vs. Placebo in Stage IV Breast Cancer

Pain Scores (Brief Pain Inventory) Kohno N et al, J Clin Oncol 23, 2005

Bisphosphonates: Side Effects

Oral administration:

– Poorly absorbed from the GI tract (0.5-4%)

– Non-nitrogen-containing: diarrhea

– Nitrogen-containing: esophagitis, nausea

IV administration:

– Fever, flu symptoms, arthralgias/myalgias, hypocalcemia

– Renal insufficiency (related to dose, volume, rate)

Potential for interference with mineralization

– Skeletal ½-life several years

– Osteonecrosis of the jaw

– Atypical femoral fractures

RANKL Inhibition as a Target for the Prevention of Skeletal Complications of Metastases

• RANKL is the primary mediator of osteoclast formation, function, and survival and plays a vital role in physiologic and cancer-induced bone resorption

• Metastatic tumour cells stimulate RANKL activity, leading to a self-reinforcing cycle of bone resorption (“vicious cycle” hypothesis)1

• The fully human monoclonal antibody, denosumab, binds and inhibits RANKL thereby preventing bone destruction

• In phase 2 trials, denosumab significantly lowered bone turnover markers and reduced SREs, including in pts with elevated uNTx levels despite IV bisphosphonate therapy2,3

1Roodman GD. N Engl J Med 2004;350:1655-1664, 2Fizazi K, et al. J Clin Oncol 2009;27:1564-1571. 3Lipton A, et al. J Clin Oncol 2007;25:4431-4437.

Denosumab vs Zoledronic Acid in the Pivotal

Phase III SRE Prevention Trials

1. Stopeck AT, et al. J Clin Oncol 2010;28:5132–9. 2. Fizazi K, et al. Lancet 2011;377:813–22. 3. Henry DH, et al. J Clin Oncol 2011;29:112532.

Supplemental calcium and vitamin D

Denosumab 120 mg SC Q4W

+

Placebo IV Q4W†

Zoledronic acid 4 mg IV Q4W†

+

Placebo SC Q4W

Study 1361

Breast cancer

(N = 2049)

Study 1032

Prostate cancer

(N = 1904)

Study 2443

Other solid tumours/MM

(N = 1779)

R

A

N

D

O

M

I

z

A

T

I

O

N

In total > 5700 patients with bone metastases

Time to First On-Study SRE

Zoledronic Acid 1020 829 676 584 498 427 296 191 94 29

Denosumab 1026 839 697 602 514 437 306 189 99 26

Months Subjects at risk:

Pro

po

rtio

n o

f S

ub

jects

Wit

ho

ut

SR

E

HR 0.82 (95% CI: 0.71, 0.95)

P < 0.0001 (Noninferiority)

P = 0.01 (Superiority)*

* Adjusted for multiplicity

0

1.00

0 3 6 9 12 15 18 21 24 27 30

0.25

0.50

0.75

KM Estimate of Median Months

Denosumab Zoledronic Acid

Not reached 26.5

18% Risk Reduction

Stopeck et al. JCO 2010: 28: 5132

Time to First On-Study SRE or Hypercalcemia: Extended Analysis

Zoledronic acid 1020 831 673 581 492 424 355 263 185 109 38 4

Denosumab 1026 834 688 594 506 441 381 276 191 100 37 8

KM Estimate of Median Mos

Denosumab

Zoledronic acid

32.4

25.1

HR: 0.82 (95% CI: 0.71-0.95; P = .0076)

Study Mo

0

1.0

Pro

po

rtio

n o

f P

ati

en

ts

Wit

ho

ut

SR

E o

r H

yp

erc

alc

em

ia

0.2

0.4

0.6

0 3 6 9 12 15 18 21 24 27 33 30

0.8 18%

Risk Reduction

Patients at Risk, n

Stopeck A, et al. SABCS 2010. Abstract P6-14-01.

Time to First-and-Subsequent On-Study SRE* (Multiple Event Analysis)

0 3 6 9 12 15 18 21 24 27 30

0

0.5

1.0

1.5

Cu

mu

lati

ve M

ean

Nu

mb

er

of

SR

E

Months

Total # of Events

Denosumab

Zoledronic acid

474

608

Rate Ratio 0.77 (95% CI: 0.66, 0.89)

P = 0.001†

*Events that occurred at least 21 days apart; †Adjusted for multiplicity

23% Risk Reduction

Stopeck et al. JCO 2010: 28: 5132

Types of SREs in Each Treatment Group

28.1

17.2

2.81.4

23.5

13.5

2.91.4

0.0

5.0

10.0

15.0

20.0

25.0

30.0

Pathologic fracture Radiation to bone Surgery to bone Spinal cord compression

Pro

port

ion

of s

ubje

cts

(%)

Zoledronic acidDenosumab

P = 0.0354

P = 0.0184

Risk of First On-study SRE by Solid Tumor

Types

Richardson G et al. COSA November 2011

Percent Decrease in uNTx Levels With

Therapy

Trial Denosumab Zoledronic Acid

Breast cancer ↓ 80% ↓ 68%

Prostate cancer ↓ 40% ↓ 28%

Solid tumor/MM ↓ 76% ↓ 65%

Comparing baseline to Wk 13 values

Stopeck A, et al. SABCS 2010. Abstract P6-14-01.

Overall Adverse Events

Patient incidence, n (%) ZA

(N = 2744)

Denosumab

(N = 2755)

All adverse events (AEs) 2654 (96.7) 2650 (96.2)

CTCAE Grade 3, 4, or 5 AEs 1941 (70.7) 1934 (70.2)

Serious AEs 1573 (57.3) 1549 (56.2)

AEs leading to study discontinuation 270 (9.8) 261 (9.5)

Adverse events of interest

Acute phase reactions (first 3 days) 561 (20.4) 241 (8.7)

ONJ (adjudicated) 35 (1.3) 48 (1.7)

Hypocalcemia* 131 (4.8) 261 (9.5)

N = the number of patients who received at least one dose of active drug.

*Includes hypocalcemia, blood calcium decreased, calcium deficiency, and calcium ionized decreased.

Richardson G et al. COSA November 2011

Toxicity

Between-Group Differences in Adverse Events With Unadjusted P < 0.05

Favors Denosumab Favors Zoledronic Acid

Hypocalcemia Toothache

Renal failure acute Blood urea increased

Bronchospasm Hyperthermia

Skin hyperpigmentation Metastases to spine

Hypercalcemia Edema

Alanine aminotransferase increased Lumbar vertebral fracture

Dyspepsia Renal failure

Pain Chills

Anemia Arthralgia Bone pain

Pyrexia

Risk Difference

-10 10 -5 5 0

Zoledronic Acid

(N=1013)

Denosumab

(N=1020) n (%) n (%)

247 (24.4) 170 (16.7) 238 (23.5) 186 (18.2) 291 (28.7) 250 (24.5) 232 (22.9) 192 (18.8) 58 (5.7) 29 (2.8) 97 (9.6) 72 (7.1) 25 (2.5) 2 (0.2) 74 (7.3) 52 (5.1) 56 (5.5) 35 (3.4) 47 (4.6) 28 (2.7) 40 (3.9) 22 (2.2) 35 (3.5) 17 (1.7) 21 (2.1) 9 (0.9) 19 (1.9) 7 (0.7) 15 (1.5) 4 (0.4) 10 (1.0) 2 (0.2) 8 (0.8) 0 (0.0) 7 (0.7) 1 (0.1)

37 (3.7) 57 (5.6) 34 (3.4) 56 (5.5)

Stopeck et al. JCO 2010: 28: 5132

Overall Incidence Of Hypocalcemia from the 3 Pivotal Trials

Ref: Body JJ et al. ASCO 2013 abstract

Risk Factors for Hypocalcemia

• Diagnosed with metastatic prostate cancer

(20.5%) vs Breast Cancer (8.4%)

• Taking Calcium/Vit D Supplements (12% vs

15.1%)

• Renal Insufficiency (11% vs 15.3%)

• First 6 months of therapy (7.7%) vs next 6

months of therapy (3.2%)

• Median time to hypocalcemia:

– 3.8 months with Dmab vs 6.5 months with ZA

Ref: Body JJ et al. ASCO 2013 abs

Situation Action

Pre-existing hypocalcemia or

vitamin D deficiency

Correct before starting bone-targeted

therapy

Start of bone-targeted therapy

Start daily oral supplements of

≥ 500 mg calcium and 400 IU vitamin D

Counsel patients on symptoms of

hypocalcemia

Severe renal impairment (creatinine

clearance < 30 mL/min) or dialysis Monitor calcium levels more frequently

Hypocalcemia on therapy Additional short-term calcium

supplementation may be necessary

Preventing and Managing Hypocalcemia

First prospective study of ONJ in cancer

patients with bone metastases • First prospective study to

assess the incidence, risk factors, and outcomes of ONJ through an integrated analysis comparing denosumab with zoledronic acid in three blinded active-controlled phase III trials in cancer patients with bone metastases1

1. Saad F et al. Annal. Oncol 2011; 23: 1341-7 2. Browb JE et al. ECC 2013 (abstract)

Zoledronic acid

(n = 37)

1.3%*

Denosumab

(n = 52)

1.8%*

Positive for ONJ

(n = 89)

Potential ONJ

(n = 276)

All patients

(N = 5723)

P = 0.13* Recently updated with results from open

label extension phases in breast and

prostate cancer2. Now 63 (1.9%) cases

(Dmab) vs 44 (1.3%) ZA (P=0.08)

Associated Oral Events

n (%) Zoledronic Acid

(n = 37)

Denosumab

(n = 52)

All

(N = 89)

Tooth extraction 24 (65) 30 (58) 54 (61)

Jaw pain 25 (68) 46 (88) 71 (80)

Local infection 17 (46) 26 (50) 43 (48)

n (%) Zoledronic Acid

(n = 37)

Denosumab

(n = 52)

All

(N = 89)

Mandible 31 (84) 34 (65) 65 (73)

Maxilla 5 (14) 15 (29) 20 (22)

Both 1 (3) 3 (6) 4 (4)

Location of ONJ

Saad F et al. Annal. Oncol 2011, doi:10.1093/annonc/mdr435

Systemic Risk Factors

Subjects With ONJ Subjects Without ONJ*

n (%)

ZA

(n = 37)

Denosumab

(n = 52)

All

(N = 89)

ZA

(n = 2824)

Denosumab

(n = 2810)

All

(N = 5634)

Diabetes† 11 (30) 9 (17) 20 (22) 431 (15) 443 (16) 874 (16)

Anemia (Hg <10)‡ 17 (46) 23 (44) 40 (45) 1185 (42) 1119 (40) 2304 (41)

Chemotherapy

agents

27 (73) 36 (69) 63 (71) 1950 (69) 1921 (68) 3871 (69)

Antiangiogenics 8 (22) 6 (12) 14 (16) 236 (8) 214 (8) 450 (8)

Corticosteroids 28 (76) 39 (75) 67 (75) 1786 (63) 1762 (63) 3548 (63)

Ref: Saad F et al. Annal. Oncol 2011, doi:10.1093/annonc/mdr435

Treatment

n (%) Zoledronic Acid

(n = 37)

Denosumab

(n = 52)

All

(N = 89)

Limited surgery 16 (43) 21 (40) 37 (42)

Bone resection 1 (3) 3 (6) 4 (4)

Median or n (%) Zoledronic Acid

(n = 37)

Denosumab

(n = 52)

All

(N = 89)

Resolved* 11 (30) 21 (40) 32 (36)

Time to resolution†, mos 8.7 8.0 8.2

Ongoing, present at time of

death, or unknown

26 (70) 31 (60) 57 (64)

Outcomes

*Complete mucosal coverage of exposed bone; †Among subjects with ONJ resolution

Characteristic Proportion of patients (%)†

Pain status (n = 1926)

No pain‡ 15

Mild pain‡ 39

Moderate pain‡ 22

Severe pain‡ 24

Analgesic use (n = 2046)

No analgesic use 84

Opioid-based analgesic use 16

Cleeland CS, et al. Cancer 2013;119:832-838. †Data are baseline data from the pivotal Phase III denosumab SRE prevention study in breast cancer patients.

‡Based on observed data.

Majority of Breast Cancer Patients with

Bone Metastases Report Pain

Typically bone pain is not adequately managed

46%

Time to Experiencing Pain Improvement ( 2-Point Decrease in Worst Pain Score of Brief Pain Inventory)

Months 0 3 6 9 12 15 18 21 24 27

0

Pro

po

rtio

n o

f S

ub

jects

1.00

0.25

0.50

0.75

Subjects at risk:

Zoledronic Acid 745 351 196 138 108 88 68 51 33

Denosumab 747 344 208 148 106 88 71 52 25

HR 1.02 (95% CI: 0.91, 1.15)

P = 0.72

KM Estimate of Median Days

Denosumab Zoledronic acid

82 85

Stopeck A, et al. ASCO 2010. Abstract 1024

Time to Worsening Pain in Patients With

No or Mild Pain (0-4) at Baseline

Stopeck A, et al. ASCO 2010. Abstract 1024.

Denosumab 542 369 286 247 197 170 126

Zoledronic acid 500 294 224 180 155 128 95

KM Estimate of Median Mos

Denosumab

Zoledronic acid

9.7

5.8

HR: 0.78 (95% CI: 0.67-0.92; P = .0024)

Mos

0

1.00

Pro

po

rtio

n o

f S

ub

jects

0.40

0.60

BL 3 6 9 12 15 18

0.80

0.20

Pts at Risk, n

A lower proportion of breast cancer patients on denosumab progressed from no or low analgesic use to strong opioid use vs zoledronic acid

• Cleeland CS, et al. SABCS 2010 [abstract P1-13-01 and poster].

*P < 0.05; not adjusted for multiplicity

Study month

1 3 6 9 12 15 18

* * *

*

0

2

4

6

8

10

12

14

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Denosumab (n = 863)

Zoledronic acid (n = 848)

Zoledronic acid improves QoL in breast cancer patients1

Phase IIIb, multicentre, randomised, open-label, crossover study

Zoledronic acid administered in the community setting vs the hospital

101 breast cancer patients with bone metastasis receiving hormonal therapy

Quality of life assessed by EORTC QLQ-C30

1. Adapted from Wardley, A. Br J Cancer 2005; 92: 1869–1876

*P<0.05; †P<0.001

QoL = quality of life

Administration Preferences

Issues with Adherence and Administration

Patient preferences (perceived inconveniences)

– Prefer oral to IV

– Prefer home to clinic administration

– Prefer shortest time of administration i.e. 15 vs 120 minute infusion time

Health state utility study in UK

– Subcutaneous injections preferred over intravenous

– Allows for home administration

Ref: Matza LS et al. ASCO 2012

Costs of Bone-Targeted Treatment

• Costs vary by country and health-care systems

• Most cost-effectiveness analysis limited:

– Generally do not take into account costs that may be

important to the patient:

• Lost time for patient or caregivers to receive therapy

• Time and QOL lost for treatment of SRE

– Controversial assessments on number of expected SRE

• Cost of drug acquisition and SRE rates determine cost

effectiveness of therapy

Cost-Effectiveness of Denosumab versus Zoledronic Acid

Prostate cancer Breast cancer NSCLC

Dmab ZA Diff Dmab ZA Diff Dmab ZA Diff

Total lifetime number of SREs

3.23 4.04 0.81 3.56 4.55 0.99 2.46 2.83 0.39

Total lifetime costs ($)

76,486 69,577 6,910 108,538 95,087 13,451 49,068 44,993 4,076

Cost/QALY gained ($)

49,405 78,915 67,931

Cost/SRE avoided ($)

8,567 13,557 10,513

Ref: Stopeck A et al. J Med Econ 2012

Other studies: Cost/QALY estimated 192,000 to 1.3 million, and cost/SRE avoided

estimated at up to 50,000

• Average life expectancy after bone mets = 3.1 years

• Costs of Dmab for 3.1 yrs x $1650/mo = $59,400

• Costs of Zoledronic acid for 3.1 yrs x $900/mo = $32,400

• Difference = $27,000

• SRE prevented = 1 (cost per SRE ~ 13,000)

• Cost per SRE = $14,000

Costs of Therapy: Metastatic Breast Cancer

Costs of Pamidronate for 3.1 yrs = $1860

Cost per SRE ~ $44,500

Cost-Effectiveness of Denosumab versus ZA Relative to Other Select Oncology Therapies

$320,000

$142,200

$44,000

$49,405

$62,000

$67,931

$74,000

$78,915

$110,000

$130,000

$159,200

$180,000

$0 $100,000 $200,000 $300,000

†Mean Implied Oncology Threshold in US

₮WHO Definition of U.S Threshold

Radiotherapy vs Pain meds rPC

denosumab vs zoledronic acid in CRPC

Gleevec vs IFN+Cyt in CML

denosumab vs zoledronic acid in mNSCLC

Tamoxifen vs no tamoxifen, BC risk >=3%

denosumab vs zoledronic acid in BC

Herceptin vs no Herceptin in HER-2 +ve

Armidex vs Tamoxifen in ER+ BC

Zometa vs PBO in mPC

Erbitux vs supportive care adv CRC*

Cost /QALY Gained ($)

Chung K, et al. HOPA 2012.

Incremental Benefits in Breast Cancer

64% risk of skeletal complication with no bisphosphonate at 2 yrs

Approx 33% risk reduction with pamidronate

64% 43% 34%

Further 20% risk reduction with zoledronic acid

27%

Additional 18% risk

reduction with

denosumab

Lipton A, et al. Cancer. 2000;88:3033-3037. Rosen LS, et al. Cancer. 2003;100:36-43. Stopeck A, et al.

JCO 2010;28:5127-31.

Surgical Considerations for Preventing and Treating SREs

Metastatic Epidural Spinal

Cord Compression

Ref: Cole and Patchell. The Lancet

Neurology. 2008; &:459-466

-Effects up to 5% of cancer

patients

-Most common symptom is

pain

-Medical emergency

-Diagnosis best made with

MRI

-Steroids, radiation therapy,

and decompressive surgery

Spinal Cord Compression: Randomized Trial: Radiation +/- Surgery

Able to walk after treatment:

Surgical & RT: 42/50, (84%)

Radiation: 29/51, (57%)

OR 6·2 [95% CI 2·0–19·8]

p=0·001

Duration of ability to walk:

Surgical & RT: 122 D

Radiation: 13 D

p=0.003

Continence & functionally better with

surgery & RT

Surgery + RT

RT

Patchell et al. The Lancet 2005: 366: 643.

Does age makes a

difference?

-Younger patients do

better with combined

therapy compared to

older patients

-In pts < 65 yrs, odds of

ambulating in surgical

+ XRT 5.14 times higher

than in XRT alone

(P=0.002)

Ref: Chi et al. Spine

2009; 34: 431-435

P= 0.002)

To Operate, Most Surgeons Consider:

Consider surgery:

• Size of lesion: ≥ 2.5 cm

• Lesion: ≥ 50% bone diameter

• Lesion is a Lesser trochanter avulsion

• Patient has ≥ 6 weeks life expectancy

Scoring system to predict pathologic fractures: clinically not

used Limited outcomes data: surgery for impending fracture vs.

surgery for completed fracture (favors pre-fracture tx)

• Shorter hospital stays (7 vs. 11 days)

• Greater likelihood of discharge home (vs. extended care) (79% vs 56%)

• Greater likelihood of support-free ambulation (35% vs. 12%)

Mirels Clin Ortho 2003

Ward CORR 2003

Lesion

At risk

For Fracture

Guidelines and Duration of Bone-Targeted Therapy

1. Cardoso F, et al., Ann Oncol 2011;22(Suppl 6) vi 25-30. 2. NCCN Clinical Practice Guidelines Oncology: Breast Cancer v3.2012. www.nccn.org. 3. Van Poznak CH, et al., J

Clin Oncol 2011;29:1221-7.

Study Design and Treatment Schema

A n a l y s i s

P r i

m a r y

Denosumab 120 mg SC

+ Placebo IV

Q4W

N = 1026

Placebo SC +

Zoled r onic acid 4 mg IV* Q4W

N = 1020

Yes (89%) †

2-Year Survival Fo l low - up (Q12W)

Denosumab 120 mg SC

Q4 W f o r 2 y ea r s (N = 652) Superiority

of Denosumab over

Zoledronic Acid Positive risk: benefit profile

Patient choice for open label

denosumab (N = 752)

Adults with

advanced

breast cancer

and confirmed

bone

metastases

Among patients previously receiving denosumab or zoledronic acid, 89%

in each treatment group chose to receive open-label denosumab.

Ref: Stopeck et al SABCS 2011

• No neutralizing anti-denosumab antibodies were detected and no

new safety signals were observed

• The cumulative incidence of positively adjudicated ONJ was 4.7%

for denosumab/denosumab patients when administered for up to

~5-years and 3.5% for patients who switched from zoledronic acid

to denosumab.

Open label extension

Zoledronic acid

denosumab

Denosumab

denosumab

Breast cancer (n = 652†)1

Cumulative median exposure to

denosumab, months (range)‡ NR 19.1 (0.159.8)

Denosumab ≥ 3 years, n - 216

Denosumab ≥ 4 years, n - 76

Prostate cancer (n = 281†)2

Cumulative median exposure to

denosumab, months (range)† NR 12.0 (0.167.2)

1. Stopeck AT, et al. Poster presented at SABCS 2011 [Abstract P3-16-07];

2. Fizazi K, et al. ESMO 2012

†Patients who chose to receive open-label denosumab; ‡Entire study including double-blind and open-label treatment phases.

Dosing of IV Bisphosphonate by

Markers of Bone Turnover Coleman ASCO 2012 AB # 511

Zoledronic Acid

Every

4 weeks

Zoledronic

Acid

Dosed by

Markers of

Bone

Resorption

Follow

For

SREs

R

A

N

D

O

M

I

Z

E

Met Breast

Cancer to

bone

Planned N= 1500

Study closed early due to poor accrual with N <300

BISMARK

BISMARK: uNTX Directed Therapy

Time to First SRE Coleman ASCO 2012 AB # 511

Larger number of SREs in M-Zol 150 vs 109 in S-Zol

HR 1.41 (CI 0.98 – 2.02) P= .12

More patients on M-Zol experienced multiple SREs

NTX levels were higher in M-Zol group at all time points

Trial underpowered but results suggest NTX based schedule may

represent sub-optimal management

Study of the Interval of Zoledronic Acid Dosing:

New Start of Therapy

Zoledronic Acid

Every

4 weeks

Zoledronic Acid

Every

12 weeks

Follow

For

SREs &

Toxicity

R

A

N

D

O

M

I

Z

E

Bone Metastases

•Breast

•Prostate

•Multiple Myeloma

No prior treatment

with IV BP

•Open Label

•N= approx 1500

•Await Results

•ClinicalTrials.gov # NCT00869206

CALGB-70604

Conclusions

Management of skeletal metastases often requires a multidisciplinary approach

SREs cause significant morbidity and decrease mortality

Pain Control

– RX: NSAIDs and Opiates

– Osteoclast inhibition

– External beam radiation and radiopharmaceuticals

Reduce fracture risk

– Surgery and/or radiation

– Osteoclast inhibition

Bone Targeted Therapies:

– Prevent SRE and hypercalcemia

– Palliate and Prevent Pain

– Decrease use of narcotics and improve QOL

– Do not improve overall survival or PFS

• Important differences in efficacy, toxicity, mode of

administration and cost among the available agents

• Patient preference, convenience, characteristics,

and treatment plan should be considered when

deciding on the most appropriate therapy

• Still questions on optimal dose and schedule, role

in preventing development of metastases/breast

cancer

Thank you for your attention