ZOMETA 藥理機轉

含氮雙磷酸鹽類藥物

成熟的蝕骨細胞 未成熟的蝕骨細胞

骨骼

骨骼受傷

雙磷酸鹽類藥物

雙磷酸鹽類保護骨骼作用

ZOMETA標竿臨床試驗

24 months

Pati

en

ts W

ith

SR

E, %

Pathologic fracture

Radiation therapy

Surgical intervention

Spinal cord compression

Any

• Saad F, et al. JNCI. 2002;94(19):1458-1468; Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.

•5

Patients with bone metastases from PC:

High risk for developing SREs

•Abbreviations: CI, confidence interval; SRE, skeletal-related event.

•DePuy V, et al. Support Care Cancer. 2007;15:869-876.

Pro

bab

ilit

y

0 90 180 270 360

Survival, days

0

0.1

0.2

0.3

0.4

0.5

0.7

0.8

0.9

1

0.6

No SRE (n = 355)

≥ 1 SRE (n = 116) • 360 Days Survival

No SRE: 49.7%

≥ 1 SRE: 28.2%

P = .02

• Median Survival

Times

No SRE: 338 days

(95% CI = 189, 460)

≥ 1 SRE: 248 days

(95% CI = 181, 296)

•6

SREs are associated with lower survival in PC

Established benefits of bone-modifying

agents in CRPC

•7

Abbreviations: HCM, hypercalcemia of malignancy; SRE, skeletal-related event.

Adapted from Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.

P = .028

38

26

17

4 6

2 0

49

33

25

8 7 4

1

0

10

20

30

40

50

60

Any SRE Radiation

to Bone

Fractures Spinal Cord

Compression

Change in

Antineoplastic

Therapy

Surgery

to Bone

HCM

Zoledronic acid 4 mg (n = 214) Placebo (n = 208)

Pa

tie

nts

Wit

h S

RE

, %

ZOL reduced all types of SREs in patients with

bone metastatic PCs at 2 Yrs

8

•0 •0.2 •0.4 •0.6 •0.8 •1 •1.2 •1.4 •1.6 •1.8 •2

•.028

•P Value

•0.603

•0.670

•.027 No Prior SRE

•40%

•33%

Prior SRE

• Risk Ratio (ZOL 4 mg vs Placebo)

•In favor of ZOL •In favor of placebo

•Risk

Reduction

•.002

•0.640

•36% Overall Trial

Population

•Abbreviations: SRE, skeletal-related event; ZOL, zoledronic acid.

•Adapted from Saad F, et al. Clin Genitourin Cancer. 2007;5(6):390-396.

•Before Study Entry

ZOL reduces risk of SREs in bone metastatic PCs

regardless of prior SRE history

•9

Time on Study, months

Mean

Ch

an

ge F

rom

Baselin

e

in B

PI

Pain

Sco

re

Mean n baseline BPI

Zoledronic acid 4 mg 214 2.0

Placebo 208 2.1

0

0.2

0.4

0.6

0.8

1

1.2

0 3 6 9 12 15 18 21 24

a

a a

a

a P < .05.

Abbreviations: BPI, Brief Pain Inventory.; PC, prostate cancer; ZOL, zoledronic acid

Adapted from Saad F, et al. BJU Int. 2005;96(7):964-969.

ZOL results in better control of pain in PC patients

at 2 Yrs

10

Overall survival of patients who received zoledronic acid or placebo

Zoledronic acid increased overall survival by ~ 2.75 months (P = NS)

• a After start of study drug.

• Abbreviations: NS, not significant; ZOL, zoledronic acid.

• Adapted from Saad F. Cancer Treat Rev. 2008;34(2):183-192.

0

20

40

60

80

100

0 120 240 360 480 600 720 840 960

Pro

bab

ilit

y o

f S

urv

ival, %

• Median P value

•ZOL 4 mg 546 d .103

•Placebo 469 d

•Patients, n

ZOL 4 mg 214 162 113 56 10

Placebo 208 148 94 40 5

ZOL: Effect on Survival

– A trend towards a 2.75-month improvement in OS

•11

•Time, daysa

•12

Open-label, multicenter, randomized, 2-phase study in patients with HSPC

receiving GOS ± ZOL (4 mg IV) every 3 months

Endpoints: percentage change in LS BMD from baseline at 12 and 24 mo

Measurements: LS, FN, and TH BMD were assessed at 6, 12, and 24 mo.

Additional assessments included height change, laboratory studies, bone scans,

X-rays, and CT scans

Long-term efficacy of ZOL to prevent bone loss during ADT

for PCs: ZZ Study

•GOS (10.8 mg) alone

every 3 mo

•GOS (10.8 mg) + ZOL (4 mg IV) every 3 mo

200 patients

M0 prostate cancer

HT-naive;

confirmed locally

advanced, LN+, or

recurrent PC

No bone mets

Phase 1: 12 months

Ra

nd

om

iza

tio

n

•GOS (10.8 mg) + ZOL (4 mg IV) every 3 mo

•GOS (10.8 mg) alone

every 3 mo

•GOS (10.8 mg) + ZOL (4 mg IV) every 3 mo

R

Phase 2: 12 months

•ADT, androgen deprivation therapy; BMD, bone mineral density; CT, computed tomography; FN, femoral neck; GOS, goserelin acetate; HT, hormone

therapy; LS, lumbar spine; TH, total hip; ZOL, zoledronic acid.

•www.clinicaltrials.gov (NCT00063609).

13

Change in BMD after 12 months of treatment (ZZ

study)

•Casey R, et al. Poster presented at: 33rd ESMO Congress; September 12-18, 2008; Stockholm, Sweden. Abstract 627P.

5 D4.8

D3.5

4

Goserelin + ZOL (12 mo) Goserelin (12 mo)

3

2

1

0

–1

–2

–3 Lumbar spine

Patients, n 68 71 66 72 66 69

Femoral neck Total hip

D2.9

Ch

an

ge f

rom

baselin

e,

%

P < .01 for each

site at 12 mo

•14

Change in BMD after 24 months of treatmenta

•a Results were not significant for an increase in BMD; however, preservation of bone is demonstrated.

•Casey R, et al. Poster presented at: 33rd ESMO Congress; September 12-18, 2008; Stockholm, Sweden. Abstract 627P.

5 D3.6

D3.0

4

Goserelin + ZOL (24 mo)

Goserelin (24 mo)

3

2

1

0

–1

–2

–5

–4

–3

Lumbar spine Femoral neck Total hip

Goserelin (24 mo) + ZOL (12 mo) D5.3

D3.4

D3.2

D2.2

Patients, n 47 14 48 14 48 14 11 11 11

Ch

an

ge f

rom

baselin

e,

%

副作用及處理方式

•15

•16

Common nonserious adverse events

No serious adverse events related to study

Common Nonserious Adverse Events

12-month assessment 24-month assessment

GOS alone GOS + ZOL GOS alone

GOS +

ZOL

Hot flashes, n (%) 27 (29) 23 (25) 4 (18) 16 (23)

Fatigue, n (%) 12 (13) 6 (6) 3 (14) 4 (6)

Body aches, n (%) 2 (2) 3 (3) 2 (9.1) 2 (3)

Bone/Joint pain, n (%) 5 (5) 3 (3) 0 (0) 1 (1)

Nausea, n (%) 2 (2) 3 (3) 2 (9) 3 (3)

•GOS, goserelin acetate; ZOL, zoledronic acid.

•Casey R, et al. Poster presented at: 33rd ESMO Congress; September 12-18, 2008; Stockholm, Sweden. Abstract 627P.

Preventing ONJ during bone-modifying therapy

• Before BP treatment1,2

– Dental exam with appropriate preventive dentistry

– Remove abscessed and nonrestorable teeth, teeth with severe periodontal

disease, and teeth with poor long-term prognosis

– Functionally rehabilitate salvageable dentition

– Educate patients on oral hygiene and signs and symptoms of ONJ

• During BP treatment – Seek dental maintenance care at least every 6 months

– Avoid invasive dental procedures if possible

• If dental procedure is needed, provide good antibiotic coverage3

– Maintain good dental hygiene

• These recommendations also apply to Dmab4

– Meta-analysis of Dmab vs ZOL trials suggests similar or greater association of

ONJ with Dmab5

– There is no difference in rate of resolution of ONJ after Dmab or ZOL

•17

Abbreviations: BP, bisphosphonate; Dmab, denosumab; ONJ, osteonecrosis of the jaw.

1. Weitzman R, et al. Crit Rev Oncol Hematol. 2007;62(2):148-152; 2. Mehrotra B, et al. Hematology Am Soc Hematol Educ Program. 2006;356-360, 515; 3. AAOMS: Position paper on bisphosphonate-related ONJ—2009 update. http://www.aaoms.org/docs/position_papers/bronj_update.pdf; 4. Xgeva™ (denosumab) injection [package insert]. Thousand Oaks, CA: Amgen Inc., 2010; 5. Van den Wyngaert T, et al. Support Care Cancer. 2011;19(12):2035-2040.

Preventing ONJ during bone-modifying therapy

• Before BP treatment1,2

– Dental exam with appropriate preventive dentistry

– Remove abscessed and nonrestorable teeth, teeth with severe periodontal

disease, and teeth with poor long-term prognosis

– Functionally rehabilitate salvageable dentition

– Educate patients on oral hygiene and signs and symptoms of ONJ

• During BP treatment – Seek dental maintenance care at least every 6 months

– Avoid invasive dental procedures if possible

• If dental procedure is needed, provide good antibiotic coverage3

– Maintain good dental hygiene

• These recommendations also apply to Dmab4

– Meta-analysis of Dmab vs ZOL trials suggests similar or greater association of

ONJ with Dmab5

– There is no difference in rate of resolution of ONJ after Dmab or ZOL

•18

Abbreviations: BP, bisphosphonate; Dmab, denosumab; ONJ, osteonecrosis of the jaw.

1. Weitzman R, et al. Crit Rev Oncol Hematol. 2007;62(2):148-152; 2. Mehrotra B, et al. Hematology Am Soc Hematol Educ Program. 2006;356-360, 515; 3. AAOMS: Position paper on bisphosphonate-related ONJ—2009 update. http://www.aaoms.org/docs/position_papers/bronj_update.pdf; 4. Xgeva™ (denosumab) injection [package insert]. Thousand Oaks, CA: Amgen Inc., 2010; 5. Van den Wyngaert T, et al. Support Care Cancer. 2011;19(12):2035-2040.

Meta-analysis of Dmab vs ZOL trials suggests

similar or greater association of ONJ with Dmab

Monitoring hypocalcemia during Denosumab

therapy

FDA warning: “Severe hypocalcemia can occur in patients receiving Xgeva”

1

FDA recommendations during 120 mg q4 wk Dmab treatment for SRE1

Correct preexisting hypocalcemia

All patients should receive calcium and vitamin D supplements

Monitor calcium levels

Safety not assessed in patients with CrCl < 30 mL/min

EMA recommendations during 120 mg q4 wk Dmab treatment for SRE2

Correct preexisting hypocalcemia

All patients should receive calcium and vitamin D supplements

Monitor calcium levels in patients predisposed to hypocalcemia

Patients with CrCl < 30 mL/min are at risk for hypocalcemia

Clear or defined monitoring protocol for hypocalcemia ??

•20

Abbreviations: CrCl = creatinine clearance; FDA = US Food and Drug Administration; EMA, European Medicines Agency.

1. Xgeva™ (denosumab) injection *package insert+. Thousand Oaks, CA: Amgen Inc., 2012; 2. Xgeva injection *Summary of Product Characteristics]. Breda, Netherlands: Amgen Europe BV; 2012.