Bone-Targeting Agents in Prostate Cancer Care - One Thing That Is Underrated in Taiwan 黃昭淵醫師臺大醫院泌尿科

男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02

Bone-Targeting Agents in Prostate Cancer Care - One Thing That Is

Underrated in Taiwan

黃昭淵醫師臺大醫院泌尿科


Drugs to be talked about Bisphosphonate ( 雙磷酸鹽化合物 )

◦ Alendronate (Fosamax, 福善美 )◦ Clodronate (Bonfos, 骨復舒 )◦ Pamidronte (Aredia, 雷狄亞 )◦ Zoledronate (Zometa, 卓骨祂 )

RANK-ligand Inhibitor◦ Denosumab (XGEVA, 癌骨瓦 )

Bone-seeking Radioisotopes◦ Strontium-89 & Samarium-153: β-emitting particle◦ Radium-223: α-emitting particle


Drugs to be talked about Bisphosphonate ( 雙磷酸鹽化合物 )

◦ Alendronate (Fosamax, 福善美 )◦ Clodronate (Bonfos, 骨復舒 )◦ Pamidronte (Aredia, 雷狄亞 )◦ Zoledronate (Zometa, 卓骨祂 )

RANK-ligand Inhibitor◦ Denosumab (XGEVA, 癌骨瓦 )

Bone-seeking Radioisotopes◦ Strontium-89 & Samarium-153: β-emitting particle◦ Radium-223: α-emitting particle


Outline

Mode of action of bone-targeting agentsEfficacy and safety of bone-targeting agents

◦ Fracture Prevention in Early-Stage Prostate Cancer◦ Delaying Bone Metastases in Prostate Cancer◦ Treatment of Bone Metastases Secondary to prostate

cancer◦ Safety profile

Reimbursement criteria for bone-targeting agentsSummary


Outline






RANK Ligand Is An Essential Mediator of Osteoclast Formation, Function and Survival

Boyle WJ, et al. Nature 2003;423:337–42; Roodman GD, N Engl J Med 2004;350:1655–64.


A Vicious Cycle of Bone Destruction May Develop in the Presence of Tumour Cells

PDGF, platelet-derived growth factor; TGF, transforming growth factor; IGF, insulin-like growth factor; FGF, fibroblast growth factor; TNF, tumour necrosis factor.

Boyle WJ, et al. Nature 2003;423:337–42; Roodman GD. N Engl J Med 2004;350:1655–64.


Bisphosphonates Embed in Bone And Induce Apoptosis of Activated Osteoclasts

Green JR. Oncologist 2004;9(Suppl 4):3–13; Roodman GD. N Engl J Med 2004;350:1655–64; Mundy GR. Nat Rev Cancer 2002;2:584–93.


Denosumab Inhibits RANK Ligand to Interrupt the ‘Vicious Cycle’ of Bone Destruction

Boyle WJ, et al. Nature 2003;423:337–42; McClung MR, et al. N Engl J Med 2006;354:821–31; Mundy GR. Nat Rev Cancer 2002;2:584–93.


Outline






Treatment-related fractures

Disease-related skeletal complications

Castrate-sensitive nonmetastatic

Castrate-resistant nonmetastatic

Castrate-resistant metastatic

New bone metastases

Spectrum of Bone Disease in Prostate Cancer


1. Kanis JA. Osteoporosis. Blackwell Healthcare Communications Ltd; 1997. 2. Eastell R, et al. J Bone Mineral Res. 2002;17(suppl 2). Abstract 1170. 3. Lee WY, et al. J Clin Endocrinol Metab. 2002;87:329-335. 4. Maillefert JF, et al. J Urol. 1999;161:1219-1222. 5. Gnant M. Breast Cancer Res Treat. 2002; 76(suppl 1):S31. Abstract 12. 6. Shapiro CL, et al. J Clin Oncol. 2001;19:3306-3311.

ADT-Associated Bone Loss

Healthy men[1]

Early menopausal women[1]

Late menopausal women[1]

AI therapy in postmenopausal women[2]

Androgen deprivation therapy [4]

AI therapy plus GnRH agonist[5]

Ovarian failure secondary to chemotherapy[6]

Bone marrow transplant[3]

0

Lumbar Spine BMD Loss at 1 Yr (%)

2 4 6 8

0.5%

1.0%

2.0%

2.6%

3.3%

4.6%

7.0%

7.7%


ADT and Fractures

Yrs After Diagnosis

Un

ad

juste

d F

ractu

re-F

ree S

urv

ival (%

)

2 3 4 5 6 7 8 9 1010

100

90

80

70

60

50

40

30

20

10

Over a 4-yr period 19.4% fractures on ADT 12.6% fractures not on ADT

No ADT (N = 32,931)GnRH agonist, 1- 4 doses (n = 3763)GnRH agonist, 5-8 doses (n = 2171)GnRH agonist, ≥ 9 doses (n = 5061)Orchiectomy (n = 3399)

Shahinian VB, et al. N Engl J Med. 2005;352:154-164.


Higher Death Rate Observed at 36 Mos in Pts With Vertebral Fracture at Study Entry

Saad F, et al. ECCO/ESMO 2009. Abstract 7005.

0

1

2

3

5

7

9

All Patients Placebo

Su

bje

cts

(%

)

10

Denosumab

8

6

4

7.6%

5.1%

9.2%

4.6%

5.8% 5.6%

HR: 1.57; P = .062Adj HR*: 1.55; P = .0698

HR: 2.14; P = .0194Adj HR*: 2.13; P = .021

HR: 1.09; P = .813Adj HR*: 1.08; P = .837

Prevalent vertebral fracture

No prevalent vertebral fracture

*Adjusted for age and ADT duration

Subject incidence

Sample size

25

329

53

1035

16

174

23

504

9

155

30

531


Alendronate Increases BMD During GnRH Agonist Therapy

Greenspan SL, et al. Ann Intern Med. 2007;146:416-424.

-3

-2

-1

0

1

2

3

4

5

BM

D P

erc

ent

Ch

an

ge

Alendronate

Placebo

LumbarSpine

TotalHip

12-Mo Data


Pamidronate IV Every 3 Mos

P ≤ .005 for each comparison

Smith MR, et al. N Engl J Med. 2001;345:948-955.

-5

-4

-3

-2

-1

0

1

2

Pamidronate

No pamidronate

LumbarSpine

TotalHip

BM

D P

erc

ent

Ch

an

ge

Final 12-Mo Data


Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy

Michaelson MD, et al. J Clin Oncol. 2007;25:1038-1042.

-6

-4

-2

0

2

4

6

P < .005 for each comparison

Zoledronic acid 4 mg/yr IV

Placebo

LumbarSpine

Final 12-Mo Data

BM

D P

erc

ent

Ch

an

ge

TotalHip


Denosumab Increased BMD at All Skeletal Sites

10

8

6

4

2

0

-2

-4

-601 3 6 12 24 36

Mos

Cha

nge

in B

MD

F

rom

Bas

elin

e (%

)

Femoral Neck

Denosumab

Placebo

Difference at 24 mos,3.9 percentage points

10

8

6

4

2

0

-2

-4

-601 3 6 12 24 36

Mos

Cha

nge

in B

MD

F

rom

Bas

elin

e (%

)

Lumbar Spine

Denosumab

Placebo



8

6

4

2

0

-2

-4

-601 3 6 12 24 36

Mos

Cha

nge

in B

MD

F

rom

Bas

elin

e (%

)Placebo


Distal Third of Radius

Denosumab

10

8

6

4

2

0

-2

-4

-601 3 6 12 24 36

Mos

Cha

nge

in B

MD

F

rom

Bas

elin

e (%

)

Denosumab

Placebo


Total Hip10


Denosumab for Fracture Prevention in Early-Stage Prostate Cancer

12Mos24 36

P = .004 P = .004 P = .006

1.9

0.3

3.3

1.0

3.9

1.5

0

2

4

6

8

10

New

Vert

eb

ral Fr

act

ure

(%

)

Placebo

Denosumab

13 2 22 7 26 10Patients at Risk, n



Outline











New bone metastases



Consequences of Prostate Cancer Progression on Bone Metastasis

Osteoporosis Osteopenia Worsening bone pain Spinal cord compression Bone marrow compromise Hyper/hypocalcaemia Additional therapy such as

surgery and radiation


Time to Bone Metastasis in Non-metastatic CRPC (M0)

Smith MR, et al. Cancer. 2011;117:2077-2085.

25 mos

Mos Since Randomization

6 30 48 660

0.2

0.4

0.6

0.8

Pro

bab

ility

of

Bone M

eta

stase

s

0

0.1

0.3

0.5

0.7

0.9

1.0

12 18 24 36 42 6054

Cumulative incidence function

95% CI

N = 331


Relationship Between PSADT and Risk for Bone Metastasis or Death

Rel

ativ

e R

isk

for

Bon

eM

etas

tasi

s or

Dea

th

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

3.0

PSADT in Mos

20 18 16 14 12 10 8 6 4 2

Shorter PSADT

Incr

easi

ng R

isk

Smith MR, et al. ASCO GU 2012. Abstract 6.

*Placebo arm of study (n = 147)


PR04: Time to Symptomatic Bone Metastases or Prostate Cancer Death

Mason MD, et al. J Natl Cancer Inst. 2007;99:765-776.

60 960

20

40

60

80

0

100

12 24 36 48 8472 108

Mos From Random Assignment

Pro

port

ion F

ree o

f Sym

pto

mati

c B

on

e M

eta

stase

s and

Pro

state

Can

cer

Death

Patients at Risk, nPlacebo

Active254254

(1)(9)

248237

(8)(8)

234224

(16)(16)

204198

(11)(8)

185184

(4)(4)

174165

(9)(13)

145137

(6)(11)

118104

(4)(3)

7573

(7)(4)

3736

PlaceboClodronate


Denosumab in High-Risk M0 CRPC: BMFS

Smith MR, et al. Lancet. 2012;379:39-46.

Pts at Risk, nPlacebo

Denosumab

HR: 0.85 (95% CI: 0.73-0.98; P = .028)

15% Risk Reduction

Placebo

Denosumab

Median,Mos Events, n

25.2

29.54.2 370

335

Delay, Mos

Pro

port

ion o

f Pa

tients

W

ith

BM

FS

0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 4224 30 36

716716

691695

569605

500521

421456

375400

345368

300324

259279

215228

168185

137153

99111

6059

3635

Study Mos


Bone Metastasis–Free Survival in Patients With PSADT ≤ 6 Mos

HR: 0.77 (95% CI: 0.64-0.93; P = .006)

23% Risk reduction

Smith MR, et al. ASCO GU. 2012. Abstract 6.

Pro

port

ion o

f Pa

tients

Wit

h

Bon

e M

eta

stasi

s–Fr

ee S

urv

ival

1.0

0.6

0.8

0.4

0.2

0120 24 36

Study Mo427 323 223 176 122 78 47419 345 238 193 145 89 46

6 18 30

411406

274284

194207

148170

99109

6567

PlaceboDenosumab

MedianMos Events, n

Delay,Mos

18.725.9

7.224297

Patients at Risk, nPlaceboDenosumab


Bone Metastasis–Free Survival in Patients With PSADT ≤ 4 Mos

HR: 0.71 (95% CI: 0.56-0.90; P = .004)

29% Risk reduction

Pro

port

ion o

f Pa

tients

Wit

h

Bon

e M

eta

stasi

s–Fr

ee S

urv

ival

1.0

0.6

0.8

0.4

0.2

0120 24 36

Study Month289 209 138 105 71 46263 217 143 117 89 56

6 18 30

279254

176176

117123

88102

5867

3538

PlaceboDenosumab

18.325.8

7.5167124

Smith MR, et al. ASCO GU. 2012. Abstract 6.

MedianMos Events, n

Delay,Mos

Patients at Risk, nPlaceboDenosumab


Outline











New bone metastases



Skeletal-Related Events and Clinical Consequences of Bone Metastases

Skeletal-Related Events Other Clinical Symptoms

Pathologic fractures* Spinal cord compression* Radiation therapy to bone* Surgery to bone* Hypercalcemia Change in antineoplastic

therapy

Bone pain Analgesic usage Quality-of-life deterioration Shortened survival

*Universally accepted skeletal-related events.


Bone Metastases Can result in Serious and Debilitating Skeletal-Related Events (SREs)

Spinal Cord Compression3

Pathologic Fracture4

Surgery to Bone3

Radiation to Bone5

Pressure on the spinal cord leading to

nerve damage

Bone fractures that occur spontaneously or result

from minor trauma

Procedures to set or stabilize a fracture, or to

prevent imminent fracture or spinal cord compression

Radiation for pain control, to treat or prevent

pathologic fractures, or to treat or prevent spinal

cord compression1. Coleman RE. Cancer. 1997;80(8 suppl):1588-1594.2. Lipton A. Support Cancer Ther. 2007;4:92-100.3. Shehadi JA, et al. Eur Spine J. 2007;16:1179-1192. With permission from SpringerScience+Business Media.4. NCI. Understanding radiation therapy.


PR05: Symptomatic Bone PFS

Dearnaley DP, et al. J Natl Cancer Inst. 2003;95:1300-1311.

Pro

port

ion o

f Pa

tients

Aliv

e a

nd

Wit

hout

Sym

pto

mati

c B

one

Pro

gre

ssio

n

0

0.2

0.4

0.6

0.8

0.1

0.3

0.5

0.7

0.9

1.0

0 12 48 6024 36 84

Mos From Randomization

72

Pts at Risk, n (Events)Active

Control155156

(42)(57)

11397

(36)(32)

7262

(17)(17)

5342

(8)(9)

3025

(9)(4)

811

(0)(5)

43

(0)(0)

21

ClodronateControl

Events112124

Total155156

HR: 0.79 (95% CI: 0.61-1.02;x2 = 3.39 [df = 1]; P = .066)


Time to First SRE: Zoledronate vs Placebo

SREs: ZOL 4 mg 38%; placebo 49% (P = .028)

◦ 11% absolute risk reduction in ≥ 1 SRE

Pain/analgesia scores increased less with ZOL

No improvement in tumor progression, QoL, OS

0

20

40

60

80

100

0 120 240 360 480 600 720

Days

Median, Days

P Value

ZOL 4 mg 488.009

Placebo 321

ZOL 4 mg 214 149 97 70 47 353

Placebo 208 128 78 44 32 203

Perc

ent

Wit

hout

Event

Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. Saad F, et al. ASCO 2003. Abstract 1523. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882.


Zoledronic Acid Studies Primary Endpoint: SRE

% W

ith

ou

t th

e E

vent

0

20

40

60

80

10

30

50

70

90

0 90 360 450180 270 540

Days After the Start of Study Drug

Patients at Risk, nZol 4 mg

Zol 8/4 mgPlacebo

214221208

163155149

113102103

926869

704643

541

000

Zol 4 mgZol 8/4 mgPlacebo

Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.

100


Zoledronic acid 951 733 544 407 299 207 140 93 64 47

Denosumab 950 758 582 472 361 259 168 115 70 39

Patients at Risk, n Study Mo

0

1.00

Pro

port

ion o

f Sub

ject

s W

ith

out

SR

E

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

KM Estimate ofMedian Mos

DenosumabZoledronic acid

20.717.1

HR: 0.82 (95% CI: 0.71-0.95;P = .0002, noninferiority;P = .008, superiority)

18%Risk

reduction

Time to First On-Study SRE: Denosumab vs Zoledronic Acid

Fizazi K, et al. Lancet. 2011;377:813-822.


Denosumab vs ZOL in CRPC: No Effect on Overall Disease Progression and Survival

Overall Survival Time to Disease Progression

HR 1.03 (95% CI 0.91–1.17; p=0.65) HR 1.06 (95% CI 0.95–1.18; p=0.30)


ALSYMPCA: Overall Survival

Radium-223 541 450 330 213 120 72 30 15 3 0

Placebo 268 218 147 89 49 28 15 7 3 0

Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.

OS

(%

)

Radium-223 (n = 541)Median OS: 14.0 mos

Placebo (n = 268)Median OS: 11.2 mos

HR: 0.695 (95% CI: 0.552-0.875; P = .00185)

3 6 9 12 15 18 21 24 27

MosPts at Risk, n

0

10

20

30

40

50

60

70

80

90

100

0


Outline






Characteristics of Antiresorptive Agents Used for Patients with Prostate Cancer

International Journal of Endocrinology, 2015; http://dx.doi.org/10.1155/2015/838202


Preventing and Managing Hypocalcaemia

41

1. Denosumab (XGEVA®) Summary of Product Characteristics; 2. Zoledronic acid (Zometa®) Summary of Product Characteristics;

3. Block G, et al. NFI. Orlando, USA. April 15–17 , 2010. Abstract;

4. NIH dietary supplement fact sheet: Vitamin D. Available at: http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ (accessed Jan 2014).

Vitamin D promotes calcium absorption in the gut and helps to maintain adequate serum calcium and phosphate concentrations4

Situation Action13

Pre-existing hypocalcaemiaCorrect before startingbone-targeted therapy

Start of bone-targeted therapyStart daily oral supplements of≥ 500 mg calcium and 400 IU vitamin D

Severe renal impairment (creatinine clearance < 30 mL/min) or dialysis

Denosumab: monitor calcium levels (recommended)Zoledronic acid: not indicated

Hypocalcaemia on therapyAdditional calcium supplementation may be necessary


藥物使用前的評估是否能接受 BPs 或 Dmab 的使用 ?

沒有絕對不能接受 BPs 或 Dmab 使用的患者，只有日後產生骨壞死風險的高低。日後產生骨壞死風險的高低決定於 –

使用前使用前有無照會牙科進行口腔檢查，並接受口腔衛教？使用前有無遵照牙科醫囑進行治療？拔牙等侵入性治療，是否能在使用前至少 2-3 星期前完成？

使用期間使用期間是否能維持良好口腔衛生？是否至少每半年牙科追蹤及洗牙？是否能發現早

期牙齒疾患，及時治療？是否活動假牙不合或配戴疼痛感時，能及時修整？使用期間是否能避免產生拔牙、植牙、牙週病手術 ( 骨修整 ) 等侵入性手術的機會？


藥物使用中如何預防顎骨壞死的產生 ?

保持良好口腔衛生，至少每 6 個月定期口腔檢查 ( 含洗牙、蛀牙填補、根管治療、修整不合活動假牙及顎骨牙齒 X 光檢查 ) 。

牙科就診時，要讓牙科醫師知道你正在使用抗骨吸收藥物 ( 頻率及使用期間 ) 。並沒有絕對禁忌之口腔手術，但仍建議儘量避免拔牙或植牙等可能造成顎骨傷口的侵

入性治療。根管治療雖屬非侵入性治療，但需避免操作時超出根尖部(overinstrumentation) 。

若因牙科或內科急症考量，必要時拔牙或侵入性手術仍是適當的。當施行口內侵入性治療術前，先以抗生素預防及漱口水使用。傷口施行覆蓋縫合 (primary closure) 。

若有全口多處部位需進行侵入性治療，建議分次分部位進行，待傷口癒合正常，再進行另一部位治療，以避免產生多發部位顎骨壞死現象。

無證據證明停藥再施行牙科侵入性治療可減低發生顎骨壞死的風險，但對使用口服藥超過 4 年者，停藥 2 個月也許會有幫忙。 ( Denosumab?- 若要進行牙科侵入性治療， 2-3 個月的停藥有可能減少顎骨壞死發生率 )

當有牙齒鬆動、牙齦腫脹、疼痛時，儘快告知處方醫師，並至口腔顎面外科醫師處就診，以確定是否有顎骨壞死的產生，並及早治療。


Outline


◦Fracture Prevention in Early-Stage Prostate Cancer◦Delaying Bone Metastases in Prostate Cancer◦Treatment of Bone Metastases Secondary to

prostate cancer◦Safety profile



Bone-Targeting Agents in Taiwan

成分適應症健保給付規定

Clodronate• 惡性腫瘤之蝕骨性骨頭轉移• 惡性高血鈣症

• 血清鈣濃度超過 2.75 mmol/L (11.0mg

%) 或游離鈣大於 5.6 mg /dL 者• 惡性腫瘤之蝕骨性骨頭轉移之病患，在使

用嗎啡、可待因等止痛劑後仍不易控制者。• Multiple Myeloma, Breast Cancer,

Prostate Cancer併有蝕骨性骨轉移之病患

Pamidronate• 惡性腫瘤之蝕骨性骨頭轉移• 惡性高血鈣症

Zoledronic aicd

• 與標準癌症治療併用，適用於多發性骨髓瘤及固體腫瘤併有骨骼轉移之病人。用於攝護腺癌病人之骨骼轉移時，應至少接受過一種荷爾蒙治療而仍持續惡化者

• 治療惡性腫瘤之高血鈣併發症(HCM)

• 用於治療惡性腫瘤之高血鈣併發症 (HCM) ，且限用於血清鈣濃度超過 2.75

mmol/L (11.0mg/dL) 或游離鈣大於5.6 mg/dL

• Multiple Myeloma ， Breast

Cancer ， Prostate Cancer併有蝕骨性骨轉移之病患

Denosumab• 預防後期惡性腫瘤已擴散至骨骼

的患者發生骨骼相關事件• 乳癌、前列腺癌併有蝕骨性骨轉移之病患


Guidelines for Management of Bone Metastases in Prostate Cancer

1. Heidenreich A, et al. EAU 2013. Available from http://www.uroweb.org/guideline (accessed Dec 2013).

2. NCCN Clinical Practice Guidelines Oncology. Prostate Cancer V4.2013. Available from www.nccn.org (accessed Nov 2013);

3. Horwich A, et al. Ann Oncol 2013;24:114162;

4. Cookson MS, et al. Castration-resistant prostate cancer: AUA guideline. J Urol 2013;190:42938.

N/A, not applicable. See guidelines for details on pre- and on-treatment monitoring/requirements.

European Associationof Urology

(2013)1

National Comprehensive Cancer Network

(2013)2

European Societyfor Medical Oncology

(2012)3

American Urological Association (2013)4

Drugs recommended

Bisphosphonates, denosumab

Denosumab,zoledronic acid

Denosumab,zoledronic acid

Denosumab, zoledronic acid

Patient population

CRPC andbone metastases

CRPC andbone metastases

CRPC and bonemetastases from CRPC at

high risk for clinically relevant SREs

Tumour burden (e.g. > 3 bone metastases, high alkaline phosphatase) and anatomic site of

bony metastases as well as previous history of

SRE can be used to judge SRE risk

CRPC andbony metastases

Optimal duration of treatment

N/A “Unclear” “Unknown” N/A


Outline


◦Fracture Prevention in Early-Stage Prostate Cancer◦Delaying Bone Metastases in Prostate Cancer◦Treatment of Bone Metastases Secondary to

prostate cancer◦Safety profile



Incremental benefits of bone resorption inhibitors


Summary of Phase III Trials Investigating the Use of Antiresorptive Drugs

International Journal of Endocrinology, 2015; http://dx.doi.org/10.1155/2015/838202


Thank you for your attention!

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Bone-Targeting Agents in Prostate Cancer Care - One Thing That Is Underrated in Taiwan 黃昭淵醫師 臺大醫院 泌尿科

Bone-Targeting Agents in Prostate Cancer Care - One Thing That Is Underrated in Taiwan 黃昭淵醫師臺大醫院泌尿科