Bone targeting: bisphosphonates, RANK-ligands and ...€¦ · metastatic bone disease Treat underlying disease. This can be very important, eg efficacy of first line ADT –Hormonal

Bone targeting: bisphosphonates,

RANK-ligands and radioisotopes

Dr Lisa Pickering

Consultant Medical Oncologist

ESMO Preceptorship Singapore 2017

Institutional Research

Support/P.I.Novartis, Pfizer, Pierre Fabre

Employee N/A

ConsultantAstellas, BMS, EUSA Pharma, Ipsen, Janssen,

MSD, Novartis, Pfizer

Major Stockholder N/A

Speakers Bureau BMS, EUSA Pharma, Novartis, Pfizer

Honoraria Astellas, Ipsen, Janssen, MSD, Pfizer

Scientific Advisory BoardAstellas, EUSA Pharma, Ipsen, Janssen, MSD,

Novartis, Pfizer, Sanofi

Disclosures

Why target bone in prostate

cancer?

▪ Treat established bone metastases:

▪ Bone-related progression

▪ Bone-related symprtoms

▪ Reduce risk of developing bone

metastases?

▪ Improve survival?

CRPC pattern of disease over time

100

90

80

70

60

50

40

% o

f Pati

ents

30

20

10

0>24 15-24 12-15 9-12 6-9 3-6 <3

Time Prior to Death, months

Visceral

involvement

Bone

involvement

1. Coleman RE. Cancer. 1997. 2. Bubendorf L, et al. Hum Pathol. 2000. 3. Pezaro CJ et al. Eur Urol.

▪ The skeleton is the most common site of metastasis in

prostate cancer1

▪ 90% of men with metastatic prostate cancer have

bone metastases2

Bone metastases are associated with

significant morbidity:

Skeletal-related events (SREs)

▪ Pain, Fracture

▪ Spinal cord compression

▪ Radiation or surgery to bone

▪ Hypercalcemia

▪ Morbidity: decreased emtional & physical QoL1, 2

▪ Cost: higher healthcare costs for patients with SREs3,4

Malignancy Bone Lesions, % SREs5, %

Breast 65-75 68

Prostate 906 49

Lung 30-40 48

Myeloma 95-100 51

1. Weinfurt KP, et al. Ann Oncol. 2005;16:579-584. 2. Janjan NA, et al. J Pain Symptom Manage. 1998. 3. Delea TE, et al. J Thorac Oncol. 2006;1:571-

576. 4. McKiernan J, et al. ASCO 2004. Abstract 6057. 5. Saad F, et al. Cancer. 2007;110:1860-1867. 6 Bubendorf L, et al. Hum Pathol. 2000.

When targeting bone, need to

consider bone biology:

Bone remodeling: a reminder…Bone

Formation

Osteoblasts express

osteoclastogenic

factors

Stimulation of

osteoblast

differentiation

Stimulation

of osteoclast

formation

Release of

osteoinductive

factors

Bone

Resorption

Prostate cancer and bone interaction: A

vicious cycle with “uncoupling” of

usual bone biology

Osteoblastic

factorsBone-derived

growth

factors

New bone

Prostate cancer cells

OsteoclastsMineralized bone matrix

Osteoblasts

Osteolytic

factors

Guise TA, et al. Clin Cancer Res. 2006;12:6213s-6216s.Greg Mundy, Nat Rev Cancer 2002

To add a few specifics…

The pathophysiology of cancer-related

bone metastases in CaP

Osteoblastic[1]

▪ Tumour production of osteoblast growth factors: PDGF, IGF, &

bone morphogenic proteins: adrenomedullin & endothelin-1

▪ New bone formations leads to the release of growth factor: IL-6

Osteolytic[2]

▪ Tumour secretion of factors that stimulate osteolysis: PTHrP,

RANKL, IL-11, IL-8, and IL-6

▪ Osteolytic release of growth factors stored in the bone matrix

that stimulate tumor cells (eg, TGF-β)

In prostate cancer, both mechanisms are involved

1. Guise TA, et al. Clin Cancer Res. 2006;12:6213s-6216s. 2. Pinzone JJ, et al. Blood. 2009;113:517-525.

Management strategies for

metastatic bone disease

▪ Treat underlying disease. This can be very

important, eg efficacy of first line ADT

– Hormonal therapy

– Systemic chemotherapy

– External beam radiation

▪ Bone-directed therapy

– Bisphosphonates (prevent bone resorption)

– RANKL inhibitor (prevent bone resorption)

– Bone-targeting radionuclides

1. Horwich A, et al. Ann Oncol. 2010;21(suppl 5):v129-v133. 2. NCCN. Clinical practice guidelines in oncology. v.1.2014.

• Bisphosphonates eg zoledronic acid

– Induce osteoclast apoptosis

– Inhibit osteoclast maturation, migration and function

– Directly induce cancer cell apoptosis (importance?)

• RANK-L inhibitors eg denosumab

– Humanised monoclonal antibody to RANK-ligand

– RANK-ligand pivotal for osteoblast:osteoclast

interaction

– Therefore inhibits osteoclast activity

Management strategies in relation to

pathophysiology

Zoledronic Acid in CRPC

▪ Patients in 8-mg arm reduced to 4 mg due to renal toxicity

▪ Primary outcome: proportion of patients having ≥ 1 SRE

(included change in anti-neoplastic therapy to treat bone pain)

▪ Secondary outcomes: time to first on-study SRE, proportion of

patients with SREs, and time to disease progression

Eligibiilty

▪ Castration resistant

prostate cancer

▪ Bone metastases

(>3 on bone scan)

(N = 643)

Zoledronic acid 4 mg q3w

(n = 214)

Placebo q3w

(n = 208)

R

A

N

D

O

M

I

S

E

Zoledronic acid 4 mg q3w

(initially 8 mg)

(n = 221)

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

Zoledronic Acid in CRPC:

Time to First SRE

0

20

40

60

80

100

0 120 240 360 480 600 720Days

Median, Days P Value

ZOL 4 mg 488 .009

Placebo 321

ZOL 4 mg 214 149 97 70 47 35 3

Placebo 208 128 78 44 32 20 3

Pati

en

ts W

ith

ou

t E

ven

t (%

)

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


Pts at Risk, n

Zoledronic Acid in CRPC:

Time to First SRE

0

20

40

60

80

100

0 120 240 360 480 600 720Days

Median, Days P Value

ZOL 4 mg 488 .009

Placebo 321

ZOL 4 mg 214 149 97 70 47 35 3

Placebo 208 128 78 44 32 20 3

Pati

en

ts W

ith

ou

t E

ven

t (%

)



Pts at Risk, n

• 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 tumour progression, QoL, OS

Pain scores better with

zoledronic acid than placebo



No difference in overall survival

from with zoledronic acid

compared with placebo



Mature

osteoclast

CFU-M

Prefusion

osteoclast

Multinucleated

osteoclast

Growth

factors

Hormones

Cytokines

RANKRANKL

OPG

Bone

Denosumab

RANKL inhibition: Mechanism of action

▪ Tumour cells

– Increase expression of RANKL

– Decrease expression of OPG

– Increase bone resorption through osteoclast activity

Adapted from Boyle WJ, et al. Nature. 2003;423:337-342. Fizazi K, et al. J Clin Oncol. 2009;27:1564-1571.

Denosumab in prostate cancer:

Phase III, non inferiority, RCT

▪ All patients received supplemental calcium and vitamin D

▪ Primary endpoint: time to first on-study SRE

▪ Secondary endpoints: OS, time to progression,

Denosumab 120 mg SC +

Placebo IV q4w

(n = 950)

Zoledronic acid 4 mg IV +

Placebo SC q4w

(n = 951)

Eligibility

• CRPC

• Bone metastases

(N = 1901)

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


Denosumab ZOL Acid HR (95% CI) P Value

Median time to 1st SRE 20.7 mos 17.1 mos 0.82 (0.71-0.95) 0.008

Tim

e t

o f

irst

on

stu

dy S

RE

Denosumab vs Zol Acid: Time to first SRE

Denosumab vs Zol Acid: Time to first SRE


Denosumab ZOL Acid HR (95% CI) P Value

Median time to 1st SRE 20.7 mos 17.1 mos 0.82 (0.71-0.95) 0.008

OS 19.4 19.8 1.03 (0.91-1.17) 0.65

TTP 8.4 8.4 1.06 (0.95-1.18) 0.30

Tim

e t

o f

irst

on

stu

dy S

RE

Time to first & subsequent on-study

SREs* (Multiple Event Analysis)

*Events occurring at least 21 days apart.

Rate ratio: 0.82 (95% CI: 0.71-0.94;

P = .008)

Study Mo

0

2.0

0 3 6 9 12 15 18 21 24 27

Cu

mu

lati

ve

Me

an

Nu

mb

er

of

SR

Es

pe

r P

ati

en

t

30 33 36

0.2

0.6

1.0

1.4

1.8

0.4

0.8

1.2

1.6

18%Risk

reduction

Denosumab

Zoledronic acid 584

494

Events, n


Subject Incidence, n (%)Zoledronic Acid

(n = 945)Denosumab

(n = 943)

Infectious serious adverse events 108 (11.4) 130 (13.8)

Acute-phase reactions (first 3 days) 168 (17.8) 79 (8.4)

Renal adverse events* 153 (16.2) 139 (14.7)

Cumulative rate of Osteonecrosis Jaw-ONJ 12 (1.3) 22 (2.3)

- Year 1 5 (0.5) 10 (1.1)

- Year 2 8 (0.8) 22 (2.3)

Hypocalcemia 55 (5.8) 121 (12.8)

Fizazi K, et al. ASCO 2010. Abstract LBA4507. Fizazi K, et al. Lancet. 2011;377:813-822.

Denosumab vs zoledronic acid:

Significant adverse events

• ONJ: Attention to dentition, duration & frequecny of therapy

• Hypocalcaemia: monitor Ca, Mg, use supplementation

• Renal impairment

• Infusion reactions with zoledronic acid

Radiopharmaceutical therapies

for targeting bone metastases

▪ Three agents approved:

– Strontium-89: pure β particle emitter

– Samarium-153 EDTMP: β and γ particle

emitter

– Radium-223: α particle emitter

▪ β particle emitters historically used for

bone pain palliation but have limitations:

▪ Haematologic toxicity

▪ No effect on survival outcomes, PFS or OS

Porter et al. Int J Radiat Oncol Biol Phys. 1993;25:805-813

Samarium-153 EDTMP vs

Placebo: Efficacy in palliation

Sartor O, et al. Urology. 2004;63:940-945.

VAS Measured Pain Scores

0-2-4-6-8

-10-12

AU

PC

VA

S

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Wk

2

0

-2

-4

-6

-8

AU

PC

PD

S

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Wk

40

20

0

-20

-40

Mo

rph

ine

Eq

uiv

/Da

y

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Wk

Opioid Analgesic Consumption

PDS Measured Pain Scores

α eg radium β eg strontium

Relative mass 7300 1

Range in tissue 0.1mm 5mm

Hits to kill a cell 1–10 100–1000

LET, linear energy transfer

Henriksen G, et al. J Nucl Med. 2003;44(2):252-9

Alpha Beta

An alpha-emitter should be more active

Range ofα particleRange of

β particle

An alpha-emitter should be less toxic

Calcium

Radium

Radium is chemically similar to

calcium

Roy Larsen

So readily binds to bone

Radium-223 (50 kBq/kg)

4 weekly, x6

+ Best standard of

care

Placebo (saline)

+ Best standard of care

R

A

N

D

O

M

I

S

E

D

2:1

N = 922

• Confirmed

symptomatic

CRPC

• ≥ 2 bone

metastases

• No known

visceral

metastases

ALSYMPCA (ALpharadin in SYMptomatic

Prostate CAncer) Phase III Study Design

Clinicaltrials.gov identifier: NCT00699751. Parker et al. NEJM (2013)

ALSYMPCA: Overall survival

improvement with radium v placebo

Parker et al. NEJM (2013)

Parker et al. NEJM (2013)

ALSYMPCA: Time to first SRE

improved with radium v placebo

ALSYMPCA: Pain score better with radium-223

Nilsson S, et al. J Clin Oncol. 2013;31(Suppl 6): Abstract 5038.

0.7

1

0.9

0.8

0.4

0.6

0.5

0.1

0.3

0.2

-0.1

0

-0.2

-0.3

-0.4

Ch

an

ge

Fro

m B

as

eli

ne

Assessment Visit

Week 0 Week 16 Week 24

Week 44

(Follow up visit 2)

Radium-223

Placebo

P = .001

P = .077

P = .598

Decrease

in pain

Increase

in pain

Maxim

um

Perc

en

t C

han

ge i

n P

las

ma

To

tal A

LP

fro

m B

aselin

e t

o W

eek 1

2

A. Placebo Arm n = 211

B. Ra-223 Arm n = 497

ALSYMPCA: Waterfall plot of maximum decline in ALP up to week 12

Sartor O, et al. J Clin Oncol. 2013;31(Suppl 6): Abstract 5080.

ALSYMPCA: Radium is well-tolerated

with no excess overall or haem AEs

ANAEMIA THROMBOCYTOPENIA NEUTROPENIA

Parker C, et al. N Engl J Med 2013; 369: 213–223.

How to make best use of radium-223:

Issues for practical use

• Patient selection

– Consider in all patients with bony metastatic CRPC

• Can be combined with other CaP treatments

– Use with best available AR targeted therapy

– Select patients with response to the first course and

no problematic toxicity can be re-treated later

• Monitoring response

– PSA does not necessrily tell the story

– DW-MRI appears promising

Nov 2015 Jan 2016

WB

DW-MRI

0

5

10

15

20

25

30

35

Nov ‘15 Jan ‘16

Suggested mCRPC treatment paradigm for

patients with bone-dominant metastases

36

LHRHa + Abiraterone

Add radium-223 on PSA progression

Docetaxel

Cabazitaxel

Markers of bone resorption

• Includes eg urinary NTX and CTX

• Suppressed by zoledronic acid and denosumab

• Suppressed for many months after a single dose

• Is this useful in practice? – No routine use

Bone metastases in CaP:

Conclusions• Bone metastases affect 90% of pts with metastatic

CaP & are associated with major morbidity & cost

• Bone directed therapy limits the consequence of

bone metastases (ie SREs) in CRPC

– No proven role in non metastatic CaP or in CSPC

• Denosumab superior to ZA for SREs overall.

Neither improves survival endpoints.

• Radium delays SREs with minimal toxicity and

improves survival outcomes and can be given with

other life-prolonging hormone therapies

Thank you

Documents

Bone targeting: bisphosphonates, RANK-ligands and ...€¦ · metastatic bone disease Treat underlying disease. This can be very important, eg efficacy of first line ADT –Hormonal