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.
Saad F, et al. J Natl Cancer Inst. 2004;96:879-882.
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 (%
)
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.
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
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.
No difference in overall survival
from with zoledronic acid
compared with placebo
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.
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.
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
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
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
Fizazi K, et al. Lancet Oncol. 2011;377:813-822.
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