Role of Bone-Targeted Therapy in the Treatment of Prostate Cancer

Role of Bone-Targeted Therapy in the
Treatment of Prostate Cancer

This program is supported by an educational donation from

Optimizing Therapeutic Strategies Targeting Bone: Prostate Cancer
clinicaloptions.com/oncology

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Faculty
Matthew Raymond Smith, MD, PhD
Professor of Medicine
Harvard Medical School
Program Director, Genitourinary Oncology
Massachusetts General Hospital Cancer Center
Boston, Massachusetts

Evan Y. Yu, MD
Associate Professor
Department of Medicine/Oncology
University of Washington/Fred Hutchinson Cancer Research Center
Seattle, Washington


Faculty Disclosures
Matthew Raymond Smith, MD, has disclosed that he has
received consulting fees and research contracts from
Amgen.
Evan Y. Yu, MD, has disclosed that he has received
consulting fees from Amgen, Astellas, Medivation, and
Janssen and research contracts from Janssen and
Bristol-Myers Squibb.


Overview
 Fracture Prevention in Early-Stage Prostate Cancer
 Delaying Bone Metastases in Prostate Cancer
 Treatment of Bone Metastases Secondary to
Castration-Resistant Prostate Cancer
 Treatment of Bone Metastases Secondary to
Hormone-Sensitive Prostate Cancer
 Novel Agents With Bone Protective Effects

Fracture Prevention in
Early-Stage Prostate Cancer


Fracture Risk by Sex and Age
4000 Men Women Hip
Spine
Incidence/1,000,000 Person-Yrs

3000

2000

1000

35-39 ≥ 85 35-39 ≥ 85
Age (Yrs)
Melton LJ 3rd, et al. J Bone Miner Res. 1992;7:1005-1010.


GnRH Agonists Decrease BMD in Men
With Prostate Cancer
2
Control
1 GnRH agonist
0 P < .001 for each
Percent Change

comparison
-1

-2

-3

-4
12-mo data
-5
Lumbar Total
Spine Hip
Mittan D, et al. J Clin Endocrinol Metab. 2002;87:3656-3661.


Proportion of Patients With Fractures
1-5 Yrs After Cancer Diagnosis
+6.8%; P < .001
21 No ADT (n = 20,035)
ADT (n = 6650)
18
19.4

15
Frequency (%)

12 12.6

9
+2.8%; P < .001

6
5.2
3
2.4
0
Any Fracture Fracture Resulting in
Hospitalization
Shahinian VB, et al. N Engl J Med. 2005;352:154-164.


National Osteoporosis Foundation
Fracture Prevention Guidelines for Men
 Consider FDA-approved medical therapies based
on the following
– A vertebral or hip fracture
– Femoral neck or spine T-score ≤ -2.5
– FRAX 10-yr probability of a hip fracture ≥ 3% or 10-yr
probability of any major fracture ≥ 20%

National Osteoporosis Foundation Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2010.


The FRAX Tool: Assessing Fracture Risk

http://www.sheffield.ac.uk/FRAX


Alendronate Increases BMD During
GnRH Agonist Therapy
5 12-Mo Data

4
BMD Percent Change

3
Placebo
2 Alendronate
1

0

-1

-2

-3
Lumbar Total
Spine Hip
Greenspan SL, et al. Ann Intern Med. 2007;146:416-424.


Quarterly Zoledronic Acid Increases BMD
During GnRH Agonist Therapy
8 Final 12-Mo Data
P < .001 for each comparison
6
BMD Percent Change

4 Placebo
Zoledronic acid
2

0

-2

-4
Lumbar Total
Spine Hip
Smith MR, et al. J Urol. 2003;169:2008-2012.


Annual Zoledronic Acid Increases BMD
During GnRH Agonist Therapy
6 Final 12-Mo Data
P < .005 for each comparison
4
BMD Percent Change

2 Placebo
Zoledronic acid 4 mg/yr IV
0

-2

-4

-6
Lumbar Total
Spine Hip
Michaelson MD, et al. J Clin Oncol. 2007;25:1038-1042.


Denosumab Fracture Prevention Study

Current androgen deprivation
therapy for prostate cancer for 3 yrs
patients older than 70 yrs of
age or with T score < -1.0
(N = 1468) for 3 yrs

 Primary endpoints: bone mineral density, new vertebral fractures

Smith MR, et al. N Engl J Med. 2009;361:745-755.


Denosumab Increased BMD at All Skeletal
Sites
10 Lumbar Spine 10 Total Hip
8 8

From Baseline (%)
From Baseline (%)

Change in BMD
Change in BMD

6 Denosumab 6
4 4 Denosumab
Difference at 24 mos,
2 6.7 percentage points 2 Difference at 24 mos,
0 0 4.8 percentage points
-2 Placebo -2
-4 -4 Placebo
-6 -6
01 3 6 12 24 36 01 3 6 12 24 36
Mos Mos
10 Femoral Neck 10 Distal Third of Radius
8 8

From Baseline (%)
From Baseline (%)

Change in BMD
Change in BMD

6 6
4 Denosumab 4
Denosumab
2 Difference at 24 mos,
2
0 3.9 percentage points 0 Difference at 24 mos,
5.5 percentage points
-2 -2
Placebo Placebo
-4 -4
-6 -6
01 3 6 12 24 36 01 3 6 12 24 36
Mos Mos


Denosumab for Fracture Prevention
10 Denosumab
Placebo
New Vertebral Fracture (%)

8
P = .004 P = .004 P = .006
6

3.9
4 3.3
1.9
2 1.5
1.0
0.3
0
12 24 36
Mos
Patients at Risk, n 13 2 22 7 26 10



Fracture Risk: Conclusions
 Osteoporosis and fractures are an important health problem in
men
 Various factors increase fracture risk including older age, low
BMI, smoking, alcohol use, and low BMD
 ADT increases fracture risk
 Some but not all men require drug therapy to prevent fractures
during ADT
 Effective therapies are available
– Bisphosphonates increase BMD
– Denosumab increases BMD and decreases vertebral fractures

Delaying Bone Metastases in
Prostate Cancer


Natural History of Castration-Resistant
Nonmetastatic Prostate Cancer
1.0 Death
Bone metastasis
Bone metastasis or death
0.8
Proportion With Event

0.6

0.4

0.2

0
0 0.5 1.0 1.5 2.0 2.5 3.0
Yrs Since Random Assignment
Smith MR, et al. J Clin Oncol. 2005;23:2918-2925.


PSA and PSADT Are Associated With
Shorter Bone Metastasis–Free Survival
1.0 PSA < 7.7 ng/mL 1.0 PSADT < 6.3 mos
PSA 7.7-24.0 ng/mL PSADT 6.3-18.8 mos
Proportion of Patients With Bone

PSA > 24.0 ng/mL PSADT > 18.8 mos
0.8 0.8
Metastases or Died

0.6 0.6

0.4 0.4

0.2 0.2

0 0
0 0.5 1.0 1.5 2.0 2.5 3.0 0 0.5 1.0 1.5 2.0 2.5 3.0
Yrs Since Random Assignment Yrs Since Random Assignment
Smith MR, et al. J Clin Oncol. 2005;23:2918-2925..


Phase III Study: BMFS With Denosumab in
M0 CRPC With Aggressive PSA Kinetics
Bone metastasis or death
Double-blind randomization

Denosumab 120 mg SC q4w
(n = 716)
Patients with M0
CRPC at high risk for
bone metastases: Calcium and vitamin D Survival
PSA ≥ 8.0 ng/mL supplementation follow-up
or PSADT ≤ 10.0 mos
(N = 1432)
Placebo 120 mg SC q4w Off investigational
(n = 716) product

 Primary endpoint: BMFS
 Secondary endpoints: time to first bone metastasis (either
symptomatic or asymptomatic), OS

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


Denosumab Increases Bone Metastasis–
Free Survival
1.0 HR: 0.85 (95% CI: 0.73-0.98; P = .028)
Proportion of Patients

0.8

0.6

0.4
Median
0.2 Survival, Mos Events, n
Denosumab 29.5 335
Placebo 25.2 370
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Patients at Risk, n Mos
Denosumab 716 695 605 521 456 400 368 324 279 228 185 153 111 59 35
Placebo 716 691 569 500 421 375 345 300 259 215 168 137 99 60 36


Time to First Bone Metastasis With
Denosumab
1.0 HR: 0.84 (95% CI: 0.71-0.98; P = .032)

0.8

0.6

0.4
Median
0.2 Time, Mos Events, n
Denosumab 33.2 286
Placebo 29.5 319
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Mos


Denosumab in High-Risk M0 CRPC:
Secondary Endpoints
 OS: no improvement with denosumab  Time to first bone metastasis prolonged
vs placebo with denosumab vs placebo

 Fewer symptomatic bone metastases
with denosumab vs placebo

OS Time to Symptomatic Bone Metastasis
Proportion of Patients Alive

Without Symptomatic Bone
1.0 1.0

0.8 0.8

Metastases
HR: 0.67 (95% CI: 0.49-0.92;
0.6 HR: 1.01 (95% CI: 0.85-1.20; 0.6 P = .013)
P = .91) 33% Risk reduction
0.4 0.4
Events, n (%)
0.2 Placebo 0.2 Placebo 96 (13)
Denosumab Denosumab 69 (10)
0 0
0 6 12 18 24 30 36 42 0 6 12 18 24 30 36
Study Mo Study Mo

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


Denosumab and Adverse Events
Adverse Events, n (%) Placebo (n = 705) Denosumab (n = 720)
Any adverse event 655 (93) 676 (94)
Most common adverse events
Back pain 156 (22) 168 (23)
Constipation 119 (17) 127 (18)
Arthralgia 112 (16) 123 (17)
Diarrhea 102 (14) 111 (15)
Urinary tract infection 96 (14) 108 (15)
Serious adverse events 323 (46) 329 (46)
Most common serious adverse events
Urinary retention 31 (4) 54 (8)
Hematuria 24 (3) 35 (5)
Prostate cancer 21 (3) 15 (2)
Anemia 12 (2) 22 (3)
Urinary tract infection 14 (2) 15 (2)
Grade 3, 4, or 5 adverse events 353 (50) 381 (53)
Adjudicated positive osteonecrosis of the jaw 0 33 (5)
Hypocalcaemia 2 (< 1) 12 (2)
Smith MR, et al, Lancet. 2012;379:39-46.


Relationship Between PSADT and Risk for
Bone Metastasis or Death*
3.0
2.8
Relative Risk for Bone
Metastasis or Death

2.6
2.4
Increasing Risk

2.2
2.0
1.8
1.6
*Placebo arm of
1.4 study (n = 147)

20 18 16 14 12 10 8 6 4 2
PSADT in Mos
Shorter PSADT
Smith MR, et al. ASCO GU 2012. Abstract 6.


Bone Metastasis–Free Survival in Patients
With PSADT ≤ 10 Mos
1.0
HR: 0.84 (95% CI: 0.72-0.99;
P = .042)
Bone Metastasis–Free Survival
Proportion of Patients With

0.8 16% Risk reduction

0.6

0.4

Median Delay,
0.2 Mos Mos Events, n
Placebo 22.4 309
6.0
Denosumab 28.4 273
0
0 6 12 18 24 30 36
Patients at Risk, n Study Mo
Placebo 580 561 460 398 335 296 273 235 199 159 125 102 74
Denosumab 574 557 486 410 351 306 282 249 215 171 138 109 77
Smith MR, et al. ASCO GU. 2012. Abstract 6.


1.0
HR: 0.77 (95% CI: 0.64-0.93;
P = .006)


0.6

0.4

Median Delay,
Placebo 18.7 242
7.2
Denosumab 25.9 97
0
0 6 12 18 24 30 36
Patients at Risk, n Study Mo
Placebo 427 411 323 274 223 194 176 148 122 99 78 65 47
Denosumab 419 406 345 284 238 207 193 170 145 109 89 67 46


1.0
HR: 0.71 (95% CI: 0.56-0.90;
P = .004)


0.6

0.4

Median Delay,
Placebo 18.3 167
7.5
Denosumab 25.8 124
0
0 6 12 18 24 30 36
Patients at Risk, n Study Month
Placebo 289 279 209 176 138 117 105 88 71 58 46 35
Denosumab 263 254 217 176 143 123 117 102 89 67 56 38


Bone Metastasis Delay: Conclusions
 Bone metastases are a major cause of prostate cancer
morbidity
 Denosumab is the first bone-targeted therapy to delay bone
metastases in men with prostate cancer
– Not approved for this indication
 In men with high-risk nonmetastatic CRPC, denosumab
increases bone metastasis–free survival, time to first bone
metastasis, and time to symptomatic bone metastasis
– Dose higher/more frequent (120 mg q4 wks vs 60 mg q6 mos)
than what is approved to prevent fractures in men with CTIBL
 Effects of denosumab on bone metastasis–free survival were
maintained in men at particularly high risk

Treatment of Bone Metastases
Secondary to Castration-
Resistant Prostate Cancer


Skeletal-Related Events and Clinical
Consequences of Bone Metastases
Skeletal-Related Events Other Clinical Symptoms
 Pathologic fractures*  Bone pain
 Spinal cord compression*  Analgesic usage
 Radiation therapy to bone*  Quality-of-life deterioration
 Surgery to bone*  Shortened survival
 Hypercalcemia
 Change in antineoplastic
therapy
*Universally accepted skeletal-related events.


Combined Analysis of 2 Phase III Trials of
Pamidronate in Metastatic CRPC
Eligibility Criteria R
A
 Prostate cancer with N Pamidronate 90 mg q3w x 9
confirmed skeletal D (n = 169)
metastases O
 Bone pain secondary to bone M
metastases I
 No previous bisphosphonate Z Placebo q3w x 9
E (n = 181)
D

SRE (Study Wk 27), n (%) Pamidronate Placebo
Any SRE 42 (25) 46 (25)
Radiation to bone (pain relief) 25 (15) 29 (16)
Vertebral fracture 11 (7) 10 (6)
Spinal cord compression 5 (3) 3 (2)
Surgery to bone 5 (3) 6 (3)
Small EJ, et al. J Clin Oncol. 2003;21:4277-4284.


Zoledronic Acid in Castration-Resistant
Prostate Cancer
Eligibility Criteria R Zoledronic acid 4 mg q3w
A (n = 214)
N
 Patients with prostate D
cancer O Zoledronic acid 4 mg q3w
 Castration resistant M
 Bone metastases (initially 8 mg)
I (n = 221)
(N = 643) Z
E
Placebo q3w
D
(n = 208)

 Patients in 8-mg arm reduced to 4 mg because of renal toxicity
 Primary outcome: proportion of patients having ≥ 1 SRE
 Secondary outcomes: time to first on-study SRE, proportion of patients with
SREs, and time to disease progression
Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.


Time to First SRE: Zoledronic Acid vs
Placebo
 SREs: ZOL 4 mg 38%; placebo 49% (P = .028)
100 – 11% absolute risk reduction in ≥ 1 SRE
 Pain/analgesia scores increased less with ZOL
Percent Without Event

80
 No improvement in tumor progression, QoL, OS
60

40
Median, Days P Value
20 ZOL 4 mg 488 .009
Placebo 321
0
0 120 240 360 480 600 720
Days
ZOL 4 mg 214 149 97 70
47 35
3
Placebo 208 128 78 44 32 20
Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. Saad F, et al. ASCO 2003. Abstract 1523. Saad F,
et3 J Natl Cancer Inst. 2004;96:879-882.
al.


Treatment Guidelines for Zoledronic Acid
and Renal Dysfunction
 Calculate baseline CrCl to determine patient-specific starting dose

 For patients with CrCl > 60 mL/min, the recommended starting dose is 4 mg infused
over no less than 15 mins every 3-4 wks

 For patients with reduced CrCl the following schedule is recommended

Starting Dose Recommendations for Patients With Reduced CrCl
Baseline CrCl, mL/min Recommended Dose,* mg
50-60 3.5 mg
40-49 3.3 mg
30-39 3.0 mg
< 30 Not recommended
CrCl calculated using Cockcroft-Gault formula
*Doses calculated assuming target AUC of 0.66 (mg .hr/L) (CrCl = 75 mL/min)

Zoledronic acid [package insert]. 2012.


Treatment Algorithm for Continuing
Zoledronic Acid
For the second and all subsequent doses
Measure serum creatinine prior to each q3- to 4-wk dose

If significant change in creatinine* If no significant change in creatinine

Withhold therapy Give the starting dose

Resume starting dose when creatinine returns to within 10% of baseline

*An increase of 0.5 mg/dL for patients with normal baseline serum creatinine (< 1.4 mg/dL) or
an increase of 1.0 mg/dL for patients with abnormal baseline serum creatinine (≥ 1.4 mg/dL)

Zoledronic acid [package insert]. 2012.


Denosumab vs Zoledronic Acid: Double-
Blind, Placebo-Controlled Phase III Trial
Denosumab 120 mg SC +
Placebo IV* q4w
Patients with CRPC and bone (n = 950)
metastases, and no
current or past IV
bisphosphonate treatment
(N = 1901) Zoledronic acid 4 mg IV* +
Placebo SC q4w
(n = 951)

 Calcium and vitamin D supplemented in both treatment groups
 Primary endpoint: time to first on-study SRE (fracture, radiation or surgery to
bone, spinal cord compression)

*Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine clearance and
subsequent dose intervals determined by serum creatinine.
No SC dose adjustments made due to increased serum creatinine.
Fizazi K, et al. Lancet. 2011;377:813-822.


Time to First On-Study SRE
1.00 HR: 0.82 (95% CI: 0.71-0.95; Risk
Proportion of Subjects Without SRE

P = .0002, noninferiority; 18% reduction
P = .008, superiority)
0.75

0.50

KM Estimate of
0.25 Median Mos
Denosumab 20.7
Zoledronic acid 17.1
0
0 3 6 9 12 15 18 21 24 27
Study Mo
Patients at Risk, n

Zoledronic acid 951 733 544 407 299 207 140 93 64 47
Denosumab 950 758 582 472 361 259 168 115 70 39
Fizazi K, et al. Lancet. 2011;377:813-822.


Adverse Events of Interest
Subject Incidence, n (%) Zoledronic Acid Denosumab
(n = 945) (n = 943)
Infectious adverse events 375 (39.7) 402 (42.6)
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 ONJ† 12 (1.3) 22 (2.3)
Yr 1 5 (0.5) 10 (1.1)
Yr 2 8 (0.8) 22 (2.3)
Hypocalcemia 55 (5.8) 121 (12.8)
New primary malignancy 10 (1.1) 18 (1.9)
*Includes renal failure, increased blood creatinine, acute renal failure, renal impairment, increased blood
urea, chronic renal failure, oliguria, hypercreatinemia, anuria, azotemia, decreased creatinine renal
clearance, decreased urine output, abnormal blood creatinine, proteinuria, decreased glomerular
filtration rate, and nephritis.
†
P = .09
Fizazi K, et al. ASCO 2010. Abstract LBA4507. Fizazi K, et al. Lancet. 2011;377:813-822.

Treatment of Bone Metastases
Secondary to Hormone-Sensitive
Prostate Cancer


CALGB 90202: Zoledronic Acid in
Hormone-Sensitive PC With Bone Mets
Progression to
androgen-independent
prostate cancer
Zoledronic acid IV
Patients with prostate over 15 mins, Day 1,
cancer metastatic to q4w + ADT
bone who are Zoledronic acid IV
receiving ADT over 15 mins, Day 1,
(Planned N = 680; q4w + ADT
> 90% accrued as of Placebo IV over
August 2012) 15 mins, Day 1, q4w +
ADT

 Currently, there is no proven role for zoledronic acid in this setting
 Primary endpoint: time to first SRE
 Secondary endpoints: OS, PFS, toxicity
ClinicalTrials.gov. NCT00079001.


Do Bisphosphonates Prolong Survival?
 MRC PR05 study
– Hormone-sensitive metastatic prostate cancer
– Clodronate 2080 mg PO QD vs placebo
– Endpoints
– Primary: progression of symptomatic bone metastases or
death
– Secondary: OS, safety
 PR05: OS benefit (P = .032) with early separation of
curves
 MRC PR04: no benefit in PSA detectable–only disease
Dearnaley DP, et al. Lancet Oncol. 2009;10:872-876.


Denosumab and Zoledronic Acid:
Indications in Advanced Prostate Cancer
Indication Denosumab Zoledronic Acid
120 mg SC Monthly 4 mg IV Monthly
Bone metastases Yes No
from hormone-
sensitive disease
Bone metastases Yes Yes
from CRPC

Novel Agents With
Bone-Protective Effects


Novel Agents With Both Antitumor and
Bone-Protective Effects
 Recent study reports of benefits of abiraterone,[1]
enzalutamide (MDV-3100),[2] and radium-223[3] describe
reduction in SREs
 These studies demonstrate an OS benefit and report
SREs as supportive measure of clinical benefit
 Hypothesized to be related to direct antitumor effects

1. Logothetis C, et al. ASCO 2011. Abstract 4520. 2. Scher H, et al. 2012 ASCO GU Cancers
Symposium. Abstract LBA1. 3. Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.


COU-AA-301: Abiraterone Acetate
Improves OS in Metastatic CRPC
100
HR: 0.646 (95% CI: 0.54-0.77;
80 P < .0001)
Abiraterone acetate
Median OS: 14.8 mos
Survival (%)

60 (95% CI: 14.1-15.4)

40
Placebo
Median OS: 10.9 mos
20 (95% CI: 10.2-12.0)
Median OS with 2 previous Median OS with 1 previous
chemos: chemo:
0 14.0 mos AA vs 10.3 mos placebo 15.4 mos AA vs 11.5 mos placebo
0 3 6 9 12 15 18 21
Patients at Risk, n Mos
AA 797 736 657 520 282 68 2 0
Placebo 398 355 306 210 105 30 3 0

de Bono J, et al. N Engl J Med. 2011;364:1995-2005.


COU-AA-301: Effect of Abiraterone
Acetate on Pain Palliation and SREs
 Nearly one half of COU-AA-301 patients report significant pain at baseline
70 100 AA Placebo

Pts Not Experiencing
60
Pts Experiencing

155/349
80
Palliation (%)

Palliation (%)
50 (44.4%) Median: 10.25 mos
40 44/163 60
30 (27.0%)
40
20 Median: 5.55 mos
10 20
P = .0010 (log rank)
0 0
AA (n = 797) Placebo (n = 398) 0 3 6 9 12
Mos
Efficacy Measure Abiraterone Placebo P Value
(n = 797) (n = 398)
Median OS, mos 14.8 10.9 < .0001
Median radiographic PFS, mos 5.6 3.6 < .0001
Time to first SRE* 301 150 < .0001
(25th percentile), days
Logothetis C, et al. ASCO 2011. Abstract 4520.


Phase III AFFIRM Trial of Enzalutamide
(MDV3100) in Post-Docetaxel CRPC: OS
 OS improved with enzalutamide vs placebo
 Median follow-up: 14.4 mos
HR: 0.631 (95% CI: 0.529-0.752; P < .0001)
100
37% reduction in risk of death
90
80 Enzalutamide: 18.4 mos
70 (95% CI: 17.3-NYR)
Survival (%)

60
50
40
30
20 Placebo: 13.6 mos
(95% CI: 11.3-15.8)
10
0
0 3 6 9 12 15 18 21 24
Pts at Risk, n Duration of OS (Mos)
MDV3100 800 775 701 627 400 211 72 7 0
Placebo 399 376 317 263 167 81 33 3 0
Scher HI, et al. ASCO GU 2012. Abstract LBA1.


AFFIRM Trial of Enzalutamide in Post-
Docetaxel CRPC: Time to First SRE
HR: 0.621 (P < .0001)
100
90
Enzalutamide: 16.7 mos
80
(95% CI: 14.6-19.1)
70
SRE Free (%)

60
50
40
30
20 Placebo: 13.3 mos
10 (95% CI: 5.5-NYR)
0
0 3 6 9 12 15 18 21 24
Time to Event (Mos)
Pts at Risk, n
Enzalutamide 800 676 548 379 209 87 19 2 0
Placebo 399 278 196 128 68 33 11 0 0

De Bono JS, et al. ASCO 2012. Abstract 4519^.


Other Novel Agents Targeting Bony
Metastases in CRPC
 Radium-223
 Cabozantinib: MET/VEGFR-targeted agent
 Dasatinib: Src inhibitor

Saylor PJ, et al. J Clin Oncol. 2011;29:3705-3714.


Radium-223 Targets Bone Metastases
 Radium-223
functions as a
calcium mimic
 Targets sites of
new bone growth Ca
within and around
bone metastases Ra
 Excreted by the
small intestine

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


ALSYMPCA: Phase III Trial of Radium-223
in Symptomatic Prostate Cancer
Stratified by total ALP, previous docetaxel, and
bisphosphonate use; randomized 2:1
Up to 6 treatments at 4-wk intervals

Patients with symptomatic Radium-223 50 kBq/kg +
CRPC and ≥ 2 bone
BSC
metastases with no
known visceral
metastases, either
post-docetaxel or unfit
for docetaxel Placebo (saline) +
(N = 921) BSC

 Primary endpoint: OS
 Secondary endpoints: time to first SRE, time to total ALP progression, total ALP
response, ALP normalization, time to PSA progression, safety, QoL
Parker C, et al. ASCO GU 2012. Abstract 8.


ALSYMPCA: Overall Survival
100
HR: 0.695 (95% CI: 0.552-0.875;
90
P = .00185)
80
70
60
OS (%)

Radium-223 (n = 541)
50 Median OS: 14.0 mos
40
30 Placebo (n = 268)
Median OS: 11.2 mos
20
10
0
0 3 6 9 12 15 18 21 24 27
Pts at Risk, n Mos
Radium-223 541 450 330 213 120 72 30 15 3 0
Placebo 268 218 147 89 49 28 15 7 3 0


ALSYMPCA: Time to First SRE
100
HR: 0.610 (95% CI: 0.461-0.807;
90 P = .00046)
80
Pats Without SRE (%)

70
60 Radium-223 (n = 541)
Median: 13.5 mos
50
40
Placebo (n = 268)
30 Median: 8.4 mos
20
10
0
0 3 6 9 12 15 18 21
Pts at Risk, n Mos
Radium-223 541 379 214 111 51 22 6 0
Placebo 268 159 74 30 15 7 2 0
Sartor O, et al. ASCO GU 2012. Abstract 9.


Radium-223: Effect on Specific SREs
 Time to first SRE HR: 0.610 (P = .00046)
– Median: 13.6 vs 8.4 mos for placebo

Patients, n (%) Time to First Event
(Radium-223 vs Placebo)
SRE
Radium-223 Placebo P Value* HR
(n = 541) (n = 268) (95%CI)
External beam 0.65
122 (23) 72 (27) .0038
radiotherapy (0.48-0.87)
Spinal cord 0.44
17 (3) 16 (6) .016
compression (0.22-0.88)
Pathologic 0.45
20 (4) 18 (7) .013
bone fracture (0.24-0.86)
0.80
Surgical intervention 9 (2) 5 (2) .69
(0.27-2.4)

3 of 4 SRE components improved
Sartor AO, et al. ASCO 2012. Abstract 4551.


ALSYMPCA: Adverse Events of Interest
All Grades Grade 3/4
Adverse Event, n
(%) Radium-223 Placebo Radium-223 Placebo
(n = 509) (n = 253) (n = 509) (n = 253)
Hematologic
Anemia 136 (27) 69 (27) 54 (11) 29 (12)
Neutropenia 20 (4) 2 (1) 9 (2) 2 (1)
Thrombocytopenia 42 (8) 14 (6) 22 (4) 4 (2)
Nonhematologic
Bone pain 217 (43) 147 (58) 89 (18) 59 (23)
Diarrhea 112 (22) 34 (13) 6 (1) 3 (1)
Nausea 174 (34) 80 (32) 8 (2) 4 (2)
Vomiting 88 (17) 32 (13) 10 (2) 6 (2)
Constipation 89 (18) 46 (18) 6 (1) 2 (1)



Cabozantinib (XL184): Target Profile
Kinase IC50, nM RTK Cellular IC50, nM,
Autophosphorylation
MET 1.8
MET 8
VEGFR2 0.035
VEGFR2 4
RET 5.2
KIT 4.6 Cabozantinib, mg/kg

AXL 7.0 V 3 10 30 100

TIE2 14 pMET H441
tumors*
FLT3 14 MET
S/T Ks (47) >200
pVEGFR2 Mouse
ATP competitive, reversible lung†
VEGFR2
*No growth factor stimulation.
†
VEGF-A administered 30 min prior to harvest.
Data courtesy of Ron Weitzman and Dana Aftab.


Role of MET in Prostate Cancer and Bone
Metastases
Androgen Deprivation Activates MET Signaling
Stromal
HGF HGF
(autocrine + paracrine)
AR MET Androgen deprivation
AR X MET

Activated MET Is Highly Expressed in Bone Metastases

Zhang S, et al. Mol Cancer. 2010;9:9.


Cabozantinib (cMET/VEGFR2 Inhibitor)
Demonstrates Significant Bone Effects
Bone Scan Evaluable (N = 108) n (%)
Complete resolution 21 (19)
Partial resolution 61 (56)
Stable 23 (21)
Progressive disease 3 (3)
Effects on Osteoblast (t-ALP) and Osteoclast (CTx) Activity
100 100 Bisphosphonate treated
% Best Change From Baseline

80 80 Bisphosphonate naive
60 60
40 40
20 20
0 0
-20 -20
-40 -40
-60 -60
-80 -80
-100 -100
Pts With Baseline t-ALP Samples From Wk 6 and 12
Hussain M, et al. ASCO 2011. Levels ≥ 2 x ULN and (N = 118)
Abstract 4516. ≥ 12 Wks of Follow-up (N = 28)


Cabozantinib: Effects on Bone Pain and
Narcotic Use

% Change in Average Worst Pain From Baseline
Nonrandomized Expansion Trial
20 Prospective: Pts With Average
Worst Pain ≥ 4 at Baseline
Randomized Discontinuation 0 ** *
Trial; Post Hoc Investigator n (%)

Improved
Survey
-20
Bone metastases and bone pain at
baseline (n = 83): pain improvement
at Wk 6 or 12 56 (67) -40
Narcotics for bone pain at baseline
(n = 67): pain improvement at Wk 6 -60
or 12 47 (70)
Evaluable for narcotics change
-80
(n = 55): decrease or discontinuation
of narcotics 31 (56)
-100 Previous docetaxel
Previous docetaxel +
abiraterone and/or cabazitaxel
7/27 (26%) patients discontinued *Previous radionuclide therapy
narcotics entirely Median best pain reduction from baseline: 46%

Hussain M, et al. ASCO 2011. Abstract 4516. Basch EM, et al. 2011 AACR-NCI-EORTC Abstract B57.


MET and VEGFR Interactions in Bone
Tumors
 MET is activated in bone Stroma
metastases Angiogenesis
VEGF

– Tumor cells express MET Proliferation
differentiation
HGF
survival

– Autocrine and paracrine Osteoblast
HGF
VEGF

activation of MET by HGF VEGF HGF
NP-1
MET
– VEGF activation of MET Migration
proliferation
via neuropilin-1 HGF survival

Migration VEGF Tumor Cell
proliferation
 Osteoblasts and osteoclasts survival

– Express MET and VEGFRs Osteoclast

Zhang S, et al. Mol Cancer. 2010;9:9.


Cabozantinib: Randomized Phase III Trials
Patients with bone-
Cabozantinib 60 mg QD +
metastatic CRPC, moderate Pain Endpoint Trial[1]
Mitoxantrone Placebo
to severe bone pain, and  Primary endpoint:
previous treatment with durable pain response
docetaxel, abiraterone, or at Wk 12
enzalutamide  Secondary endpoints:
(Planned N = 246) Mitoxantrone/Prednisone + bone scan response by
Cabozantinib Placebo IRF, OS

Cabozantinib 60 mg QD +
Patients with bone- OS Endpoint Trial[2]
Placebo
metastatic CRPC, and  Primary endpoint: OS
previous treatment with
 Secondary endpoints:
docetaxel, abiraterone, or bone scan response by
enzalutamide IRF
(Planned N = 246) Prednisone 5 mg BID +
Placebo
1. ClinicalTrials.gov. NCT01522443.
2. ClinicalTrials.gov. NCT01605227.


Dasatinib: Src Inhibition
 Src and related kinases are overexpressed in prostate
cancer tumor cells
 Normal osteoclast function depends on Src kinase
 Src inhibition blocks
– Tumor cell proliferation
– Osteoclast proliferation
– Osteoclast activity/osteolysis


Phase II Study: Dasatinib Monotherapy in
Metastatic CRPC With No Previous Chemo
50 Tumor Size (by RECIST) 160
140
Urine N-Telopeptide
Change From Baseline (%)

40
120
Maximum Tumor Size

30 100

Maximum uNTx
20 80
10 60
40
0
20
-10 0
-20 -20
-40
-30
-60
-40 -80
-50 -100 Bisphosphonate No bisphosphonate

200 PSA 100 Bone Alkaline Phosphatase

150 80
60
100 Maximum BAP
Maximum PSA

40
50 20
0 0
-20
-50
-40
-100 -60
-150 -80 Bisphosphonate No bisphosphonate

Yu EY, et al. Clin Cancer Res. 2009;15:7421-7428.


Phase I/II Study: Dasatinib Plus Docetaxel
in CRPC
 N = 46 patients with CRPC
 Responses
– Durable 50% PSA declines in 26/46 (57%) patients
– 18/30 (60%) RECIST-evaluable patients had a PR
– 14 (30%) patients had disappearance of a lesion on bone scan
 Bone markers
– 33/38 (87%) had decrease in uNTx
– 26/34 (76%) had a decrease in BAP
 Toxicity: grade 3/4 in 13/46 (28%)
Araujo J, et al. Cancer. 2011;118:63-71.


Docetaxel/Prednisone ± Dasatinib in
CRPC: Phase III Study

Docetaxel +
Prednisone +
Patients with Placebo daily
metastatic
CRPC and evidence
of progression
(Planned N = 1500) Docetaxel +
Prednisone +
Dasatinib 100 mg/day PO

 Primary endpoint: OS
 Secondary endpoints: ∆ uNTx, time to first SRE, ∆ pain intensity, time to PSA
progression, tumor response rate, PFS, safety/tolerability

ClinicalTrials.gov. NCT00744497


Summary
 Bisphosphonates increase bone mineral density during androgen-deprivation
therapy
 Denosumab increases bone mineral density and decreases fractures during
androgen-deprivation therapy
 In men with high-risk CRPC, denosumab significantly increased bone
metastasis–free survival, time to bone metastasis, and time to symptomatic
bone metastasis
 Disease-related skeletal complications are common in men with metastatic
prostate cancer
 Zoledronic acid decreases risk of SREs in men with castrate-resistant disease
and bone metastases
 Denosumab is superior to zoledronic acid for delay in first skeletal-related
events and rate of skeletal-related events in this setting
 Newer systemic therapies with good antitumor efficacy have also been shown
in secondary endpoint analyses to prevent and delay the occurrence of SREs

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Role of Bone-Targeted Therapy in the Treatment of Prostate Cancer

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