cco md bone_health_prostate_cancer_slides

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

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clinicaloptions.com/oncologyOptimizing Therapeutic Strategies Targeting Bone: Prostate Cancer

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Faculty

Matthew Raymond Smith, MD, PhDProfessor of Medicine Harvard Medical SchoolProgram Director, Genitourinary OncologyMassachusetts General Hospital Cancer CenterBoston, Massachusetts

Evan Y. Yu, MDAssociate ProfessorDepartment of Medicine/OncologyUniversity of Washington/Fred Hutchinson Cancer Research CenterSeattle, 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


Inci

den

ce/1

,000

,000

Per

son

-Yrs

Age (Yrs)

4000

3000

2000

1000

35-39 ≥ 85 ≥ 85

HipSpine

Men Women

Melton LJ 3rd, et al. J Bone Miner Res. 1992;7:1005-1010.

Fracture Risk by Sex and Age

35-39


LumbarSpine

TotalHip

P < .001 for each comparison

12-mo data

Per

cen

t C

han

ge

Mittan D, et al. J Clin Endocrinol Metab. 2002;87:3656-3661.

GnRH Agonists Decrease BMD in Men With Prostate Cancer

-5

-4

-3

-2

-1

0

1

2

GnRH agonistControl


Proportion of Patients With Fractures1-5 Yrs After Cancer Diagnosis

0

3

6

9

12

15

18

Any Fracture Fracture Resulting in Hospitalization

Fre

qu

ency

(%

)

+2.8%; P < .001

+6.8%; P < .001

ADT (n = 6650)

No ADT (n = 20,035)

12.6

21

5.2

19.4

2.4

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

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

-3

-2

-1

0

1

2

3

4

5

BM

D P

erce

nt

Ch

ang

e

AlendronatePlacebo

LumbarSpine

TotalHip

12-Mo Data


Quarterly Zoledronic Acid Increases BMD During GnRH Agonist Therapy

LumbarSpine

TotalHip

Smith MR, et al. J Urol. 2003;169:2008-2012.

-4

-2

0

2

4

6

8P < .001 for each comparison

Final 12-Mo Data

Zoledronic acidPlacebo

BM

D P

erce

nt

Ch

ang

e


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

6P < .005 for each comparison

Zoledronic acid 4 mg/yr IV Placebo

LumbarSpine

Final 12-Mo Data

BM

D P

erce

nt

Ch

ang

e

TotalHip


Primary endpoints: bone mineral density, new vertebral fractures

Denosumab Fracture Prevention Study

Current androgen deprivation therapy for prostate cancer patients older than 70 yrs of age or with T score < -1.0

(N = 1468)

Denosumab q6mfor 3 yrs

Placebo q6mfor 3 yrs

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


Denosumab Increased BMD at All Skeletal Sites

1086420

-2-4-6

01 3 6 12 24 36Mos

Ch

an

ge

in

BM

D

Fro

m B

as

eli

ne

(%

)

Femoral Neck

Denosumab

Placebo

Difference at 24 mos,3.9 percentage points

1086420

-2-4-6

01 3 6 12 24 36Mos

Ch

an

ge

in

BM

D

Fro

m B

as

eli

ne

(%

) 86420

-2-4-6

01 3 6 12 24 36Mos

Ch

an

ge

in

BM

D

Fro

m B

as

eli

ne

(%

)

Lumbar Spine

Denosumab

Placebo


Denosumab

Placebo


Total Hip

86420

-2-4-6

01 3 6 12 24 36Mos

Ch

an

ge

in

BM

D

Fro

m B

as

eli

ne

(%

)

Placebo


Distal Third of Radius


Denosumab

10

10


Denosumab for Fracture Prevention

12Mos

24 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

Ver

teb

ral

Fra

ctu

re (

%) Placebo

Denosumab

13 2 22 7 26 10Patients at Risk, n



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

Smith MR, et al. J Clin Oncol. 2005;23:2918-2925.

DeathBone metastasisBone metastasis or death

1.0

0.8

0.6

0.4

0.2

00 0.5 1.0 1.5 2.0 2.5 3.0

Yrs Since Random Assignment

Pro

po

rtio

n W

ith

Eve

nt


Smith MR, et al. J Clin Oncol. 2005;23:2918-2925..

PSA and PSADT Are Associated With Shorter Bone Metastasis–Free Survival

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n o

f P

atie

nts

Wit

h B

on

e M

etas

tase

s o

r D

ied

0 0.5 1.0 1.5 2.0 2.5 3.0Yrs Since Random Assignment

PSA < 7.7 ng/mLPSA 7.7-24.0 ng/mLPSA > 24.0 ng/mL

1.0

0.8

0.6

0.4

0.2

00 0.5 1.0 1.5 2.0 2.5 3.0Yrs Since Random Assignment

PSADT < 6.3 mosPSADT 6.3-18.8 mosPSADT > 18.8 mos


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

Patients with M0 CRPC at high risk for

bone metastases:PSA ≥ 8.0 ng/mL

or PSADT ≤ 10.0 mos(N = 1432)

Double-blind randomization

Calcium and vitamin D supplementation

Off investigational product

Denosumab 120 mg SC q4w(n = 716)

Placebo 120 mg SC q4w(n = 716)

Survival follow-up

Bone metastasis or death

Phase III Study: BMFS With Denosumab in M0 CRPC With Aggressive PSA Kinetics

Primary endpoint: BMFS

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



Denosumab Increases Bone Metastasis– Free Survival

Pro

po

rtio

n o

f P

atie

nts

0

1.0

0.8

0.6

0.4

0.2

0 453 6 9 12 15 18 21 24 27 30 33 36 39 42Mos

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

DenosumabPlacebo

Median Survival, Mos

29.525.2

Events, n335370

Patients at Risk, nDenosumabPlacebo

716716

3536

695691

605569

521500

456421

400375

368345

324300

279259

228215

185168

153137

11199

5960


Time to First Bone Metastasis With Denosumab


Pro

po

rtio

n o

f P

atie

nts

0

1.0

0.8

0.6

0.4

0.2

0 453 6 9 12 15 18 21 24 27 30 33 36 39 42Mos

HR: 0.84 (95% CI: 0.71-0.98; P = .032)

DenosumabPlacebo

Median Time, Mos

33.229.5

Events, n286319


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

Denosumab in High-Risk M0 CRPC: Secondary Endpoints OS: no improvement with denosumab

vs placebo Time to first bone metastasis prolonged

with denosumab vs placebo

Fewer symptomatic bone metastases with denosumab vs placebo

Study Mo

0.2

Study Mo

0 6 12 18 24Pro

po

rtio

n o

f P

atie

nts

Ali

ve

0

0.4

0.8

1.0

0.6

30 36 42

PlaceboDenosumab

HR: 1.01 (95% CI: 0.85-1.20;P = .91)

OS

0.2

0 6 12 18 24

Pro

po

rtio

n o

f P

atie

nts

W

ith

ou

t S

ymp

tom

atic

Bo

ne

Met

asta

ses

0

0.4

0.8

1.0

0.6

30 36

PlaceboDenosumab

HR: 0.67 (95% CI: 0.49-0.92;P = .013)

Time to Symptomatic Bone Metastasis

Risk reduction

Events, n (%)96 (13)69 (10)

33%


Denosumab and Adverse Events

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

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)


Relationship Between PSADT and Risk for Bone Metastasis or Death*

Rel

ativ

e R

isk

for

Bo

ne

Met

asta

sis

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

Ris

k

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

*Placebo arm of study (n = 147)


Bone Metastasis–Free Survival in Patients With PSADT ≤ 10 Mos

HR: 0.84 (95% CI: 0.72-0.99;P = .042)

16% Risk reduction

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

Pro

po

rtio

n o

f P

atie

nts

Wit

h

Bo

ne

Met

asta

sis–

Fre

e S

urv

ival

1.0

0.6

0.8

0.4

0.2

0120 24 36

Study Mo580 460 335 273 199 125 74574 486 351 282 215 138 77

6 18 30

561557

398410

296306

235249

159171

102109

Patients at Risk, nPlaceboDenosumab

PlaceboDenosumab

MedianMos Events, n

Delay,Mos

22.428.4

6.0309273



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

23% Risk reduction


Pro

po

rtio

n o

f P

atie

nts

Wit

h

Bo

ne

Met

asta

sis–

Fre

e 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




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

29% Risk reduction

Pro

po

rtio

n o

f P

atie

nts

Wit

h

Bo

ne

Met

asta

sis–

Fre

e 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


MedianMos Events, n

Delay,Mos



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 MetastasesSkeletal-Related Events

Pathologic fractures*

Spinal cord compression*

Radiation therapy to bone*

Surgery to bone*

Hypercalcemia

Change in antineoplastic therapy

Other Clinical Symptoms

Bone pain

Analgesic usage

Quality-of-life deterioration

Shortened survival

*Universally accepted skeletal-related events.


Combined Analysis of 2 Phase III Trials of Pamidronate in Metastatic CRPC

Prostate cancer with confirmed skeletal metastases

Bone pain secondary to bone metastases

No previous bisphosphonate

Pamidronate 90 mg q3w x 9 (n = 169)

Placebo q3w x 9 (n = 181)

RANDOMIZED

Small EJ, et al. J Clin Oncol. 2003;21:4277-4284.

Eligibility Criteria

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)


Zoledronic Acid in Castration-Resistant Prostate Cancer

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

Patients with prostate cancer

Castration resistant Bone metastases

(N = 643)

Zoledronic acid 4 mg q3w(n = 214)

Placebo q3w(n = 208)

RANDOMIZED

Eligibility Criteria

Zoledronic acid 4 mg q3w(initially 8 mg)

(n = 221)

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)

– 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 321ZOL 4 mg 214 149 97 70 47 353

Placebo 208 128 78 44 32 203

Per

cen

t 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.


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

CrCl calculated using Cockcroft-Gault formula

*Doses calculated assuming target AUC of 0.66 (mg.hr/L) (CrCl = 75 mL/min)

Starting Dose Recommendations for Patients With Reduced CrCl

Zoledronic acid [package insert]. 2012.

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


*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)

Measure serum creatinine prior to each q3- to 4-wk dose

If significant change in creatinine*

Withhold therapy

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

If no significant change in creatinine

Give the starting dose

For the second and all subsequent doses

Zoledronic acid [package insert]. 2012.

Treatment Algorithm for Continuing Zoledronic Acid


Denosumab vs Zoledronic Acid: Double-Blind, Placebo-Controlled Phase III Trial

Patients with CRPC and bone metastases, and no current or past IV

bisphosphonate treatment(N = 1901)

*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.

Denosumab 120 mg SC +Placebo IV* q4w

(n = 950)

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)

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


Zoledronic acid 951 733 544 407 299 207 140 93 64 47Denosumab 950 758 582 472 361 259 168 115 70 39

Patients at Risk, nStudy Mo

0

1.00

Pro

po

rtio

n o

f S

ub

ject

s W

ith

ou

t S

RE

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

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


Subject Incidence, n (%) Zoledronic Acid (n = 945)

Denosumab (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)

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

*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

Adverse Events of Interest

Treatment of Bone Metastases Secondary to Hormone-Sensitive

Prostate Cancer


CALGB 90202: Zoledronic Acid in Hormone-Sensitive PC With Bone Mets

Currently, there is no proven role for zoledronic acid in this setting

Primary endpoint: time to first SRE

Secondary endpoints: OS, PFS, toxicityClinicalTrials.gov. NCT00079001.

Patients with prostate cancer metastatic to

bone who are receiving ADT

(Planned N = 680; > 90% accrued as of

August 2012)

Zoledronic acid IV over 15 mins, Day 1,

q4w + ADT

Placebo IV over 15 mins, Day 1, q4w +

ADT

Zoledronic acid IV over 15 mins, Day 1,

q4w + ADT

Progression to androgen-independent

prostate cancer


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 CancerIndication Denosumab

120 mg SC MonthlyZoledronic Acid 4 mg IV Monthly

Bone metastases from hormone-sensitive disease

Yes No

Bone metastases from CRPC

Yes Yes

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.


AA 797 736 657 520 282 68 2 0

Placebo 398 355 306 210 105 30 3 0

HR: 0.646 (95% CI: 0.54-0.77; P < .0001)

Placebo Median OS: 10.9 mos (95% CI: 10.2-12.0)

0 3 6 9 12 15 18 210

20

40

60

80

100

Su

rviv

al (

%)

Mos

Abiraterone acetate Median OS: 14.8 mos (95% CI: 14.1-15.4)

Median OS with 2 previous chemos:14.0 mos AA vs 10.3 mos placebo

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

Median OS with 1 previous chemo: 15.4 mos AA vs 11.5 mos placebo

COU-AA-301: Abiraterone Acetate Improves OS in Metastatic CRPC

Patients at Risk, n


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

Logothetis C, et al. ASCO 2011. Abstract 4520.

155/349(44.4%)

44/163(27.0%)

Pts

Ex

per

ien

cin

g

Pal

lia

tio

n (

%)

70605040302010

0AA (n = 797) Placebo (n = 398)

Pts

No

t E

xp

erie

nc

ing

P

alli

ati

on

(%

)

100

80

60

40

20

00 3 6 129

Mos

PlaceboAA

Median: 10.25 mos

P = .0010 (log rank)

Median: 5.55 mos

Efficacy Measure Abiraterone (n = 797)

Placebo (n = 398)

P Value

Median OS, mos 14.8 10.9 < .0001

Median radiographic PFS, mos 5.6 3.6 < .0001

Time to first SRE* (25th percentile), days

301 150 < .0001


Scher HI, et al. ASCO GU 2012. Abstract LBA1.

OS improved with enzalutamide vs placebo

Median follow-up: 14.4 mos

Phase III AFFIRM Trial of Enzalutamide (MDV3100) in Post-Docetaxel CRPC: OS

HR: 0.631 (95% CI: 0.529-0.752; P < .0001)37% reduction in risk of death

Placebo: 13.6 mos(95% CI: 11.3-15.8)

Enzalutamide: 18.4 mos(95% CI: 17.3-NYR)

Duration of OS (Mos)0 3 6 9 12 15 18 21 24

Su

rviv

al (

%)

010

2030

40

5060

70

80

90

100

MDV3100Placebo

800399

775376

701317

627263

400167

21181

7233

73

00

Pts at Risk, n


AFFIRM Trial of Enzalutamide in Post-Docetaxel CRPC: Time to First SRE

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

HR: 0.621 (P < .0001)

Placebo: 13.3 mos(95% CI: 5.5-NYR)

Enzalutamide: 16.7 mos(95% CI: 14.6-19.1)

Time to Event (Mos)0 3 6 9 12 15 18 21 24

SR

E F

ree

(%)

0

10

2030

40

5060

70

80

90

100

Enzalutamide Placebo

800399

676278

548196

379128

20968

8733

1911

20

00

Pts at Risk, n


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 within and around bone metastases

Excreted by the small intestine

Ra

Ca

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


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

Patients with symptomatic CRPC and ≥ 2 bone metastases with no

known visceral metastases, either

post-docetaxel or unfit for docetaxel

(N = 921)

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

Radium-223 50 kBq/kg + BSC

Placebo (saline) + BSC

Stratified by total ALP, previous docetaxel, and bisphosphonate use; randomized 2:1

Up to 6 treatments at 4-wk intervals

ALSYMPCA: Phase III Trial of Radium-223 in Symptomatic Prostate Cancer


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 0Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.

OS

(%

) O

S (

%)

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

Placebo (n = 268)Median OS: 11.2 mosPlacebo (n = 268)Median OS: 11.2 mos

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

33 66 99 1212 1515 1818 2121 2424 2727

MosMosPts at Risk, nPts at Risk, n

0

10

20

30

40

50

60

70

80

90

100

00


ALSYMPCA: Time to First SRE

Radium-223 541 379 214 111 51 22 6 0

Placebo 268 159 74 30 15 7 2 0

0

10

20

30

40

50

60

70

80

90

100

Pat

s W

ith

ou

t S

RE

(%

)

HR: 0.610 (95% CI: 0.461-0.807; P = .00046)HR: 0.610 (95% CI: 0.461-0.807; P = .00046)

Radium-223 (n = 541)Median: 13.5 mosRadium-223 (n = 541)Median: 13.5 mos

Placebo (n = 268)Median: 8.4 mosPlacebo (n = 268)Median: 8.4 mos

00 33 66 99 1212 1515 1818 2121

Pts at Risk, nPts at Risk, n MosMos

Sartor O, et al. ASCO GU 2012. Abstract 9.


Radium-223: Effect on Specific SREs

SRE

Patients, n (%) Time to First Event (Radium-223 vs Placebo)

Radium-223(n = 541)

Placebo(n = 268)

P Value* HR(95%CI)

External beam radiotherapy

122 (23) 72 (27) .00380.65

(0.48-0.87)

Spinal cord compression

17 (3) 16 (6) .0160.44

(0.22-0.88)

Pathologic bone fracture

20 (4) 18 (7) .0130.45

(0.24-0.86)

Surgical intervention 9 (2) 5 (2) .690.80

(0.27-2.4)

Sartor AO, et al. ASCO 2012. Abstract 4551.

Time to first SRE HR: 0.610 (P = .00046)

– Median: 13.6 vs 8.4 mos for placebo

3 of 4 SRE components improved


ALSYMPCA: Adverse Events of Interest

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

Adverse Event, n (%)

All Grades Grade 3/4

Radium-223(n = 509)

Placebo(n = 253)

Radium-223(n = 509)

Placebo(n = 253)

HematologicAnemiaNeutropeniaThrombocytopenia

136 (27)20 (4)42 (8)

69 (27)2 (1)

14 (6)

54 (11)9 (2)22 (4)

29 (12)2 (1)4 (2)

NonhematologicBone painDiarrheaNauseaVomitingConstipation

217 (43)112 (22)174 (34)88 (17)89 (18)

147 (58)34 (13)80 (32)32 (13)46 (18)

89 (18)6 (1)8 (2)10 (2)6 (1)

59 (23)3 (1)4 (2)6 (2)2 (1)


Cabozantinib (XL184): Target Profile

Kinase IC50, nM

MET 1.8

VEGFR2 0.035

RET 5.2

KIT 4.6

AXL 7.0

TIE2 14

FLT3 14

S/T Ks (47) >200

Data courtesy of Ron Weitzman and Dana Aftab.

ATP competitive, reversible

RTK Cellular IC50, nM, Autophosphorylation

MET 8

VEGFR2 4

Cabozantinib, mg/kg

pMETMET

V 3 10 30 100

VEGFR2

pVEGFR2

H441tumors*

Mouselung†

*No growth factor stimulation.†VEGF-A administered 30 min prior to harvest.*No growth factor stimulation.†VEGF-A administered 30 min prior to harvest.


Androgen Deprivation Activates MET Signaling

HGF(autocrine + paracrine)

AR MET AR MET

Stromal HGF

Androgen deprivation X

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

Activated MET Is Highly Expressed in Bone Metastases

Role of MET in Prostate Cancer and Bone Metastases


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)

Pts With Baseline t-ALP Levels ≥ 2 x ULN and

≥ 12 Wks of Follow-up (N = 28)

Samples From Wk 6 and 12 (N = 118)Hussain M, et al. ASCO 2011.

Abstract 4516.

% B

es

t C

ha

ng

e F

rom

Ba

se

lin

e

-100

-80

-60

-40

-20

0

20

40

60

80

100

-100

-80

-60

-40

-20

0

20

40

60

80

100 Bisphosphonate treated

Bisphosphonate naive

Effects on Osteoblast (t-ALP) and Osteoclast (CTx) Activity


Cabozantinib: Effects on Bone Pain and Narcotic UseRandomized Discontinuation Trial; Post Hoc Investigator Survey

n (%)

Bone metastases and bone pain at baseline (n = 83): pain improvement at Wk 6 or 12 56 (67)

Narcotics for bone pain at baseline (n = 67): pain improvement at Wk 6 or 12 47 (70)

Evaluable for narcotics change(n = 55): decrease or discontinuation of narcotics 31 (56)

Nonrandomized Expansion Trial Prospective: Pts With Average

Worst Pain ≥ 4 at Baseline

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

7/27 (26%) patients discontinuednarcotics entirely

Imp

rove

d

20

0

-20

-40

-60

-80

-100%

Ch

ang

e i

n A

vera

ge

Wo

rst

Pai

n F

rom

Bas

elin

e

** *

Previous docetaxelPrevious docetaxel + abiraterone and/or cabazitaxel*Previous radionuclide therapy

Median best pain reduction from baseline: 46%


MET and VEGFR Interactions in Bone Tumors MET is activated in bone

metastases

– Tumor cells express MET

– Autocrine and paracrine activation of MET by HGF

– VEGF activation of MET via neuropilin-1

Osteoblasts and osteoclasts

– Express MET and VEGFRs

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

Stroma

AngiogenesisVEGF

HGF

VEGF HGFHGF

HGF

VEGF

VEGFOsteoblast

Tumor Cell

Osteoclast

Migrationproliferation

survival

Proliferationdifferentiation

survival

Migrationproliferation

survival

MET

NP-1


Patients with bone-metastatic CRPC, moderate

to severe bone pain, and previous treatment with

docetaxel, abiraterone, or enzalutamide

(Planned N = 246)

Pain Endpoint Trial[1]

Primary endpoint: durable pain response at Wk 12

Secondary endpoints: bone scan response by IRF, OS

Cabozantinib 60 mg QD +Mitoxantrone Placebo

Mitoxantrone/Prednisone +Cabozantinib Placebo

Patients with bone-metastatic CRPC, and previous treatment with

docetaxel, abiraterone, or enzalutamide

(Planned N = 246)

OS Endpoint Trial[2]

Primary endpoint: OS

Secondary endpoints: bone scan response by IRF

Cabozantinib 60 mg QD +Placebo

Prednisone 5 mg BID +Placebo

1. ClinicalTrials.gov. NCT01522443.2. ClinicalTrials.gov. NCT01605227.

Cabozantinib: Randomized Phase III Trials


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


Tumor Size (by RECIST)

PSA

Urine N-Telopeptide

Bone Alkaline Phosphatase

50403020

10

0-10

-20

-30-40-50

Max

imu

m T

um

or

Siz

eC

han

ge

Fro

m B

asel

ine

(%)

200

150

100

50

0

-50

-100

-150

Max

imu

m P

SA

Ch

ang

e F

rom

Bas

elin

e (%

)

160140120100

604020

-20-40

-80-100

Max

imu

m u

NT

xC

han

ge

Fro

m B

asel

ine

(%)

100

80

60

20

0

-20

-60

-80

Max

imu

m B

AP

Ch

ang

e F

rom

Bas

elin

e (%

)

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

80

0

-60

Bisphosphonate No bisphosphonate

Bisphosphonate No bisphosphonate

40

-40

Phase II Study: Dasatinib Monotherapy in Metastatic CRPC With No Previous Chemo


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

ClinicalTrials.gov. NCT00744497

Docetaxel +Prednisone +Placebo daily

Docetaxel +Prednisone +

Dasatinib 100 mg/day PO

Patients with metastatic

CRPC and evidence of progression

(Planned N = 1500)

Primary endpoint: OS Secondary endpoints: ∆ uNTx, time to first SRE, ∆ pain intensity, time to PSA

progression, tumor response rate, PFS, safety/tolerability


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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