Novel Therapies and Bone Targeted Therapy Daniel P ...e-syllabus.gotoper.com/...07_Petrylak_Bone_FINAL.pdf · metastases June 1993 Strontium-89 Relief of pain in patients with confirmed

Novel Therapies and Bone Targeted Therapy

Daniel P. Petrylak, MD

Yale University Cancer Center

Skeletal-Related Events

Malignancy Bone Lesions SREs

Breast 65%-75% 68%

Prostate 90% 49%

Lung 30%-40% 48%

MM 95%-100% 51%

Coleman. Cancer. 1997;80:1588; Bubendorf. Hum Pathol. 2007;31:578; Saad. Cancer. 2007;110:

1860; Coleman. Oncologist. 2004;9:14.

• The skeleton is the most common site of metastasis

• SREs: fracture, spinal cord compression, radiation or

surgery to bone, and hypercalcemia

MM=multiple myeloma; SRE=skeletal-related event.

Bone Remodeling

Reproduced with permission from Center for Bone Biology website.

http://bonecenter.mc.vanderbilt.edu/edwardsj/. Accessed 11/23/09.

Bone

Formation

Coupling

Stimulation of

osteoclast

formation

Osteoblasts express

osteoclastogenic

factors

Release of

osteoinductive

factors

Stimulation of

osteoblast

differentiation

Bone

Resorption

Mechanisms of Bone Metastases

Reproduced with permission from Kingsley. Mol Cancer Ther. 2007;6:2609; Guise. Clin Cancer

Res. 2006;12:6213s.

CTGF=connective tissue growth factor; CXCR4=chemokine receptor 4; IGF=insulin-

like growth factor; IL=interleukin; MMP=matrix metalloproteinase; Obl=osteoblast;

PDGF=platelet-derived growth factor; PTHrP=parathyroid hormone–related protein;

TGF=transforming growth factor; VEGF=vascular endothelial growth factor.

Growth Factors

IL-6

Mechanisms of Bone Metastases (Cont)

• DKK1 is secreted by

some cancer cells

• DKK1 inhibits Wnt

signaling, leading to

osteoblast inactivation

• DKK1 enhances

osteoclast activation

through decreased

production of

osteoprotegerin and

increased production

of RANKL

DKK1=Dickkopf 1; FRZB and sFRP2=secreted frizzled protein; MIP1α=macrophage-

inflammatory protein 1a; MSC=mesenchymal stem cells; OPG=osteoprotegerin;

RANKL=receptor activator of nuclear factor–κB ligand.

Reproduced with permission from Pinzone. Blood. 2009;113:517.

Zoledronic Acid in HRPC

• Pts on the 8-mg arm are reduced to 4 mg because of renal

toxicity

• Primary outcome: proportion of pts having ≥1 SRE

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

pts with SREs, and TTP

•Pts with prostate

cancer

•Hormone

refractory

•Bone

metastases

(N=643)

Zoledronic acid 4 mg q3w

(N=214)

Placebo q3w

(N=208)

R

A

N

D

O

M

I

Z

E

D

Eligibility Criteria

Zoledronic acid 4 mg q3w

(initially 8 mg)

(N=221)

Saad. J Natl Cancer Inst. 2002;94:1458.

Zoledronic Acid in HRPC:

Time to First On-Study SRE

• P=0.011 for 4 mg zoledronic acid vs placebo

Reproduced with permission from Saad. J Natl Cancer Inst. 2002;94:1458.

0 90 180 270 360 450 540

% W

ith

ou

t th

e E

ven

t

Time After the Start of Study Drug (Days)

Zoledronic acid 4 mg

Zoledronic acid 8/4 mg

Placebo

110

100

90

80

70

60

50

40

30

20

10

0

• Tumor cells

– Increase expression of RANKL

– Decrease expression of osteoprotegerin

– Increase bone resorption through osteoclast activity

RANKL Inhibition: Mechanism of Action

CFU-M=colony-forming unit macrophage.

Osteoblast lineage Bone Osteoclast

Osteoblast lineage Bone Osteoclast

CFU-M

Prefusion

osteoclast

Multinucleated

osteoclast Growth factors

Hormones

Cytokines RANKL

RANKL

Rank

OPG

Denosumab

Reproduced with permission from Miller. Curr Osteo Rep. 2009;7:18; Fizazi. J Clin Oncol.

2009;27:1564.

RANKL Inhibition: Denosumab

• Fully human monoclonal antibody

• Specifically inhibits RANKL

• Prevents osteoclast-mediated bone resorption

• Adverse events

– ONJ and renal toxicity

• Similar incidence to IV bisphosphonates in randomized trials

– Susceptibility to new tumors

• Approximately 5% of pts developed new primary tumors (in

denosumab and placebo groups)

• July 2010: FDA priority review status for the treatment of

bone metastases to reduce SREs in pts with advanced

cancers

Fizazi. J Clin Oncol. 2009;27:1564; Smith. N Engl J Med. 2009;361:745; Stopeck. ESMO. 2009

(abstr 2LBA); Amgen press releases. Amgen Inc. website. http://www-

ext.amgen.com/media/media_pr_detail.jsp?year=2010&releaseID=1448739. Accessed 8/25/10.

FDA=United States Food and Drug Administration.

Phase III Trial of

Denosumab vs Zoledronic Acid in HRPC

• All pts received supplemental calcium and vitamin D

• Primary endpoint: (non-inferiority) time to first on-study

SRE

• Secondary endpoints: superiority

•Hormone-refractory (castration resistant)

•≥1 bone metastasis

(N=1901)

Zoledronic acid 4 mg IV +

Placebo s.c. q4wk

(N=951)

Denosumab 120 mg s.c. +

Placebo IV q4wk

(N=950)

R

A

N

D

O

M

I

Z

E

D


Fizazi. ASCO. 2010 (abstr LBA4507).

s.c.=subcutaneous.

Phase III Trial of Denosumab vs

Zoledronic Acid in HRPC: Efficacy


Endpoint Denosumab Zoledronic

Acid

HR

P Value

Median time to

first on-study SRE 20.7 mos 17.1 mos

HR=0.82 (0.71-0.95)

P=0.008*

TTP

NR

HR=1.06 (0.95-1.18)

P=0.30

OS HR=1.03 (0.91-1.17)

P=0.65

*P=0.0002 non-inferiority

NR=not reported.

Phase III Trial of Denosumab vs

Zoledronic Acid in HRPC: Adverse Events


Adverse Event Denosumab

N=943

Zoledronic

Acid

N=945

HR

P Value

Acute-phase reaction 8.4% 17.8% NR

Hypocalcemia 12.8% 5.8% NR

ONJ, N (%) 22 (2.3) 12 (1.3%) P=0.09

Risk factors

•Tooth extraction, dental appliance,

poor oral hygiene

•Chemotherapy

17

14

10

9

Treatment

•Limited surgery (eg, debridement)

•Bone resection

10

2

3

1

Outcome as of April 2010

•Resolution (mucosal coverage)

4

1

Phase III ’147 Study: Denosumab vs

Placebo in HRPC

• Primary endpoint: time to first occurrence of bone metastasis or

death from any cause

• Secondary endpoints

– Time to first occurrence of bone metastasis (excluding death)

– OS

•HRPC

•No bone

metastases

•PSA ≥8 ng/ml

≤3 mos before

randomization or

PSA doubling time

≤10 mos

•N=1432

Denosumab 120 mg q4wk

Placebo

R

A

N

D

O

M

I

Z

E

D


US National Institutes of Health website. http://clinicaltrials.gov/ct2/show/NCT00286091?term=

NCT00286091&rank=1. Accessed 01/05/11; Amgen press release.http://wwwext.amgen.com/

media/media_pr_detail.jsp?releaseID=1507379. Accessed 01/05/11.

Phase 3 Trial of Docetaxel +/- Dasatinib

• Primary endpoint: Overall survival

• Stratification factors

– Performance status

– Baseline bisphosphonate use

– Urine N-telopeptide level

•Patients with

metastatic CRPC

•Evidence of

progression

Docetaxel 75 mg/m2 q3w +

Dasatinib 100 mg po qd +

Prednisone 5 mg po bid

Docetaxel 75 mg/m2 q3w +

Placebo po qd +

Prednisone 5 mg po bid

R

A

N

D

O

M

I

Z

E

Eligibility

Criteria

N=1,500

Characteristics of Radioisotopes

Alpha Particles1 Beta Particles2

Size

Definition

Consists of helium nuclei

High LET

Do not penetrate a sheet

of paper

Consists of electrons

Relatively low LET

May be halted by an

aluminum plate

DNA hits to kill cells 1-10 100-1000

Type of DNA

Damage

Double-strand breaks

(Lethal, more difficult to

repair)3

Single-strand breaks

(More repairable) 3

LET = linear energy transfer

1. Henriksen G, et al. J Nucl Med. 2003;44(2):252-259; 2. Bruland OS, et al. Clin Cancer Res. 2006;12(20):6250s–6257s.

FDA-Approved Bone-Targeting Radionuclides

for the Treatment of Bone Metastases

FDA

Approval Bone Agent Indication

March

1997

Samarium-153-

lexidronam

Relief of bone pain in patients

with painful skeletal

metastases

June 1993 Strontium-89

Relief of pain in patients with

confirmed osteoblastic

metastatic bone lesions

Sartor. Urology. 2004;63:940; Porter. Int J Radiation Oncology Biol Phys. 1993;25:805; Quadramet

[package insert]. Princeton, NJ: EUSA Pharma, Inc.; 2008; Metastron [package insert]. Arlington Heights,

IL: Medi-Physics, Inc.; 1998; U.S. Food and Drug Administration.

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed

September 15, 2010; U.S. Food and Drug Administration.

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed

September 15, 2010.

Bone-Targeting Radionuclides for Patients

With Prostate Cancer Bone Metastases

Sartor. Urology. 2004;63:940; Nilsson. Lancet Oncol. 2007;8:587; Porter. Int J Radiation Oncology Biol

Phys. 1993;25:805.

Trial Bone Agent No.

of Pts Results

Sartor, 2004

phase III

Samarium-153-

lexidronam 101

Improvement over placebo:

VAS: 2-4 wks (P≤0.05)

PDS: 1-4 wks (P≤0.05)

Analgesic use: 3-4 wks (P<0.0284) Placebo 51

Porter, 1993

phase III

Strontium-89 +

EBR 126

Strontium-89 vs placebo:

New painful sites: 0.587 vs 1.213 (P<0.002)

Analgesic free at 3 mos: 17.1% vs 2.4% (P<0.05)

Time to further RT: 35.3 vs 20.3 wks (P=0.006) Placebo + EBR

Nilsson, 2007

phase II

Radium-223 +

EBR 33

Radium-223 vs placebo:

Change in bone ALP: -65.6% vs 9.3% P<0.0001

Median time to PSA progression: 26 vs 8 wks

(P=0.048)

Median OS: 65.3 vs 46.4 weeks (P=0.066) Placebo + EBR 31

ALP=alkaline phosphatase; PDS=pain descriptor scale (nonlinear); RT=radiotherapy;

VAS=100-mm pain intensity visual analog scale (linear).

Mechanisms of Bone Targeting

• Strontium-89: A calcium homologue, tracks

deposition of calcium

• Samarium-153 EDTMP: Samarium does not

track to bone, but when chelated with EDTMP

the phosphonic acid groups target to areas of

newly deposited bone

• Phosphorus-32: Tracks inorganic phosphorus

in the body

Optimizing Combinations of

Radiopharmaceuticals and Additional Anti-

Cancer Therapies in HRPC

• Strontium-89/External Radiation Therapy

• Strontium-89/Doxorubicin

• Strontium-89/Cis-Platinum

• Samarium-153/Docetaxel

• Alpharadin + Docetaxel

Strontium89 + Doxorubicin:

Bone Targeted Consolidation Therapy Tu et al, Lancet 357: 336-341

• Prospective randomized trial comparing doxorubicin

+ strontium89 in HRPC patients with bone metastases

• Inclusion criteria

– patients with stable or responding disease after

“induction therapy” of 2-3 cycles of KAVE

chemotherapy

• Exclusion criteria

– Prior radiation to >1 focus of bone disease

– Patients with predominantly visceral disease

Strontium89 + Doxorubicin: Bone Targeted Consolidation Therapy

Tu et al, Lancet 357: 336-341

• Patient Characteristics

– 105 HRPC received “induction” chemotherapy

– 33 not randomized (progressive disease, toxicity,

etc.)

– 72 patients randomized

• Randomized treatment

– Weekly 20 mg/m2 doxorubicin (X6 weeks) + ~4

mCi strontium89

• End Points

– Time to progression and survival

Tu et al, Lancet 357:336-41

Samarium-153 + Docetaxel in HRPC Massard et al., ASCO-Prostate 2007 #227

• Docetaxel (70 mg/m2 day) and estramustine (10 mg/kg days 1-5) q 3 weeks (average of 4 cycles) as induction therapy (n=43)

• Consolidation with docetaxel at 20 mg/m2 weekly X 6 with 6 weeks + samarium-153 EDTMP at 1 mCi/Kg during week one (n=43)

• Endpoints: PFS at 7 months and survival at one year

Samarium-153 + Docetaxel in HRPC

Massard et al., ASCO-Prostate 2007 #227

• Survival 71% at one year

• 48% were progression free at 7 months

• Pain response: 60% had a >2/10 VAS score

pain improvement

• Toxicity limited in consolidation treatment

– Grade 3-4 neutropenia (14%) and

thrombocytopenia (5%)

References: 1. Henriksen G, et al. Cancer Res. 2002;62:3120–3125. 2. Brechbiel MW. Dalton Trans. 2007;43:4918-4928.

Bone

Short range of α-particles could reduce bone marrow exposure1

Marrow

Tumor

Range of an α-emitting Radiopharmaceutical

Compared to a β-emitter

Bone Mineral

(Hydroxyapatite)

Range of β-particle

(long range

– 10 to 1000 cell diameters2)

Radionuclide Range of α-particle

(short range – ~2 to 10

cell diameters2)

6 injections at 4-week intervals

Radium-223 dichloride

(50 kBq/kg) +

best standard of care†

Placebo (saline) +

best standard of care†

•Total ALP:

< 220 U/L vs. ≥ 220

U/L

•Bisphosphonate use:

Yes vs. No

•Prior docetaxel:

Yes vs. No

• Confirmed Symptomatic CRPC

• ≥2 bone metastases

• No known visceral metastases

• Post-docetaxel or unfit for docetaxel*

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design1

Reference: 1. Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.

*Unfit for docetaxel includes patients who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable †Best standard of care defined as a routine standard of care at each center, eg. local external beam radiotherapy, corticosteroids, anti-androgens, estrogens (e.g., stilbestrol), estramustine, or ketaconazole

PATIENTS STRATIFICATION

R

A

N

D

O

M

I

Z

E 2:1

N=921

TREATMENT PHASE

>100 centers in 19 countries Planned follow-up is 3 years

ALSYMPCA Endpoints

Primary endpoint

• Overall survival

Secondary endpoints

• Time to occurrence of first SRE

• Time to total ALP progression

• Total ALP response

• Total ALP normalization

• Time to PSA progression

• Safety

• Quality of life

Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.

ALSYMPCA

Major Inclusion/Exclusion Criteria

Inclusion criteria

• Symptomatic CRPC with ≥2

bone metastases

– Confirmed by bone

scintigraphy

– No known visceral metastases

• Regular analgesic medication

use for cancer-related bone pain

or treatment with EBRT for

bone pain within previous 12

weeks

• Life expectancy of ≥6 months

Exclusion criteria

• Eligible for first course of docetaxel

(i.e., fit, willing, and where

docetaxel is available)

• Treatment with cytotoxic

chemotherapy within previous 4

weeks or planned during the

treatment period

• Failure to recover from AEs due to

cytotoxic chemotherapy

• Prior use of systemic

radiopharmaceuticals for bone

metastases

EBRT, external beam radiation therapy. Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.

ALSYMPCA : Patient Demographics and Baseline

Characteristics

Parameter Radium-223 dichloride

(n = 614)

Placebo

(n = 307)

Mean age, y 70.2 70.8

Caucasian, n (%) 575 (94) 290 (95)

Baseline ECOG score, n (%)

≤1

2

536 (87)

76 (12)

265 (86)

40 (13)

Extent of disease, n (%)

<6 metastases

6–20 metastases

>20 metastases/superscan

100 (16)

262 (43)

249 (41)

38 (12)

147 (48)

121 (40)

WHO ladder, cancer pain index ≥2, n

(%) 345 (56) 168 (55)

ITT group (n = 921) WHO pain relief ladder:

1 – Non-opioid analgesic ± adjuvant

2 – Opioid for mild to moderate pain ± non-opioid analgesic ± adjuvant

3 – Opioid for moderate to severe pain ± non-opioid analgesic ± adjuvant

Patients may have also received external-beam radiation therapy for pain


ALSYMPCA: Patient Baseline Characteristics

Parameter

Median (min, max)

Radium-223

dichloride

(n = 614)

Placebo

(n = 307)

Hemoglobin, g/dL 12.2 (8.5-15.7) 12.1 (8.5-16.4)

Albumin, g/L 40 (24-53) 40 (23-50)

Total ALP, µg/L 211 (32-6431) 223 (29-4805)

LDH, U/L 315 (76-2171) 336 (132-3856)

PSA, µg/L 146 (3.8-6026) 173 (1.5-14500)

Current bisphosphonates

Yes, n (%)

250 (40.7)

124 (40.4)

Prior docetaxel

No, n(%)

Yes, n (%)

262 (42.7)

352 (57.3)

133 (43.3)

174 (56.7)

ITT group (n = 921)


Radium-223

dichloride

(n = 614)

Placebo (n = 307)

Median OS

(months) 14.9 11.3

HR 0.695

95% CI 0.581–0.832

P value 0.00007

ALSYMPCA Updated Analysis:

Overall Survival

Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39

Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0

Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0

0

10

20

30

40

50

60

70

80

90

100

Pa

tien

ts (

%)

Treatment Radium-223 dichloride Placebo

3.6 month OS benefit


Prior docetaxel use: 3.1 months OS benefit

Radium-223 352 327 238 155 88 45 27 5 1 0 0

Placebo 174 152 104 61 35 15 5 4 1 1 0

Radium-223 (n = 352)

Median: 14.4 months

Placebo (n = 174)

Median: 11.3 months

HR = 0.710

95% CI, 0.565-

0.891

P = 0.00307

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36 40 Month

%

ALSYMPCA : Overall Survival Stratified by Prior Docetaxel Use

No prior docetaxel use: 4.6 months OS benefit

Radium-223 (n = 262)

Median: 16.1 months Placebo (n = 133)

Median: 11.5 months

HR = 0.745

95% CI, 0.562-

0.987

P = 0.03932

Radium-223 262 236 168 119 70 31 14 7 1 0

Placebo 133 113 74 42 24 14 9 3 1 0

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36

%

Month

42.7% of Radium-223 dichloride arm

43.3% of placebo arm had no prior

docetaxel


ALSYMPCA: Survival Benefit Across Patient

Subgroups

≥


ALSYMPCA: Time to First SRE

Month 0 3 6 9 12 15 18 21 24 27 30

Radium-223 614 487 332 193 125 62 31 8 8 1 0

Placebo 307 207 108 51 33 17 8 6 3 1 0

0

10

20

30

40

50

60

70

80

90

100

Pa

tien

ts (

%)

Radium-

223

dichloride

(n = 614)

Placebo (n = 307)

Median time to

SRE (months) 12.2 6.7

Hazard ratio 0.64

95% CI 0.52–0.78

P value <0.0001

Treatment Radium-223 dichloride Placebo


ALSYMPCA: Time to First SRE

Components

N (%) of Events

Time to Event

(Radium-223 dichloride vs.

Placebo)

SRE Component

Radium-223

dichloride

(n = 614)

Placebo

(n = 307) P value

HR

(95% CI)

External-beam

radiotherapy 186 (30.3) 105 (34.2) 0.00117

0.67

(0.52-0.85)

Spinal cord

compression 25 (4.1) 21 (6.8) 0.025

0.51

(0.28-0.93)

Pathologic bone

fracture 32 (5.2) 20 (6.5) 0.09

0.62

(0.35-1.09)

Surgical

intervention 12 (2) 7 (2.3) 0.479

0.71

(0.28-1.8)

Reference: Sartor et al. J Clin Oncol. 2012;30 (suppl): abstract 4551. Presented at ASCO 2012.

ALSYMPCA: Overall Safety Data

Radium-223

dichloride

(n = 600)

Placebo

(n = 301)

All AEs 558 (93) 290 (96)

Grade 3 or 4 AEs 349 (58) 197 (66)

Serious AEs (SAEs) 281 (47) 181 (60)

Discontinuation due to AEs 99 (17) 62 (21)

Deaths due to AEs 96 (16) 67 (23)

Patients with adverse events (AEs), n (%)


ALSYMPCA: Median Number of Injections

Radium-223

dichloride

(n = 614)

Placebo

(n = 307)

Patients treated, n 599 302

Median number of

injections, range 6 (1-6) 5 (1-6)

Received all 6 injections, n (%) 387 (63) 145 (47)

ITT group (n = 921)


ALSYMPCA: Adverse Events of Interest

All Grades Grades 3 or 4

Radium-223

dichloride

(n = 600)

Placebo

(n = 301)

Radium-223

dichloride

(n = 600)

Placebo

(n = 301)

Hematologic

Anemia 187 (31.2) 92 (31) 77 (13) 40(13)

Neutropenia 30 (5) 3 (1) 13 (2) 2 (1)

Thrombocytopenia 69 (11.5) 17 (5.6) 39 (6.5) 6 (2)

Non-hematologic

Bone pain 300 (50) 187 (62) 125 (21) 77 (26)

Diarrhea 151 (25) 45 (15) 9 (1.5) 5 (1.7)

Nausea 213 (35.5) 104 (35) 10 (2) 5 (2)

Vomiting 111 (18.5) 41 (14) 10 (2) 7 (2)

Constipation 108 (18) 64 (21) 6 (1) 4 (1)

Patients with AEs, n (%)


Functional Assessment of Cancer Therapy for

Patients with Prostate Cancer (FACT-P)

• The FACT-P is a validated questionnaire used to assess QoL in men with

prostate cancer1

• Items are rated on a 0 to 4 Likert-type scale where higher sum scores, after

transforming the scores for negatively worded items, represent better QoL

• The FACT-P has 39 items and is composed of 5 subscales2

– Physical well-being (PWB) (7 items)

– Social/family well-being (SWB) (7 items)

– Emotional well-being (EWB) (6 items)

– Functional well-being (FWB) (7 items)

– Prostate cancer (PCS) (12 items)

• Total score (PWB + SWB + EWB+ FWB + PCS) has a range of 0 to 1562

– Minimally important difference (MID) is 10 points

• Trial outcome index (TOI; PWB + FWB +PCS) has a range of 0 to 1042

– MID is 9 points

Functional Assessment of Cancer

Therapy General Version (FACT-G)

Prostate cancer-specific module

Reference: 1. ESPER et al. Urology 1997;50:920 2. Parker et al. Ann Oncol. 2012 (suppl; abstr 898PD).

Percent of Patients with QoL Measurements

Based on FACT-P: Post-baseline Visits

Patients represented in chart must have baseline quality of life

measurements

Responder Analysis Based on Changes

in FACT-P Summary Scores

Responder Analysis Based on Changes

in FACT-P Subscale Scores

QoL Responder Analysis: FACT-P Summary Scores

and Subscale Scores at Week 16 and/or Week 24

MID, minimally important difference; NS, Not significant; †For each subscale, MID = 3

Radium-223 ( n = 434) Placebo (n = 191)

P < 0.1 P < 0.05

P < 0.05

Reference: Parker et al. Ann Oncol. 2012 (suppl; abstr 898PD).

NS NS

P < 0.05

P < 0.1

• For improvement in quality of life, as measured by FACT-P total

score, treatment with radium-223 dichloride resulted in a

significantly higher percentage of responders vs. placebo (27%

vs. 18% P = 0.024), and the difference in responder rates based

on TOI was trending toward significance

• There was a trend toward improvement in all subscales of the

FACT-P, with P < 0.05 for the PCS and EWB subscales

Quality of Life Responder Analysis

Mean Changes From Baseline in FACT-P Total

and TOI Scores

Ch

an

ge

from

Base

lin

e

-2 -1 0 1

-6 -5 -4 -3

-10 -9 -8 -7

-13 -12 -11

Week 0 Week 16 Week 24 Week 42

Visit Assessment Visit Assessment

-2 -1 0 1

-6 -5 -4 -3

-10 -9 -8 -7

Ch

an

ge

from

Base

lin

e

-13 -12 -11

Week 0 Week 16 Week 24 Week 42

FACT-P Total

Score

TOI Score

Radium-223 dichloride Placebo

TOI, trial outcome index

Reference: Parker et al. Ann Oncol. 2012 (suppl; abstr 898PD).

• Mean change scores for both FACT-P Total score and TOI score

appear to decline relative to baseline over time, however, rate of

decline appears faster for the placebo group compared with the

radium-223 dichloride

Chemotherapy Post-Radium-223

Dichloride Treatment Subgroup

Analysis

Patients Treated with Chemotherapy After

Radium-223 Dichloride*

*Post-hoc analysis

Reference: Sartor et al. Ann Oncol. 2012 (suppl; abstr 936P).

The proportion of patients receiving chemotherapy following

ALSYMPCA

• 90 out of 615 patients (15%) in the radium-223 dichloride

group

• 54 out of 307 patients (18%) in the placebo group

The most common chemotherapeutic agents administered after study drug

treatment were docetaxel (n = 105), mitoxantrone (n = 23), and

cyclophosphamide (n = 19)

Patient Demographics and Baseline

Characteristics*

Radium-223

(n = 93)

Placebo

(n = 54)

Mean age, years 67.2 68.2

Caucasian race, n (%) 86 (93) 50 (93)

Baseline ECOG PS, n (%)

≤ 1

2

88 (95)

5 (5)

47 (87)

7 (13)

WHO ladder, cancer pain index, ≥ 2, n (%) 48 (52) 29 (54)

Total ALP, n (%)

< 220 U/L

≥ 220 U/L

59 (63)

34 (37)

38 (70)

16 (30)

Current use of bisphosphonates, n (%)

Yes

No

45 (48)

48 (52)

24 (44)

30 (56)

Median number of study drug injections, range 6 (2–6) 5.5 (1–6)

Patients receiving all 6 injections of study drug, n (%) 66 (71) 27 (50)

Any prior use of docetaxel, n (%)

Yes

No

63 (68)

30 (32)

32 (59)

22 (41)

ALP = alkaline phosphatase; ECOG = Eastern Cooperative Oncology Group *Post-hoc

analysis Reference: Sartor et al. Ann Oncol. 2012 (suppl; abstr 936P).

Cytotoxic Chemotherapy Following ALSYMPCA Participation: Safety*

Month

Med

ian

pla

tele

t

co

un

t (x

10

9/L

)

Radium, n 93 51 42 24 13 14 8

Placebo, n 54 34 20 14 7 9 6 M

edia

n h

emo

glo

bin

cou

nt

g/d

L

Month Radium, n 93 51 42 24 13 14 8

Placebo, n 54 34 20 14 7 9 6

Platelets Hemoglobin


*Post-hoc analysis


Cytotoxic Chemotherapy Following ALSYMPCA Participation: Safety*

Month

Med

ian

ab

solu

te

neu

tro

ph

il c

ou

nt

(x1

09/L

)

Radium, n 91 47 42 23 12 13 8

Placebo, n 49 30 19 12 7 8 6

Neutrophils


*Post-hoc analysis


Conclusions

• Alpha emitting isotope therapy improves

survival in men with castration resistant

prostate cancer

• Minimal toxicity

• Combination studies with

hormonal/chemothearpeutic agents are

underway

Cabozantinib is a Potent Targeted Therapy That

Inhibits MET and VEGFR2

Clinical activity in mCRPC1

• High rates of bone scan improvement

• Reduction in bone markers

• Regression of soft tissue disease

• PFS improvement

• Pain improvement and narcotics reduction

• PSA changes discordant with other

measures of antitumor activity

1 M. Hussain et al. ASCO 2011 (Abstract #4516)

Bone scan images

Baseline Follow-up

Bone Scan Response By Independent Radiology Review

Computer-assisted evaluation of BSLA

Bone scan evaluable (N=93)a n (%)

Bone scan response 62 (67)

Complete (100% reduction of BSLA) 4 (4)

Partial (≥30% reduction of BSLA) 58 (62)

Stable 15 (16)

Progressive disease 7 (8)

Median duration of response, months (range) 5.4 (5.0 – 6.9)

BSLA, bone scan lesion area a Bone metastases at baseline and ≥1 post-baseline scan available for 84 patients

Median change in bone scan lesion area: 60% reduction

Change in Bone Scan Lesion Area Patients with ≥1 post-baseline bone scan (n=84)

+++

CCC

CC

C C CC CC CC CC C C C C* * **

*

Docetaxel + Abiraterone or MDV3100

Radionuclide

Docetaxel

Cabazitaxel

Prior therapies:

C

% C

ha

ng

e f

rom

Ba

se

lin

e

-100

-80

-60

-40

-20

0

20

40

60

80

100

+: >100% increase

• Evidence of tumor regression in 80% of patients

• Overall RECIST response: PR = 1 (3%); SD = 25 (66%); PD = 9 (24%); UE = 3 (8%)

• PSA declines observed in 36% of patients − PSA changes do not always correlate with other parameters of clinical benefit

Change in Measurable Soft Tissue Lesions Patients with ≥1 post-baseline assessment (n=35)

-60

-40

-20

0

20

40

60

80

*


Radionuclide

Docetaxel

Cabazitaxel

Prior therapies:

C

% C

ha

ng

e f

rom

Ba

se

lin

e

C

C C C C C C C C C *

Change in Circulating Tumor Cells Baseline CTCs ≥5 and Week 6 and/or Week 12 assessment (n=62)

• 92% demonstrated best CTC decrease ≥30%

• Median best CTC change: 86% decrease

• Conversion to <5 CTCs: 39% at Week 6

-100

-80

-60

-40

-20

0

20

40

60

80

100

Be

st

% C

ha

ng

e in

CT

Cs

300

C

C CC C C C CC C C C C**

* *

C

*


Radionuclide

Docetaxel

Cabazitaxel

Prior therapies:

C

Change in Pain Scores Patients with baseline score ≥4 (n=39)

• 64% had a pain decrease ≥30%

• Median change in pain: 46% reduction

• 56% decreased narcotics use, including 31% who discontinued narcotics

-100

-80

-60

-40

-20

0

20

40

% C

ha

ng

e f

rom

Ba

se

lin

e

* * **C

C C C C C C C C

*


Radionuclide

Docetaxel

Cabazitaxel

Prior therapies:

C

Effects on Bone Biomarkers

Median change in CTx at Week 12: 37% reduction

-100

-50

0

50

100

Be

st

% C

ha

ng

e

286

Bisphosphonate/Denosumab-Treated

Bisphosphonate/Denosumab-Naïve

CTx BSAP

Patients with Week 12+ assessment

of serum bone-specific ALP (n = 73)

Patients with quantifiable baseline serum CTx

and Week 12 assessment (n = 50)

120

-100

-50

0

50

100

% C

ha

ng

e a

t w

ee

k 1

2

Conclusions

• Alpha emitting isotope therapy improves

survival in men with castration resistant

prostate cancer

• Minimal toxicity

• Combination studies with

hormonal/chemotherapeutic agents are

underway

• New agents are targeting bone and have

promising activity

Documents

Novel Therapies and Bone Targeted Therapy Daniel P ...e-syllabus.gotoper.com/...07_Petrylak_Bone_FINAL.pdf · metastases June 1993 Strontium-89 Relief of pain in patients with confirmed