Christopher J. Logothetis, M.D.

Serial Microenvironment Targeted Therapy Of Prostate Cancer

• Chemotherapy• The role of bone • Accelerating progress• Summary advances

Docetaxel in Castrate Resistant & Metastatic Prostate Cancer

Tannock et al

Control Primary

Systemic Therapy

Optimize therapy in advanced setting: Expect increased benefit when applied

in earlier disease state.

Solid Tumor Therapy Paradigm

Accepted Model of Cancer Progression

Treatment Sensitive Treatment Resistant

Accepted Model of Cancer Progression

Treatment Sensitive Treatment Resistant0 20 40 60 80 100 120

0

0.2

0.4

0.6

0.8

1.0

# At Risk, "AA": 135 92 55 27 12# At Risk, "CH": 125 92 58 32 7

Median (95% CI)

Androgen Ablation 65 (56, 93) Chemohormonal 74 (61, 120+)

P = 0.41

Months from Initiation of Hormone Therapy

Ove

rall

Surv

ival P

robabili

ty

A

No effect on survival(androgen dependent PCa)

Solid Tumor Therapy Paradigm

Therapeutic agents effective in far advanced disease

states will be more effective in earlier states

Autocrine

Paracrine

PhysiologyEpithelial dysregulation

Time

Leth

ality

Che

mot

hera

py re

sist

ance

Proposed Progression Model

• Chemotherapy• The role of bone • Accelerating progress• Summary advances

Epithelial

Bone development program

Bone -Epithelial Central to Prostate Cancer Progression

0

.2

.4

.6

.8

1

Ove

rall

Sur

viva

l

0 10 20 30 40 50 60 70 80

Time from Registration, mo

Adriamycin OnlySr-89/AdriamycinNon-Randomized

Bone Consolidation Trial

Tu et al Lancet 2003

MDA-BF-1 in Activated Osteoblasts in Bone Metastasis

Vakar-Lopez et al. J. Pathol. 2004, 203: 688-695

PC/MDA-BF1

6 weeks

control Side

control Side

PC3

MDA-BF-1 inhibits osteolytic response of PC-3 cells in vivo

6 weeks

Epithelium

Stroma

Localized Lymph Node Bone

Androgen independent

MDA- BF1 in ProgressiveProstate Cancer

PCa cells bone

osteoblast

old lamella bone

new woven bone

MDA-BF-1

MDA-BF-1

“Two Compartment Model”

Interaction of Autocrine & Paracrine loops in Epithelial and Host drives the organ

specific progression of prostate cancer

Epithelial

Bone microenvironment

Microenvironment in Prostate Cancer

Prostate Cancer Progression Model

Bone Microenvironment Dependence

Nora Navone et al

Normal Physiologic

State

Early Cancer

Invasive Cancer

Early-Stage Metastatic

Cancer

Lethal Cancer

Endocrine-to-Paracrine Androgen Signaling Transition

Efstathiou et al. Clin Cancer Res. 2010.

Role of endocrine-to-paracrine androgen signaling transition

Proposed Model of Prostate Cancer Progression

Androgen-Mediated Progression of Prostate Cancer

Endocrine

Gonadal

Adrenal

Testosterone

AR DHT

Androgen-Mediated Progression of Prostate Cancer

Endocrine

Gonadal

Adrenal

Testosterone

AR DHT

Microenvironment

CYP17

Where Androgen Signaling & Tumor Microenvironment TransectEndocrine

Gonadal

Adrenal

Testosterone

AR DHT

Microenvironment

CYP17

Androgen rich

AR Genomic Signaling

PSA

AR AR

AR

CYP17

AR

Increased intracrine steroid biosynthesis

PSA

mAR mAR

mAR

AR overexpressionmutant/isoform AR

SRC/SH2

ARP

P

Cell survival/anti-apoptotic

Interface of AR signalingwith other pathways (src, cMET, Hh and others)

Adaptive Response of Androgen Signaling in CRPC

Castration/ Disease Progression

Androgen rich

AR Genomic Signaling

PSA

AR AR

AR

CYP17

AR

Increased Intracrine steroid biosynthesis

Adaptive Response of Androgen Signaling in CRPC

Castration/ Disease Progression

COU-AA-301: Abiraterone Acetate Improves Overall Survival in Metastatic CRPC

De Bono et al. N Engl J Med. In press.

21

HR = 0.646 (0.54-0.77) P < 0.0001

Placebo: 10.9 months (95% CI: 10.2-12.0)

Abiraterone acetate: 14.8 months (95% CI: 14.1-15.4)

100

80

60

40

20

Surv

ival

(%)

00 3 6 9 12 15 18

PlaceboAA

Time to Death (Months)

CRPC, castrate resistant prostate cancer.

FDA Approved Apr 28, 2011

Bone Discovery PlatformStudy Design

Bone Marrow Biopsy and Aspirate Intervals

Baseline* Maximum Response*/**

Progression*Week 8*

*Tissue:1) Serum and plasma blood and bone marrow aspirate2) Transilial bone marrow biopsy

**Variable time point/optional

Abiraterone Acetate

Maximizing Yield of “Blind” Transilial Bone Marrow Biopsy

CT Directed

Abiraterone Acetate Bone Marrow Trial 2007-0590

(56 pts)

Bone marrow involvement detected by transilial biopsy (all time points)

30 (54%)

Baseline tumor infiltrated bone marrow 27 (48%)

Paired tumor infiltrated bone marrow (>5%) 17 (30%)

Baseline specimens evaluable for IHC (>5% tumor infiltration)

25 (45%)

Baseline tumor infiltration ≥20% (FISH) 15 (27%)

Bone marrow aspirates 50 (89%)

Cancer Acquisition Rates (“Directed” Transilial Bone Marrow Biopsy)

≥ 30% Reduction: 59% (34/56)

≥ 50% Reduction: 48% (28/56)

≥ 90% Reduction: 16% (9/56)

Modulation of Serum PSA Following Abiraterone Acetate Treatment

PSA

Cha

nge

(%)

-90

-75

-50

-30

0

25

50

75

100

Pretreatment Androgen SignalingPretreatmentAndrogen Signaling Components

0No

expression

1(<25%)

2(25%-75%)

3(>75%)

Nuclear AR 0 0 8 17

CYP17 4 5 8 8

MeanRange in ng/mL (n)

Bone marrow aspirate testosterone (ng/mL)

0.0560.0000-0.257 (50)

Bone marrow aspirate dihydrotestosterone

0.001(0.000-0.04)

Blood testosterone (ng/mL)

0.0440.0000-0.214 (52)

Blood dihydrotestosterone

0.01(0.00-0.0459)

AR CYP17

Persistent Androgen Signaling in CRPC With Bone Metastases

Pretreatment CYP17 Expression in the Tumor Correlates With Increased BMA

Testosterone Concentration

CYP17 Expression in Tumor ≥10%

No CYP17 Expression in Tumor

P Value,Wilcoxon

BMA-T, ng/mL (mean ± SD) 0.074 ± 0.070 0.026 ± 0.019 0.045

0.0

0.05

0.10

0.15

0.20

0.25

BMA

-T.P

lasm

a M

S (n

g/m

L)

CYP17 ≥10% No CYP17 Expression

BMA, bone marrow aspirate; BMA-T, bone marrow aspirate, testosterone.

Blood Testosterone

0.000.050.100.150.200.25

Week 8

Conc

entr

atio

n (n

g/m

L)

Pretreatment

Bone Marrow Testosterone

0.000.050.100.150.200.250.30

Week 8

Conc

entr

atio

n (n

g/m

L)

End of Study Pretreatment

Sustained Depletion of Testosterone Following Abiraterone Acetate

End of Study

Intense and Homogeneous Nuclear AR Expression With CYP17 Co-expression

Correlate With Longer Treatment DurationPrimary Resistance*

N (%)Stable Response

N (%)P Value

>90% nuclear AR expression and

≥10% CYP17 expression in the tumor epithelium 1 (7) 13 (93)

<0.001Lack of one or both 10 (91) 1 (9)

*Time to treatment discontinuation

<4 months (122 days) Time (Days)

Prog

ress

ion

Prop

orti

on

0 100 200 300 400 500

0.0

0.2

0.4

0.6

0.8

1.0

Persistent nuclear AR expression in patients with benefit from ABI at end of treatment

Nuclear AROverexpression at

Progression

Benefit 9/11

PrimaryResistance

2/6

(P value :0.04)

Pretreatment End of Treatment

Modulation of AR Copy Number(Preliminary Observations)

0 20 40 60 80 100 120 140 160 180

0 wks

Responder , 8 wks

0 wks

Responder , 8 wks

0 wksResponder , 8 wks

0 wksResponder, 8 wks

0 wksPrimary Resistance 8 wks

0 wksPrimary Resistance, 8 wks

Copy NumberqPCR on ≥500 cells.

Androgen rich

AR Genomic Signaling

PSA

AR AR

AR

CYP17

AR

Increase steroid biosynthesis

PSA

mAR mAR

mAR

AR Overexpression mutant/isoform AR

Adaptive Response of Androgen Signaling in CRPC

Castration/ Disease Progression

Bone Marrow Biopsy Study

MDV 3100

Baseline Week 8 Progression

Modulation of Serum PSA Following MDV3100 Treatment

PSA

Cha

nge

(%)

-90-75

-50

-30

0

25

50

75

100 ≥ 30% Reduction: 56% (29/52)

≥ 50% Reduction: 46% (24/52)

≥ 90% Reduction: 20% (10/52)

Nuclear Localization Cytoplasmic Localization

Shift in AR subcellular localization following MDV3100

in patients with PSA decline

Pretreatment Week 8

AR Inhibition (MDV 3100) Increased Testosterone Concentration

Pretreatment(mean)

Week 8(mean)

P value(wilcoxon)

Bone Marrow Τ 0.026 0.04 0.0001

Bone Marrow DHT 0.0 0.003 0.335

Blood Τ 0.041 0.066 <0.0001

Blood DHT 0.002 0.007 0.008

Patients

T C

hang

e in

BM

(%)

-100-80

-60

-40

-20

20

4060

80

100

PatientsT

Cha

nge

in P

lasm

a (%

)

-100

-80

-60-40

-20

20

40

60

80

100

Persistent androgen signaling driven by altered receptor or

adaptive steroid synthesis is a hallmark of prostate cancer progression and a central component of the tumor

microenvironment

Increased pSrc expression correlates with resistance to MDV3100

Non responders Responders P valueWilcoxon’s rank test

Mean pSrc Expression (%)(Range)

70(0-90)

10(0-30)

0.002

Androgen rich

AR Genomic Signaling

PSA

AR AR

AR

CYP17

AR

Increase steroid biosynthesis

PSA

mAR mAR

mAR

Generation of mutant/isoform AR

SRC/SH2

ARP

P

Cell survival/anti-apoptotic

Non-genomic AR signalingActivation of SRC kinase,cMET,Hh

Adaptive Response of Androgen Signaling in CRPC

Castration/ Disease Progression

Increased Phospho-Src at Progression More Evident in Patients With Primary Resistance to Abiraterone

Acetate (Preliminary Observations)

P-Src

H&E

Phospho-Src Increase at End of

Treatment

Benefit 4/8

Primary resistance

5/6

(P value: 0.05)

Pretreatment End of Treatment

Patient with primary resistance to abiraterone acetate

Activation of Src kinase signaling in MDA-Pca-133 donor tumor and xenograft

AR Phospho-Src

Donor tumor

AR Phospho-Src

XenograftV. Tzelepi

0

500

1000

1500

2000

Day 0 Day 12 Day 16 Day 20 Day 24 Day 28 Day 32

Tum

or g

row

th (M

ean

sem

) mm

3

Effect of dastinib, a Src kinase inhibitor, in tumor growth of MDA-Pca-133 xenograft

Control, n=5

Castrated, n=4

Dasatinib, n=5

Cast/Dasatinib, n=4

Days of Dasatinib treatment

J. Song and G. Gallick

0

500

1000

1500

2000

Day 0 Day 12 Day 16 Day 20 Day 24 Day 28 Day 32

Tum

or g

row

th (M

ean

sem

) mm

3

Effect of dastinib, a Src kinase inhibitor, in tumor growth of MDA-Pca-133 xenograft

Control, n=5

Castrated, n=4

Dasatinib, n=5

Cast/Dasatinib, n=4

Days of Dasatinib treatment

J. Song and G. Gallick

Inhibition of Paracrine AR signaling & interacting ”SE” will enhance efficacy of therapy

P=0.045

TreatedControl

155.5 mm3 30.5 mm3

MRI

Park, Gallick, Navone

Dasatinib Inhibits Growth of Bone-selected MDA PCA 118b Cells Growing Intratibially

Osteoclast Function:Dasatinib Inhibits Formation of

Multi-nucleated OsteoclastsM-CSF MCSF + RL

1.25nM

5nM

10nM

20nM

0

500

1000

1500

M-CSF + RL:+ + + + + +

Dasat. (nM): 0 1.3 2.5 5 10 20

TRAP

+ Ost

eocl

asts

/wel

l

Cont.

Araujo and Darnay, unpublished

Phase 1/2 Dasatinib + Docetaxel Trial on Metastatic Prostate

Dasatinib was administered orally on a once-daily schedule Docetaxel was administered intravenously every 21 days At least three patients were enrolled at each dose level

Continuous daily dasatinib

Day 1

Docetaxel

(PK analysis)

Day 14

(Dasatinib

PK analysis)

Day 21

Docetaxel

(Combination PK analysis)

Day 3

Docetaxel Docetaxel

John Araujo, MD, PhD. PI

Maximum UNTx change from baseline

Bisphosphonate No bisphosphonate

Max

% C

hang

e fr

om B

asel

ine

BENEFIT

100

80

60

40

0

20

-20

-40

-60

-80

-100

PSA response curve during and post docetaxel (continued on

Dasatinib)

9/09 Last Docetaxel

19 months on single agent dasatinib with undetectable PSA

PSA response curve during and post docetaxel (continued on

Dasatinib)

5/09 Last Docetaxel

22 months on single agent dasatinib

Dasatinib In Castrate Resistant & Metastatic Prostate Cancer

Docetaxel 75 mg/m2 Dasatinib 100 mg po daily Prednisone 5 mg po BID

Docetaxel 75 mg/m2 Prednisone 5 mg po daily Placebo

StratificationPS 0, 1 vs. 2Urinary NTX

RANDOMIZE

mCRPC1st line

• Chemotherapy• The role of bone • Accelerating progress• Summary advances

Docetaxel in Castrate Resistant &Metastatic Prostate Cancer

Tannock et al

Prostate Cancer

CVD

KAVE

TE+E

TE+C

η = µ +αY + βZ1st

2nd

No.30

30

30

30

120

New Approach

Regimen+

+

Patientsuccess

∆ to β β

α α

• Rapid selection of most effective regimen

• Arrives to patient success rapidly

+-

+β

Current Practice

Protocol Allocation Prostate Cancer

TEE KAVE CVD TEC

First Regimen 61 57 48 66Second Regimen 22 13 13 25

TOTAL 83 70 61 91

Most EfficaciousSequence

CVD (1) TEC (2)

Beneficial Effect of a “Reasoned” Treatment Approach

Months from initiation of chemotherapy0 20 40 60 80

0.0

0.2

0.4

0.6

0.8

1.0

Taxotere

Serial CHT

Months from initiation of chemotherapy0 20 40 60 80

0.0

0.2

0.4

0.6

0.8

1.0

Relative Impact of Serial Therapy on Overall Survival

Taxotere vs Mitanzantrone Taxotere vs. Serial chemotherapy*

*simulation

Serial CHT

Taxotere

Chemotherapy & Castrate Resistant Prostate Cancer

• Castrate Resistant Prostate Cancer is a chemotherapy sensitive Combination(s) may provide advantage

• Serial use of chemotherapy applied based on “principles of cancer therapy”can provide further benefit

• Integration into primary treatment

Relative Efficacy

Interaction Between

Regimens

Impact Overall Survival

Serial Application of Therapy

Increased Phospho-Src at Progression More Evident in Patients With Primary Resistance to Abiraterone

Acetate (Preliminary Observations)

P-Src

H&E

Phospho-Src Increase at End of

Treatment

Benefit 4/8

Primary resistance

5/6

(P value: 0.05)

Pretreatment End of Treatment

Patient with primary resistance to abiraterone acetate

Synergy Between Microenvironment Targeting

Therapies

Abirateroneacetate

RANDOMIZATION

OFF

STUDY

Sunitinib +abiraterone

acetate

Dasatinib +abiraterone

acetate

Sunitinib +abiraterone

acetate

Dasatinib +abiraterone

acetate

Circulating Microenvironment

T1T2 T3

A+S vs. A+D A+S → A+D

A+D → A+S

Allocation new Rx

Effect of SerialTargeted Therapies

Relative Efficacy

Interaction

Between Regimen

s

Impact Overall Survival

Link To Biology

Serial Application of Therapy

Microenvironment pathways implicated in resistance to

maximal androgen ablation are prioritized for individualized

therapy development

XL184 :Initial Clinical Observations

woven bone

• Chemotherapy• The role of bone • Accelerating progress• Summary advances

Androgen Receptor Signaling in Prostate Cancer Involves Multiple Pathways

Growth Factors and Their Receptors

MAPKKK

MAPKK

MAPK

AR

AKTP27

Bad

Caspase9

P13K

PTEN

DHTDHT

5-alpha Reductase(I,II,III)

P P

T T

Li J. and Kim J., 2009

Dihydrotestosterone

Genetic Networks(anticipated outcome)

DHT

Cancer Detection in REDUCE by Time, Treatment and Gleason Score

Years 1-2 Years 3-4Placebo Dutasteride Placebo Dutasteride

No. Subjects Biopsied 3345 3929 2342 2446

Gleason 5-6 401 290 216 147

Gleason 7 (3+4) 125 99 51 47

Gleason 7 (4+3) 32 28 6 17

Gleason 8-10 18 17 1 12(0.5%) (0.5%) (0.04%) (0.5%)

Dihydrotestosterone

Genetic Networks(anticipated outcome)

Androgen Signaling

DHT AR

ABI

“Earlier” Use of Androgen Biosynthesis Inhibitor

Didydrotestosterone

Genetic Networks(anticipated outcome)

Androgen Signaling

Microenvironment Dependent

DHT AR NonAR

“Blast Crisis”

Chronic Myelogenous Leukemia

“Oncogene Addiction”

BCR- ABL

“Microenvironment Dependence”

Androgen Independent Progression

Prostate Cancer

S-E Signaling Network

Elucidating signalingnetwork will lead to

combinatorial microenvironment

targeting

Autocrine

Paracrine

PhysiologyEpithelial dysregulation

Time

Leth

ality

Che

mot

hera

py re

sist

ance

Proposed Progression Model

Microenvironment Dependence

Small Cell Carcinoma

Morphologically heterogeneous Prostate Cancers with clinical features common to small cell carcinomas represent a significant subset of the lethal disease.

The “Anaplastic” Prostate Carcinomas

APARICIO, A. 2009

“A Phase II Study of Carboplatin plus Docetaxel in Patients with Anaplastic Prostate Carcinoma”

MDA 2006-0097 - PCCTC#c05-015

PSA at Registration

PSA0

20

40

60100150200

3.2

ng/d

L

APARICIO, A. 2009

DNA Methylation Profiles of the Anaplastic Prostate Carcinomas

ARSCC-1 (MDA 40) SCC-2 (MDA 46)

SCC-3 (MDA 91b) SCC-4 (MDA 144-13)

Xenografts

Sim

ilari

ty

AC-2AC-3AC-4AC-1SCC-3SCC-1SCC-2SCC-4

39.08

59.38

79.69

100.00

Ward Linkage and Absolute Correlation Coefficient Distance

-1,000 +500

APARICIO, A. 2009

AC-1 (MDA 43) AC-2 (MDA 75)

AC-3 (MDA 80) AC-4 (MDA 137)

Didydro-testosterone

Androgen Signaling Networks (Progression)

AndrogenSignaling

Micro-Environment Dependent

DHT AR NonAR

NonAR

ARInterference

-

Control Primary

Systemic Therapy

No TherapyControl Primary Systemic

Therapy

MicroenvironmentTargeting

AcknowledgmentsM. D. Anderson Cancer CenterGenitourinary Medical OncologyW. ArapJ. AraujoA. AparicioP. CornE. EfstathiouG. GallickI. Gorlov

M. Karlou Z. G. LiS. W. LinS. MaityR. MillikanN. NavoneR. PasqualiniP. Sharma

D TsavachidouT. Thompson S.M. TuV. TzelepiX. WanJ. YangA. Zurita

PathologyP. Troncoso

Texas A& M UniversityW. L. McKeehanF. Wang

ImagingV. Kundra

Rice UniversityC. Farach-CarsonInstitute for Molecular MedicineM .Kolonin

UrologyC. PettawayJ. DavisL. Pisters

University of AthensE Efstathiou

NijmegenP. Friedl

Androgen rich

AR Genomic Signaling

PSA

AR AR

AR

CYP17

AR

Increase steroid biosynthesis

PSA

mAR mAR

mAR

Generation of mutant/isoform AR

SRC/SH2

ARP

P

Cell survival/anti-apoptotic

Non-genomic AR signalingActivation of SRC kinase

Adaptive Response of Androgen Receptor Signaling in CRPC

Castration/Abiraterone treatment