“hormonal” therapy in advanced prostate cancer - … · “hormonal” therapy in advanced...

1

“Hormonal” Therapy in Advanced

Prostate Cancer - Beyond Simple

Castration

Martin Gleave MD, FRCSC, FACS

Distinguished Professor, UBC

B.C. Leadership Chair in Prostate Research

Director, The Prostate Centre at VGH

Chair, GU Tumour Group, BCCA

Chairman, NCIC GU Clinical Trials Group, & CUOG

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Hormonal therapy for CaP: Hormonal therapy for CaP: Beyond Simple CastrationBeyond Simple Castration

History of Androgen Therapy

� male sex hormones are collectively known as androgens, which is derived from the Greek andros, (man) and gennan (to produce)

� 1786: John Hunter described seasonal variations in the size of the testicles and prostate gland in animals. Later tested the effects of castration on secondary sex organs.

� 1893: William White measured changes in the prostate gland after castration using dogs. Proposed using castration to treat urinary obstruction disorders.

� 1935: Clyde Deming reported that castration decreased the size of the prostate in primates but had no effect on BPH.

Hormonal therapy for CaP: Hormonal therapy for CaP: Beyond Simple CastrationBeyond Simple Castration

� Charles Huggins

� Canadian-born; Urologic-scientist at U of Chicago

� Most men had incurable/metastatic disease

� Castration = surgical or estrogen

� Limited understanding of molecular basis of androgen

action or resistance

Nobel Laureate, 1966Nobel Laureate, 1966

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Hormonal Therapy for CaP: Hormonal Therapy for CaP: Approaches and IssuesApproaches and Issues

� Androgen Action

� Androgen Deprivation Therapy

� Maximal androgen blockade

� Timing

� Immediate vs deferred

� Intermittent vs continuous

� Androgen Resistance - CRPC

� Targeted therapies

Androgen Axis and Hormonal

Therapy

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

Cell Survival and Proliferation

4

Androgen Actiontestosterone

Androgen

Receptor

Bound AR-

DHT complex

5α-R

DHT

ARAR

AR

ARE

Androgen Receptor: Interactions

QuickTime™ and aTIFF (Uncompressed) decompressor


http://www.androgendb.mcgill.ca/

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Androgen Action: Genomic and Non-genomic AR Activity

Modified from Gruber CJ, NEJM 2002, 346:340

Nuclear Androgen

Receptor

Androgen

Androgen

Receptor

Androgen

� AR is a ligand dependent nuclear transcription factor, part of the

steroid receptor super-family

Increased secretory activity

mitogenic + anti-apoptotic effects

Androgen Axis and Hormonal Therapy

testosterone

5αR ⇒ DHT

6

Androgens rapidly phosphorylate Hsp27 in a dose and time dependent manner

0 1 2.5 5 7.5 10 (nM) R1881

0

0.5

1

1.5

2

2.5

3

3.5

4

1 2 3 4 5 6

Hs

p2

7 p

ho

sp

ho

ryla

tio

n (

fold

/co

ntr

ol)

Ser 78

Ser 82

pHsp27 (S-78)

Total Hsp27

0 1 2.5 5 7.5 10 (nM) R1881

0

1

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6

1 2 3 4 5

Hsp

27

pho

sp

ho

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tio

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fold

/co

ntr

ol)

Ser 78

Ser 82

0 5 15 30 60 Time (min)

0 5 15 30 60 Time (min)

A B

pHsp27 (S-82)

pHsp27 (S-78)

Total Hsp27

pHsp27 (S-82)

The rapid time frame of androgen action is consistent with non genomic effect of androgen

Hsp27 is phosphorylated predominantly on Ser 78, and 82

Can Res 67: 10455, 2007

Hsp 27 AR

CSS

DAPI Merge DAPI Merge

Hsp 27 AR

R1881 (15 min)

Androgen receptor interacts and co-localizes

with Hsp27 in LNCaP cells

WL IgG AR Hsp27

IP

AR

Hsp27

Can Res 67: 10455, 2007

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Effects of Hsp27 Expression Levels and AR Transactivation

Hsp27 antisense ↓↓↓↓↓↓↓↓ AR Induction of PSA-luciferase

0

100000

200000

300000

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Mismatch Antisense Hsp27

Lu

cife

ras

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ctiv

ity

0nM R1881

10nM R1881

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2500000

3000000

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empty vector Hsp27

0 nM R1881

10nM R1881

Hsp27 WT ↑↑↑↑↑↑↑↑ AR Induction of PSA-luciferase

Lu

cife

rase

activity

CasodexR1881

- - +- + +

pHsp27 (S-78)

pHsp27 (S-82)

Total Hsp27

Effect of hsp27 on AR Activity requires the AR since it is blocked by antiandrogen, CasodexHsp27 knockdown decreases AR and PSA levels

Hsp27

AR

30 50 70 30 50 70 (nM)

MM Hsp27 ASO

Vinculin

Can Res 67: 10455, 2007

Effects of Hsp27-AR interactions on genomic and

non-genomic activity of androgen/AR

OGX-427

Day 0 Day 4 Day 8

MM

Day 0 Day 4 Day 8

0

5

10

15

20

25

30

35

40

45

Day 0 Day 4 Day 8

Time of treatment

Se

rum

PS

A (

ng

/ml)

MM

OGX-427

Can Res 67: 10455, 2007

Androgens

AR

Hsp90

PSAARE ARE

AR

Survival

p38 P

Hsp27P

Hsp27AR

P

Hsp27AR

P

cytoplasm

nucleus

Hsp90

AR

Proteasomal

degradation

Androgens

AR

Hsp90

PSAARE ARE

Apoptosis

p38 P

Hsp27

cytoplasm

nucleus

Hsp90

AROGX-427

X

X

XAR

MDM2

Hsp27

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Androgen Action: Androgen Action: ProPro--survival and Mitogenicsurvival and Mitogenic

010203040506070 S ub G 0 G0-G1 S G2-MPercentage of cell cycle population C SSR 1881

0

1

2

3

4

5

6

0 2 4 6

Days

Cell G

rowth

CSS

R1881

A B

0510152025303540 Sub G0 G0-G1 S G2-MPercentage of cell cycle population CSSR1881C

0

20

40

60

80

100

120

0h 24h 48h 72h

Ce

llG

row

th (

%)

R1881

CSS

D

+ paclitaxel + paclitaxel

HOW??HOW??

AndrogenAndrogen--Induced Changes in Induced Changes in Gene Expression Gene Expression

010203040506070 Sub G0 G0-G1 S G2-MPercentage of cell cycle population CSSR1881

miR 125b - AR regulated miRNA that negatively

regulates expression levels of Bak1, a proapoptotic

member of Bcl-2 family (Shi XB, PNAS, 2007)

- + - + - + R1881

AR-ChIP

sCLU mRNA

Total RNA

R1881

Clusterin is an AR-regulated Cytoprotective Gene

Cochrane et al, JBC, 2006

0

10

20

30

40

50

60

70

80

90

100

1E-040.0050.0010.005 0.01 0.05 0.1 0.5 1

LNCaP/C

LNCaP/C

% v

iab

le c

ell

s

Taxol (nM)

Miyake et al, Cancer Res, 2000

sCLU-2 - cytoprotective chaperone that interacts with

and inhibits Bax, a proapoptotic Bcl-2 family member

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Androgen Transcriptionally Regulate CLU Expression

Clusterin

mRNA

Total

RNA

clusterin

tubulin

60 kDa

40 kDa

1 nM R1881

1 µM Casodex

ClusterinmRNA

- + + - + + - + +

- - + - - + - - +

TotalRNA

0

2

4

6

8

10

12

14

LN

Ca

P

Fo

ld In

du

ctio

n

T21 T23 PSA

nM R1881 0 0.1 1 10 0 0.1 1 10 0 0.1 1 10


� T ⇒⇒⇒⇒ DHT regulates transcriptional activity of AR

� AR has both genomic and non-genomic effects

� Potentiates IGF-1 responsiveness through increased IGF-1R levels (Kruekl et al, Cancer Res, 2004)

� Increases expression levels and/or activation of cytoprotective

chaperones� eg - clusterin, phospho-Hsp27

� Increases expression miRNA that negatively regulates expression of

pro-apoptotic genes� eg - Bak

Apoptotic Rheostat

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Hormonal therapy for CaP: Hormonal therapy for CaP: Approaches and IssuesApproaches and Issues

� Androgen Action� Anti-apoptotic, effects on chemosensitivity

� ADT - (Dosing and Scheduling Issues)

� Maximal androgen blockade - Relevance today?

� Timing



� Androgen Resistance - CRPC

Rationale for Combined Androgen Blockade

Adrenal androgens

Peripheral cells

Adipose muscle

Circulation

Adrenalglands

LH

ACTH

LHRH CRH

Leydigcells oftestes

Hypothalamus

Pituitary gland

Feedback

control

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10101010----Year Survival: Randomized Trials of MAB Year Survival: Randomized Trials of MAB Year Survival: Randomized Trials of MAB Year Survival: Randomized Trials of MAB vs AS Alonevs AS Alonevs AS Alonevs AS Alone

Prostate Cancer Trialist’s Collaborative Group. Maximum androgen blockade

in advanced prostate cancer: an overview of the randomized trials. Lancet

2000;355:1494.

� PCTCG meta analyses of MAB vs monotherapy

� 27 trials: 8,275 men

� 1.8% improvement in 5 year survival for MAB compared with monotherapy

� 25.4% vs 23.6%

� HR 0.96 (p=0.026)

10101010----Year Overall Survival: MetaYear Overall Survival: MetaYear Overall Survival: MetaYear Overall Survival: Meta----analyses analyses analyses analyses Randomized Trials of MAB vs AS AloneRandomized Trials of MAB vs AS AloneRandomized Trials of MAB vs AS AloneRandomized Trials of MAB vs AS Alone

Prostate Cancer Trialist’s Collaborative Group. Maximum androgen blockade

in advanced prostate cancer: an overview of the randomized trials. Lancet

2000;355:1494.

� PCTCG meta analyses of MAB vs monotherapy

� 27 trials: 8,275 men

� 1.8% improvement in 5 year survival for MAB compared with monotherapy

� 25.4% vs 23.6%

� HR 0.96 (p=0.026)

Meta-analyses:

4 month survival advantage with LHRH-A + NSAA (eg.

Bicalutamide, flutamide)

New RCT data - Overall survival improved in MAB arm- 0.78 HR:

Usami M, Akaza H, Arai Y et al. Bicalutamide 80 mg combined with a luteinizing

hormone-releasing hormone agonist (LHRH-A) versus LHRH-A monotherapy in

advanced prostate cancer: findings from a phase III randomized, double-blind,

multicenter trial in Japanese patients. Prostate Cancer Prostatic Diseases 2007;

10(2): 194–201.

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� Androgen Axis and Action

� Anti-apoptotic, chemo- and radio-sensitization


� Relevance today?

� implications for ↑↑↑↑↑↑↑↑ T suppression, AR blockade

� We are now recommending LHRH + bicalutamide at BCCA

� AR remains an important and relevant target

� Inhibition of intracrine T production (eg. abiraterone)

� Super AR antagonists

� AR disruptors (eg. Hsp27, Hsp90, HDAC inhibitors)


� Androgen Axis and Action� Anti-apoptotic, effects on chemosensitivity


� Relevance today? - implications for > T suppression, AR blockade

� Timing



� Neoadjuvant, adjuvant, combination regimens

� Androgen Resistance - HRPC

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Effects of Timing of Androgen Ablation on Timeto AI Progression in Shionogi Tumour Model

So et al, BJU Int. 2004 Apr;93(6):845-50

•Time to androgen-independent recurrence is directly proportional to tumor burden at time of castration

Optimal Timing of ADT Optimal Timing of ADT --Immediate vs Delayed?

1. Xenografts: improved survival when castrated at low tumour volume

2. EORTC: improved survival with immediate HT post-RT (Bolla et al, NEJM

1995)

3. ECOG: 2% vs 30% PCa mortality with immediate vs delayed HT in N+

disease post-RP (Messing et al, NEJM 2000)

4. EPC Data (Casodex monotherapy trial)

-prolongs time to radiographic and biochemical progression (predictable)

-overall survival reduced in Casodex arm in low risk CaP! (HR 1.47)

-overall survival improved in Casodex arm in high risk CaP! (HR 0.68)

Evidence Supporting Immediate Therapy

�emphasizes need for careful selection (use life expectancy, risk factors, PSAdt as guide)

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Immediate vs Delayed Androgen Ablation?

1. Xenografts: improved survival when castrated at low tumour volume

2. EORTC: improved survival with adjuvant therapy post-radiotherapy

3. MRC: Delayed time to progression and improved survival M0 CaP

4. ECOG: 2% vs 30% PCa mortality with immediate vs delayed HT in

- N+ disease post-RP (NEJM 2000)

5. EPC Data (Casodex monotherapy trial)

-reduces radiographic and biochemical time to progression (predictable)

-OS adversely affected in Casodex arm in low risk CaP! (HR 1.47)

-OS improved in Casodex arm in high risk CaP! (HR 0.68)

Evidence Supporting Immediate Therapy

�No supporting evidence that delayed therapy equivalentto immediate in other tumours, but EPC emphasizes need for careful selection

Immediate vs Delayed Androgen Ablation + RT

RT alone 75% 44% 56%RT + HT 95% 85% 78%

Radiotherapy Plus Adjuvant HT

Bolla et al NEJM, 1998

LC cNED Survival

p<0.001 p<0.001 p<0.001

•Bolla et al, EORTC•Phase III; Tx, high grade or T3-T4, n=415•randomized to RT alone vs RT + adj Zoladex X 3 yrs.

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Survival Benefit of Earlier Hormone Therapy in Nonmetastatic Disease

Medical Research Council Prostate Cancer Working Party Investigators Group. Br J Urol. 1997 79:235-246.

-reduces radiographic and biochemical time to progression (predictable)

-OS adversely affected in Casodex arm in low risk CaP! (HR ~1.4)

-OS improved in Casodex arm in high risk CaP! (HR ~1.4)

EPC Survival — Trial 25Localized vs Locally Advanced PatientsEPC Survival — Trial 25Localized vs Locally Advanced Patients

HR=1.47 (1.06, 2.03)'Casodex' events = 90 (25.6%)placebo events = 64 (17.8%)

Time to death (years)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00.0 0.5 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.01.0

Pro

po

rtio

n s

urv

ivin

g

placebo'Casodex'

HR=0.68 (0.50, 0.92)'Casodex' events = 73 (28.6%)placebo events = 94 (37.6%)

Time to death (years)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00.0 0.5 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.01.0

Pro

po

rtio

n s

urv

ivin

g

placebo

'Casodex'

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Prostate cancer is not the only cause of death in men

• delayed progression

• decreased local complications

• improved survival

• psychological benefits

Balancing the Benefits of Early Hormone Therapy

• short-term side effects

• expense

• long-term metabolic effects» decreased muscle mass» osteoporosis» anemia» lipid profile» immune surveillance» cardiovascular risk» Cognition/mood

� IAS offers opportunity to improve quality of life

� balances benefits of immediate androgen ablation � reduces treatment-related side effects and expense

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Weeks Post-Castration0 2 4 6 8 10 12 14 16 18 20 22

0

100

200

300

P4 P5

N5

P1

N1N3

Seru

m P

SA

(µµ µµ

g/L

)

PSAmRNA

Intact N1 P1 N3 P4 N5 P5 AIP

PSAmRNA

IAS

CAS

IAS Prolongs Time to Non-Androgen Regulated PSA Gene Expression in the LNCaP model

Sato et al, J Steroid Biochem Molec Biol 58:139, 1996

Time (months)

Se

rum

PS

A (

µµ µµg

/L)

On Therapy

Off Therapy

Se

rum

Testo

stero

ne

(nm

ol/L

)

Urology 45:839, 1995Mol Urol. 3:287, 1999

0

5

10

15

20

25

30

0 6 12 18 24 30 36 42 48 54 60

PSA

Testosterone

5

10

15

20

0

Cycle 1 Cycle 2 Cycle 3 >Cycle 4(n=14) (n=32) (n=13) (n=11)

Clinical Experience with IAS

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Clinical Studies of IAS

1. Goldenberg et al (1995): 47 patients

• Mean time on 9 months; 50% off therapy; up to 5 cycles

2. Higano et al (1996): 22 patients

• median f/u 22 months, 2 completed cycles, 38% of time off therapy

3. Grossfield et al (1998): 47 patients, localized disease

• median f/u 24 months, 3 completed cycles, 50% of time off therapy

4. Crook et al (1999): 52 pateints localized CaP, post XRT

• up to 5 completed cycles, 8 months on; 50% of time off therapy

5. Bruchovsky et al: 100 pts, Multicentre Phase II, Post-XRT Failures

• median f/u 24 months, 1 completed cycle, 50% of time off therapy

• improved Q of L off treatment

Phase III Studies of Intermittent vs

Continuous ADT

1. SWOG/NCIC PR-8: 1300 accrued - closed aug 2008

• Hormone naïve M1 disease; 9 months on, restart PSA > 10-20

2. NCIC PR-7/SWOG 1300 accrued; closed 2007

• M0, post-RT failures; 9 months on, restart PSA 6-15

• Problem - low CaP death rate

German and Portugeuse IAS Trials

•Locally advanced, metastatic; 800 pts enrolled

•no difference in time to AI progression or survival (AUA, 2006, 2007)

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� Androgen Axis and Action

� Anti-apoptotic, effects on chemosensitivity


� Relevance today?

� Timing



� Neoadjuvant, adjuvant, combination regimens

� Androgen Resistance - HRPC

Hormonal Therapy in Advanced Prostate cancer:

Neoadjuvant and Adjuvant Strategies

Cons

•Cell cycle arrest

•Increased Bcl-2 & clusterin

•Affects PSA as marker of RT response

Theoretical Pros & Cons of NHT Prior to RT

•Shionogi model data

•Lower tumor volume

•Androgens are anti-apoptotic

•Reduced hypoxia

Pros

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Theoretical Pros & Cons of NHT Prior to RT

Pros

QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.

Yapp et al, Radiation Research, 2004,

•Shionogi model data

•Lower tumor volume

•Androgens are anti-apoptotic

•Reduced hypoxia

% hypoxic cells decreases after castration

•High recurrence rate with radiation monotherapy •RTOG 85-31•RTOG 86-10•RTOG 92-02•EORTC 22863 - Bolla et al

•Laverdiere et al

•Combined HT + XRT:•reduced local recurrence•decreased PSA recurrence•improved survival in high risk disease & longer term HT

Combined Hormone Therapy + RT for Localized Prostate Cancer

5 randomized studies

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Does RT Add anything above and beyond HT in High Risk Localized CaP?

NCIC CTG- PR.3

Continuousandrogen ablation

Continuousandrogen ablation

withradiation therapy

High Risk Loc CaPprostatecancer

PI: P. Warde; Intergroup participation (NCIC, MRC UK, SWOG)Primary Endpoint: Survival Sample Size: 1200 Accrual: 1200 (study now closedAnalysis: 2006

NHT Prior to Surgery:

Randomized Studies of 0 vs 3 Months NHT

•7 Phase 3 trials conducted during 1990’s compared 0 vs 3 months NHT prior to RP

•All powered for change in pos. margin rates as primary endpoint

•All studies show ~50% decrease in pos. margin rates

•No studies show improved bNED rates!

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CUOG P95A: Randomized 3 vs 8 Months

NHT Study

Gleave et al, J Urol. 166(2):500-6, 2001Gleave et al, J Urol. 166(2):500-6, 2001

• Mean pre-surgery PSA significantly lower in 8 month group �0.056 vs 0.12 µg/L (p<0.0001)

• Positive margin rates significantly lower in 8 month group �12% vs 23% (p=0.0106)

• Mean pre-surgery PSA significantly lower in 8 month group �0.056 vs 0.12 µg/L (p<0.0001)

• Positive margin rates significantly lower in 8 month group �12% vs 23% (p=0.0106)

N = 549

Surrogates of Treatment ResponseChanges in Serum PSA and Path Stage

N = 549

Surrogates of Treatment ResponseChanges in Serum PSA and Path Stage

QuickTime™ and a decompressor


CUOG P95A 3 vs 8 Months NHT Study:

PSA-Free Survival


PSA-Free Survival

33%30%33%30%

7 Year Follow-upOverall Survival = 93%

Overall PSA Relapse Rate - 31%

7 Year Follow-upOverall Survival = 93%

Overall PSA Relapse Rate - 31%

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PSA Recurrence

by Risk Group

PSA Recurrence

by Risk Group







High Risk (n=97)52% vs 59%

High Risk (n=97)52% vs 59%

Intermediate Risk (n=177)32% vs 25%

Intermediate Risk (n=177)32% vs 25%

Low Risk (n=229)25% vs 22%

Low Risk (n=229)25% vs 22%




High vs Low Volume Centres


High vs Low Volume Centres

24%39%24%39%

K-M PSA Relapse Rate K-M PSA Relapse Rate

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CUOG P95A: 3 vs 8 Months NHT Study

Summary

• Overall Survival = 93% with Overall PSA relapse - 31%

• Despite improved biochemical and pathologic surrogates, no significant difference in PSA recurrence rates at 5 years post surgery

�Path response rates not predictive of improved bNED

• Subgroup analyses revealed significant site-to-site differences in PSA relapse rates that were independent of prognostic risk factors.

�Illustrate effects of surgical technique on study endpoints,

highlighting a need to stratify for site of surgery in future

randomized multimodal RP trials

� generates an interesting hypothesis that a benefit of prolonged

NHT may exist when employed by more experienced/higher-

volume surgeons.

• Overall Survival = 93% with Overall PSA relapse - 31%

• Despite improved biochemical and pathologic surrogates, no significant difference in PSA recurrence rates at 5 years post surgery

�Path response rates not predictive of improved bNED

• Subgroup analyses revealed significant site-to-site differences in PSA relapse rates that were independent of prognostic risk factors.

�Illustrate effects of surgical technique on study endpoints,

highlighting a need to stratify for site of surgery in future

randomized multimodal RP trials

� generates an interesting hypothesis that a benefit of prolonged

NHT may exist when employed by more experienced/higher-

volume surgeons.

Hormonal Therapy in Advanced Prostate Cancer:

Future Directions

� Taxotere-based hormone naïve disease

� M1 hormone naïve

� Adjuvant post RP in high risk pts

� Salvage in high risk PSA failures post RP

� Neoadjuvant in high risk pts pre RP

� Combined NHT + adj in high risk pts pre-RT

� Chemo-hormonal combination trials

� Which order, simultaneous or sequential?

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• Taxotere (docetaxel)

• Response rate - ~50%

• ~25% improvement OS, TTP, QoL

Chemoresistant disease:

• ~18 month median survival

The Problem: Hormone Refractory Prostate Cancer

Standard Therapy:

� Future = Combination Strategies with novel biologics

� Bio-Logical, based on relevant targets

Castration Resistance and Prostate Cancer

HormoneTherapy

0

50

100

150

0 3 6 9 12 15 18 21 24 27 30

? ? Molecular mechanisms

Ser

um

PS

A

Tu

mor V

olu

me

1. Androgen receptor (AR) related

• amplification (hypersensitive)

• Mutations (promiscuous)

• Intracrine T production

• cross-talk - TK, AKT, STAT3 (phosphorylation, co-regulators)

2. Adaptation

• Up-regulation of survival genes (Bcl-2, clusterin, Hsp27, YB-1)

• Increased alternative GF pathways (her2/neu; IGF-1/IGFBP2&5; IL-6/STAT3)

• underlying basis for most cancer deaths, and result from multiple, stepwise changes in DNA structure and gene expression arising from selective pressures of treatment.

26

Mechanisms of Androgen ResistanceMechanisms of Androgen Resistance

Bcl-2, BclxLClusterinHsp27YB-1

IGF-1/IGF-1RHer-2/neuIL-6/stat-3

Hsp-chaperones

CaP Cell Survival and Proliferation

In Androgen-Depleted Environment

Hsp-chaperones

Intracrine T production


� TAB using non-steroidal anti-androgen like flutamide or bicalutamide

has small benefit in prolonging survival

BUT

� AR remains present, activated and biologically relevant in acquistion

castrate resistance

� What are the mechanisms of AR transactivation after castration?

27

Residual Prostatic Androgens with ‘Castration’

Tissue androgen levels in benign prostate (gray) and castrate recurrent prostate cancer (white) previously treated with androgen deprivation.Mohler J et al, Clin Ca Res 10:440, 2004

Intraprostatic Effects of Castration: Intraprostatic Effects of Castration: Hormone MeasurementsHormone Measurements

28

T, DHT, and Progesterone Levels Increase T, DHT, and Progesterone Levels Increase in Castrate Resistant LNCaP Tumorsin Castrate Resistant LNCaP Tumors

0

0.5

1

1.5

2

2.5

3

3.5

4

T D HT P P S A #

Co

nc

en

tra

tio

n (

ng

/g t

um

or;

#1

0E

-2 n

g/m

L)

Locke et al, Cancer Res; 2008

Hormone dependent, pre-castrate

Regressed, 7 days post castrate

Castrate Resistant

•LNCaP xenograft androgens, like PSA, increase during progression post castration

•Since mice synthesize scant adrenal androgens, we hypothesized that the tumors themselves are the source of increased androgens.

De Novo Androgen Synthesis in De Novo Androgen Synthesis in Prostate Cancer Cells: Backdoor Prostate Cancer Cells: Backdoor PathwayPathway

Pregnen-3,17-diol-20-

one

Cholesterol

Pregnenolone

Progesterone

17-OH progesterone(4-Pregnen-17-ol-3,20-dione)

Pregnan-3,20-dione

Androsterone

Androstenedione

Testosterone

Dihydrotestosterone Androstanediol

Cyp11A1Helper: STAR

HSD3B2

Cyp17A1

Cyp17A1

HSD17B3

HSD17B2,10

RDH5

AKR1C1AKR1C2 AKR1C3HSD17B

3

SRD5A1,2

SRD5A1,2

Pregnan-3α-ol-20-one

AKR1C2

Cyp17A1

Cyp17A1

AKR1C2SRD5A1 Classical

pathwayBackdoor pathway

OHA

C

B

D1

2

3 5 7

814 15

11

9

10

19

12

13 16

1718 20

4 6

STAR (30kDa)

CYP11A1 (52kDa)

CYB5A1 (17kDa)

CYP17A1 (57kDa)

HSD3B2 (40kDa)

HSD17B2 (55kDa)

HSD17B3 (32kDa)

AKR1C3 (37kDa)

SRD5A1 (29kDa)

RDH5 (29kDa)

PSA (34kDa)

Vinculin (110kDa)

AD N AI AD N AI AI AD N AI AD N AI AI AD N AIAD N AI AD N AI

Mouse 1 Mouse 2 Mouse 3 Mouse 4 Mouse 5 Mouse 6 Mouse 7


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Intraprostatic Sources of Androgen: Intraprostatic Sources of Androgen: Backdoor Pathway:Backdoor Pathway:


[14C]-acetic acid is converted to DHT in AI LNCaP tumor cells

*

1 23 4

5

6

Identification

LC Radiometric RT

(min)14

C peak #

% of total 14

C

counts

LC MS Standard RT

(min)

Unknown 20.842 1 0.6

4-Pregnen-17-ol-3,20-dione 26.516 2 0.6 25.36

DHT 30.022 3 1.8 28.93

Unknown 33.037 4 2.0

Progesterone 37.319 5 0.4 36.35

Unknown 41.709 6 3.6

Cholesterol and lipids 45.0-70.0 * 91.0

30

Novel Agents In Clinical Trials for CRPC

� Atrasentan (ZD 4054)

� Bevacizumab

� Abiraterone

� Sutent

� OGX-011

� MDV3100

� OGX-427

� Sorafenib

� Trastuzumab

� CP-751,871 (IGF-1R Ab)

� Celecoxib

� Thalidomide

� Strontium

� Imantinib

� GTI-2040

� Erlotinib

� RAD001

� ABT-751

� Failed� Bortezomib (Velcade)

� GVAX

� G3139 (Bcl-2 ASO)

� DN101/calcitriol

Agents targeting critical pathways of progression such as AR,

angiogenesis, growth factors, and apoptosis with potential to

enhance docetaxel therapy

Applied Anatomist

Applied Pathophysiologist

Evolution of the Surgeon-Scientist

31

Applied Anatomist


Applied Molecular Biologist


Courtesy of MSKCC

Applied Anatomist


???


32

Cell Membrane

ExtracellularExtracellular

IntracellularIntracellular

SignalingmoleculesSignalingmolecules

K KpY pY

Substrate

ProliferationApoptosisAngiogenesisMetastases

ProliferationApoptosisAngiogenesisMetastases

Targeting AngiogenesisTargeting AngiogenesisTargeting AngiogenesisTargeting Angiogenesis

Substrate

pY

BEVACIZUMAB, VEGF-trap

VEGF

VEGF-R J. FolkmanSurgeon-Scientist

Sutent, sorafenab Sutent, sorafenab

Modified from Bagnato A, Catt KJ. Trends Endocr Met 1998;(9):378–83

Nucleus

Atrasentan (& AZ4054) and the

Endothelin Axis: Oncogenic Mechanisms

ET-1

DAGIns P3

Plasmamembrane

Raf

G-proteinPLC

PKC

Ras

MAPK

ETAR

� Cell growth

� Inhibition of apoptosis

� Angiogenesis

� Osteoblastic remodeling

ET-1 acting via ETAR Promotes:

Ca2+ release

Joel Nelson

Surgeon-Scientist

33

Overall survivalP

rop

ort

ion

o

f p

ati

en

ts a

live

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 50 100 150 200 250 300 350 500450400 550 600 650 700 750 800 850

ZD4054 15 mg vs placebo: HR=0.65 80%CI=(0.49, 0.86); P=0.052

ZD4054 10 mg vs placebo: HR=0.55 80%CI=(0.41, 0.73); P=0.008

Time to death (days)

ZD4054 10mg

ZD4054 15mg

Placebo

25 (23)28 (26)27 (28)Chemotherapy use*, n (%)

17.324.523.5Median OS, months513334Number of deaths, n

Placebon=107

10 mg n=107

15 mgn=98

ITT population

ZD4054

Endothelin in Prostate Cancer

Phase II Proof of Concept - ZD4054

Mechanisms of CRPC:Mechanisms of CRPC:Role of ARRole of AR

� AR remains a functionally active in CRPC (Chen et al, Nat Med. 2004: 10(1):33-9)

� Prostate cancer cells can make DHT from cholesterol precursors (Locke et al,

Cancer Res. 2008 1;68:6407-15)

� AR remains an important target in CRPC � Super AR antagonists (MDV3100, AZ, BMS)



34

Abiraterone Acetate (CB7630)(CB7630)(CB7630)(CB7630)

• irreversible inhibitor of CYP17 (P450c17)

• Reduces DHEA, Androstenedione and Testosterone by both the testis and adrenal glands

• Phase 1 and 2 studies: • Antitumor activity in CRPC

• ~40% PSA response, some with >90% PSA declines

• objective RECIST responses

• Phase 3 trial - Aberaterone vs Placebo in 2nd line CRPC now underway

JCO, 2008

� AR remains an important target in CRPC

� Super AR antagonists (MDV3100, AZ, BMS)



Abiraterone Acetate (CB7630)(CB7630)(CB7630)(CB7630)Abiraterone Abiraterone -- an Inhibitor of Androgen Synthesis:an Inhibitor of Androgen Synthesis:

Effects on PSA in Men with Metastatic HRPCEffects on PSA in Men with Metastatic HRPC

% c

han

ge P

SA

%

38/54: PSA↓ ≥50% (70%)

43/54: PSA↓ ≥30% (80%)

* * * * *

-100-80-60-40-20

020406080

100

Patient

CholesterolHO

CH3

CH3

O

CH3

CH3OH

TestosteroneO

CH3

CH3O

Androstenedione Dihydro-testosterone

(DHT)

O

CH3

CH3OH

HH

Testes, Adrenal, and Prostate Cancer:Secrete Testosterone

Adrenal Glands:Secrete Androstenedione

Target Organ:Testosterone to DHT

X

35

MDV3100 -

a 2nd generation anti-androgen testosterone

Androgen

Receptor

Bound AR-

DHT complex

5α-R

DHT

%

-100

-75

-50

-25

0

25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

≥50% Decline: 23/42 (55%)

7 pt off study<12 wks

N=42 Chemo naïve

% c

ha

ng

e s

eru

m P

SA

Percent PSA Change from Baseline at 12

Weeks for Chemotherapy-Naïve Patients

X

Changes in Gene Expression After Castration Changes in Gene Expression After Castration and During AI Progression and During AI Progression Changes in Expression of StressChanges in Expression of Stress--Activated Activated Molecular Chaperones After Castration and in CRPCMolecular Chaperones After Castration and in CRPC

Androgen-

dependentTumour

regression

Androgen-

independent

Clonal selection

Adaptive responses

Hormone

withdraw

al

Progressio

nAI

ADAI

AI

clusterin

Hsp27

36

sCLU-2 and Hsp27: Stress-induced Cytoprotective Chaperones

1. Transcriptionally activated by HSF-1

a. Increased by diverse array of stress triggers (Heat shock, HT, CT, RT, velcade, herceptin)

b. Increased by cell survival factors like androgen, IGF-1

c. highly expressed in HRPC, other cancers, aggregapathies (eg Alzheimers, AMD, amyloid).

2. Over-expression confers broad spectrum treatment resistance

� Inhibits protein aggregation, facilitates UPP activity

� Interacts and inhibits activated Bax, prevents cytochrome C release

� Activates NF-kB by facilitating proteasomal degradation of Ik-B

3. ASO or siRNA knockdown (OGX-011, OGX-427)

� Enhances treatment-induced apoptosis in vitro and in vivo

� Pre-clinical anti-cancer activity in many models

Cancer Research 65(23):11083-93, 2005

Hsp27 Knockdown induces apoptosis and Delays

Progression in Human Prostate LNCaP Cancer

Proteasomal

degradation

Androgens

AR

Hsp90

PSAARE ARE

Apoptosis

p38 P

Hsp27

cytoplasm

nucleus

Hsp90

AROGX-427

X

X

XAR

MDM2

Can Res 67: 10455, 2007

treatment

0

100

200

300

400

500

600

700

800

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

OGX-427

Scr B (control)

Pe

rce

nta

ge

of

PS

A le

vel

Weeks post castration

Day of castration Week 2 Week 3 Week 4 Week 5 (After castration)

OGX-427

Week 1 Week 6

37

Phase 1 Study of OGX-427 in Solid Tumors:Investigational New Drug Application

� OncoGenex sponsored; PI - K. Chi (SPORE funded)

� Solid Tumors (Prostate, Breast, Ovary, Lung, Bladder)

� Cohorts 1-5 - single agent OGX-427 in dose escalation design

� 5 dose levels: 200mg up to 1000mg

� Cohort 6 & 7 evaluate OGX-427 in combination with docetaxel

� 3 pts with CaP had PSA declines of 43%, 58%, 62% and 3 pts with ovarian cancer had CA-125 declines of 27%, 28% and 41%.

� Declines in CTC and Hsp27+ CTC have been observed at all dose levels.

CK+/DAPI+/CD45- HSP27+

A B

Total CTC

0

10

20

30

40

50

60

70

80

90

W-L REB SL DJS A-K JRM MAB M-B

Pre-load dose 1

Cycle 1, day 1

Cycle 2, Day 1

Cycle 3, Day 1

Cycle 4, Day 1

Cycle 5, Day 1

OGX-011 Clinical Program Chart

Indication Treatment Status

HRPC OGX-011 with 2nd line chemotherapy (docetaxel or mitoxantrone)

67 patients; Fully enrolled

HRPC 1st line chemotherapy (docetaxel) with and without OGX-011


Advanced NSCLC OGX-011 with 1st line chemotherapy (gemcitabine/cisplatin or carboplatin)


Localized Prostate Cancer

OGX-011 with hormone ablation therapy 23 patients; Fully enrolled

Advanced Breast Cancer

OGX-011 with 2nd line chemotherapy (docetaxel) 15 patients; Fully enrolled

Over 300 patients enrolled in OGX-011 clinical trials

Phase 1 Clinical Trials - Completed :

Phase 2 Clinical Trials – Follow Up Ongoing:

Indication Treatment Status

Prostate Cancer OGX-011 with hormone ablation therapy 25 patients

Solid Tumors OGX-011 with chemotherapy (docetaxel) 40 patients

38

0

50

100

150

200

250

300

350

400

450

No treatment >2 m NHT OGX011-

40mg

OGX011-

80mg

OGX011-

160mg

OGX011-

320mg

OGX011-

480mg

OGX011-

640mg

Treatment Groups

Clinical Proof-of-Concept - Phase I Pre-surgery trial:Dose-dependent Decreases in Clusterin Levels in RP Specimens using LCM and Real-Time PCR

Chi et al, J Nat.Canc.Inst. 97:1287-96, 2005

NCIC IND.165: Taxotere +/- OGX-011 in 1st Line

Metastatic Castrate Resistant Prostate Cancer Time to Off Treatment & Progression Free Survival

Chi et al, ASCO, 2007* 79% of patients are still alive

OGX-011 + docetaxel Docetaxel

Median OS 27.53 mo. 16.89 mo.

Number of Treatment Cycles 9 cycles 7 cycles

Early Discontinuation of Chemo 2.5% 26.8%

Progressive Measurable Disease 4% 17%

Stable Measurable Disease 77% 50%

Primary PSA Progression 2.6% 12.5%


are needed to see this picture.Std Trt OS - 16.89 months

OGX-011 OS - 27.53 mo

39

Phase II Feasibility Trial of OGX-011 in 2nd Line Therapy

in CRPC: CUOG P-06 (PI F. Saad, E. Winquist)

R

A

N

D

O

M

I

ZE

Arm A

Docetaxel (75 mg/M2 IV) q 21 days and

OGX-011 (640 mg IV) weekly plus

Arm B

Mitoxantrone (12 mg/M2 IV) day 1 and

OGX-011 (640 mg IV) weekly plus

P

R

D O

I G

S R

E E

A S

S S

E I

ON

S F

U O

R L

V L

I O

V W

A

L U

P

n = 41

CRPC

Disease

Progression

During or

Within 6

Months of 1st

Line

Docetaxel

Treatment

n = 19

n = 22

� More treatment cycles administered to patients with OGX-011.• Median of 7.5 cycles vs. 3-4 cycles reported for most 2nd-line studies

� PSA responses higher than anticipated � >50% decrease in PSA - 40% (compared to 30% contemporary controls)

� >90% decrease in PSA - 20% (compared to 8% contemporary controls)

� Median survival > 13 months (compared to 9.6 months in historical controls)

CUOG 2nd Line Phase II Study of OGX-011 in CRPC Tumors:

Patient: 025-011

0

20

40

60

80

100

120

140

1/3/

07

1/17

/07

1/31

/07

2/14

/07

2/28

/07

3/14

/07

3/28

/07

4/11

/07

4/25

/07

5/9/

07

5/23

/07

6/6/

07

6/20

/07

7/4/

07

7/18

/07

8/1/

07

8/15

/07

8/29

/07

9/12

/07

9/26

/07

10/1

0/07

10/2

4/07

11/7

/07

11/2

1/07

12/5

/07

12/1

9/07

1/2/

08

1/16

/08

1/30

/08

2/13

/08

2/27

/08

3/12

/08

3/26

/08

4/9/

08

Date

Start 1st line therapy

End 1st line therapy

8 cycles

PSAProgression

OGX-011

2nd line therapyBaseline

In Treatment Cycle 14

40

Hormonal therapy for CaP: Hormonal therapy for CaP: SummarySummary

� Androgen/AR signaling are important pro-survival growth factors in CaP� Early HT yields optimal prolongation in survival

� BUT - Candidates require risk stratification

� IAS allows early therapy while reducing cost and side effects

� MAB (LHRH-A + NSAA) has yielded small clinically significant gains in survival

� Castrate Resistance remains critical hurdle� Understanding androgen action and mechanisms of CRPC yielding

promising new targets

� AR - super antagonists, AR disruptors, CYP17 inhibitors

� Anti-angiogenesis agents

� IGF-1, IL-6, ET-1a signaling inhibitors

� molecular chaperones like sCLU-2, Hsp27

Future of UroFuture of Uro--Oncology Oncology --Leaders or Dancing Bears? Leaders or Dancing Bears?

•Uro-oncologists must be trained tocover the spectrum of oncology

•Clinical aspects of early &

advanced disease

•Tumor and translational biology

•Clinical trials expertise

•Epidemiology

41

Bio-Logical Therapy: Multi-Targeted and Biologically Rational Combination Therapy

0

50

100

150

0 3 6 9 12 15 18 21 24 27 30

AndrogenWithdrawal

Apoptosis Enhancers

-docetaxel-inhibitors of cytoprotective

proteins eg. Bcl-2, AR,clusterin (OGX-011),

Hsp90 (geldanomycin), Hsp27 (OGX-427)

Growth Inhibitors

-signal transduction eg inhibitors of mTOR (CCI-

779), VEGF (Avastin), ET1a (AZ4054); IGF-1R;

IL-6

Castration alone

Castration +Multi-targeted

Combination therapies

Ser

um

PS

A

Tu

mor V

olu

me


� Androgen/AR signaling are important pro-survival

growth factors in CaP

� Maximal androgen blockade has not yielded

clinically significant gains in survival

� Early HT at time of minimal tumor burden yields

optimal prolongation in survival

� Candidate require risk stratification

� Neoadjuvant/adjuvant combination strategies being evaluated

� Intermittent vs Continuous trials now completed

� Androgen Resistance remains critical hurdle

42

Post-docsAmina Zoubeidi

Eliana Beraldi

Hide Miyake

Moto MuramakiIsis PharmaceuticalsBrett Monia

PI’sColleen Nelson

Larry Goldenberg

Paul Rennie

Kim Chi

Alan So

Michael Cox

Chris Ong

Sue Ettinger

Dawn Cochrane

Richard Sowery

PathologyAntonio Hurtado

Ladan Fazli

David Huntsman

Torsten Neilsen

Ted Jones

Grant FundingNCICNIH SPOREDODPCF

CollaborationsUW - B. Vessella

P. Lange, P Nelson,

Tia Higano

OncoGenex Tech. Inc.Scott Cormack

CUOG

NCIC IND GroupElizabeth Eisenhauer


� Androgen/AR signaling are important pro-survival growth

factors in CaP

� Understanding of androgen action and mechanisms of AI

progression yielding new targets

� AR disruption a relevant goal in delaying AI progression

� Cytoprotective chaperones like sCLU-2, Hsp27

� Guides rationale combination, multi-modal therapies

“hormonal” therapy in advanced prostate cancer - … · “hormonal” therapy in advanced...

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