Howard I. Scher, MDChief, Genitourinary Oncology Service

Memorial Sloan Kettering Cancer Center

October 6, 2009

Advanced Stage Disease:Management of Disease Progression and

Emerging Drug Protocols

Advanced Stage Disease

1. Clinical States: A framework for drug development.

2. Dissecting the lethal phenotype.

3. Targeting AR signaling: MDV3100.

4. CTC as a biomarker.

Prostate Cancer Clinical States: A Framework For ClinicalPractice, Drug Development and Biomarker Qualification

Rising PSA

3Clinical

Metastases:Castrate1st Line

DocetaxelStandard

2Clinical

Metastases:Castrate

Pre-

ClinicallyLocalizedDisease

1Rising PSA:

Castrate

ClinicalMetastases:

Non-Castrate

4Clinical

Metastases:Castrate2nd Line

No Standard

28,660

Castration resistant:Deaths From Disease

Diagnoses

186, 320

Non-CastrateAndrogen depletion

/blockade (bicalutamide)

MedianTrial Drugs No. Survival P=

99-16 D+E 386 18 mos. 0.02 M+P 384 16

327 D 335 18.9 0.009 M+P 337 16.4

D = docetaxel, E = estramustine, M = mitoxantrone, P = prednisone

Petrylak et al., and Tannock et al., NEJM, 2004

–

Pro

bab

ilit

y of

Su

rviv

ing

0 6 12 18 24 300.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0 Docetaxel 3 wkly

Docetaxel wkly

Mitoxantrone

For Castration Resistant Prostate Cancers Q3 Week DocetaxelCan Prolong Life And Is the First Line Standard of Care

Tax 327

Clinical Trials Are Experiments Conducted With Therapeutic Intent

1. Objective: Goals and therapeutic aim.

2. Patient population: Entry criteria: minimize heterogeneity, or enrich for specific characteristics.

3. Intervention: Mechanism: cidal, static, targeted.Dose and schedule: safety.

1. Outcomes: Endpoints: (aka response criteria).Phase 2: ? Signal, if so, how strong?Statistical design.

5. Conclusions: Was the question answered? Is continued development justified?

1. Insure a drug is no longer working before stopping therapy.2. Report PSA changes using waterfall plots.3. Confirm bone scan findings with a second scan.4. Eliminate overall response as an outcome: focus on time to event.

Outcome Measures Are Biomarkers To be Validated Analytically and Qualified Clinically

Building on Docetaxel As the First-Line Standard of Care

Rising PSAClinicallyLocalizedDisease

1Rising PSA:

Castrate

ClinicalMetastases:

Non-Castrate

2Clinical

Metastases:Castrate

Pre-

3Clinical

MetastasesCastrate1st Line

DocetaxelStandard

4Clinical

Metastases:Castrate2nd Line

No Standard

1. New agents: many classes:cytotoxics, biologics, signaling inhibitors, proapoptotic -microenvironment directed

2. Combinations:

Rising PSA

3Clinical

Metastases:Castrate1st Line

Docetaxel

2Clinical

Metastases:Castrate

Pre-

ClinicallyLocalizedDisease

Drug Development in Castration-Resistant Disease:Clinical Contexts Around Docetaxel As A Standard

1Rising PSA:

Castrate

ClinicalMetastases:

Non-Castrate

4Clinical

Metastases:Castrate2nd Line

No Standard

ChemotherapyDrug Development Contexts:1. Rising PSA castrate:2 Pre-chemotherapy: 2nd line hormonal agents, biologics.3. 1st line: Docetaxel based combinations.4. 2nd line: Investigational: e.g. cytotoxics,

targeted / directed agents.

A Partial List of Taxotere Combinations Under Evaluation As First-Line Therapy

Phase 3

• + Avastin (anti-VEGF Ab) Genentech (CALGB) - accrued

• + Atrasentan Abbott (SWOG)

• + ZD4054 Astra-Zeneca (ENTHUSE)

• + VEGF-trap Sanofi-Aventis

• + dasatinib BMS

• + Gossypol (BCL-2) Ascenta

• + clusterin antisense Oncogenix

With caveat the PSA changes are misleading!

Targeting the Bidirectional Tumor-Host Interaction in Bone

Tu and Lin, The Cancer Journal 14:35, 2008

CALGB 9040: Randomized Double Blinded Placebo controlled Phase III Trial Comparing Docetaxel + Prednisone with or without

Bevacizumab in men with CRPC

RA

ND

OM

IZE

RA

ND

OM

IZE

Docetaxel q 3 wks + Prednisone + Placebo

Docetaxel q 3 wks +bevacizumab +prednisone

EligibilityMetastatic PCT <50 ng/mlNo prior chemoAdequate hem, renal, hepatic function

StratificationHalabinomogram

N = 1020 patientsCALGB, ECOG, NCIC

Endpoint: Overall / progression free survival, PSA response rate; Hazard Ratio = 1.26 (19 months to 24 months), 90% power

Advanced Stage Disease

1. Clinical States: A framework for drug development.

2. Dissecting the lethal phenotype.

3. Targeting AR signaling: MDV3100.

4. CTC as a biomarker.

Androgen Depletion Produces Declines in PSA and Tumor Shrinkage, Followed by Regrowth as a

Castration-Resistant Lesion

Castrate “T” < 50 ng/dl

1. As initial treatment: Androgen depletion is not curative.

2. A rising PSA shows the AR is signaling and a transition to a lethal phenotype.

Clinical Insights into Castration-Resistant Progression Guiding Drug Development

1. Rising PSA levels are consistent with continued AR signaling.

2. Clinical significance of AR targeting is reinforced by the response to secondary hormone therapies, as well as the “withdrawal”/ “discontinuation” of anti-androgens.

3. This suggests antagonists later functions as an agonist as the disease progresses.

4. The AR ligand binding domain is clinically relevant and contributes to progression.

UntreatedPrimary

Metastatic CastrationResistant

Scher et al. Endocrine-RelatedCancer 11:2004;459

Oncogenic Changes in the Androgen Receptor in Castration Resistant Prostate Cancer Are Targets for Therapy

MutationsIncreased AR proteinAR mRNA overexpressionIncreased AR DNA copy numberOverexpressed androgen synthetic enzymes

o

Post-AndrogenDepletion

Advanced Stage Disease

1. Clinical States: A framework for drug development.

2. Dissecting the lethal phenotype.

3. Targeting AR signaling: MDV3100.

4. CTC as a biomarker.

MDV3100 and Abiraterone Acetate Target Specific Alterations in Castration Resistant Prostate Cancer And Show Promising Activity

ANDROGEN METABOLISM

AR

HSP90AR degraded

AR P

Abiraterone

AR PARP

MDV-3100

Transcription of TMPRSS-ETS, etcfor growth and survival

SRC

Androgenprecursors

AndrogensAdrenal synthesis

Tumor synthesis

Abiraterone

DHT

AR AR

Cell surface ligand/receptor

Akt

ARP

mutAR

ARARARAmpAR

+

Receptor Promiscuity: antiandrogens, progestins,

MDV-3100Chen et al. Curr Opin Pharm, 2008

NuclearLocalization

AROverexpression

17

Rising PSA

3Clinical

Metastases:Castrate1st Line

DocetaxelStandard

2Clinical

Metastases:Castrate

Pre-

ClinicallyLocalizedDisease

MDV3100 For Castration-Resistant Disease: Phase I/II Pre- And Post-Chemotherapy: PSA Based “Go-No Go”

1Rising PSA:

Castrate

ClinicalMetastases:

Non-Castrate

4Clinical

Metastases:Castrate2nd Line

No Standard

MDV3100:A Hormonal Therapy

Are castration resistant prostate cancers sensitive to further

androgen depletion?

Does the decision to GIVE chemotherapy render the tumor resistant to a hormonal intervention?

Four Separate Phase 1 and Phase 2 Trials Demonstrated The Activity of Abiraterone in Progressive CRPC

Pre- and Post-Chemotherapy

Trial No. > 50% PSA Decline CTC Conversion

> 5 to 4 or less

Pre-Chemotherapy

Attard (Marsden) 42 27 (70%) 10/17 (59%)

Ryan (UCSF) 30 16 (53%) ---

Post-Chemotherapy

Reid (Marsden) 47 24 (51%) 11/27 (41%)

Danila (MSK) 56 25 (47%) 9/25 (36%)

Royal Marsden, UCSF, Dana Farber, MSKCC, MDACC, JHU

Efficacy Response – 1: Efficacy Response – 1: The Phase III Registration Trial of The Phase III Registration Trial of Abiraterone Acetate in Post-Chemotherapy Abiraterone Acetate in Post-Chemotherapy (Cougar 301) (Cougar 301) Includes

the Prospective Evaluation of CTC Number

DeBono, J (Europe) and Scher, H. (North America) Co-PI, OrthoBiotech Oncology Research And Development (A Unit of Cougar Biotechnology)

R

Abiraterone 1000 mg dailyPrednisone 10 mg daily

Placebo dailyPrednisone 10 mg daily

2

1

STATISTICS

Primary: 25% survival increaseSecondary: CTC numberStatistics: Approximately 1200Biomarkers: CTC enumeration

Profiling

1. Fully accrued ahead of schedule: Analyses performed blinded and anonymously.2. Screening and cycle 1 day 1 samples prior to therapy; monthly post-therapy.3. Explore associations with clinical outcomes.4. Exploratory molecular/biologic analyses.

Baseline and sequential samples on approximately 1000 patients.

Advanced Stage Disease

1. Clinical States: A framework for drug development.

2. Dissecting the lethal phenotype.

3. Targeting AR signaling: MDV3100.

4. CTC as a biomarker.

MDV3100 and Abiraterone Acetate Target Specific Alterations in Castration Resistant Prostate Cancer And Show Promising Activity

ANDROGEN METABOLISM

AR

HSP90AR degraded

AR P

Abiraterone

AR PARP

MDV-3100

Transcription of TMPRSS-ETS, etcfor growth and survival

SRC

Androgenprecursors

AndrogensAdrenal synthesis

Tumor synthesis

Abiraterone

DHT

AR AR

Cell surface ligand/receptor

Akt

ARP

mutAR

ARARARAmpAR

+

Receptor Promiscuity: antiandrogens, progestins,

MDV-3100Chen et al. Curr Opin Pharm, 2008

NuclearLocalization

AROverexpression

22

The AR Antagonist MDV3100 Is Active Against Bicalutamide Resistant Xenografts with Overexpressed AR,

And Inhibits AR Nuclear Translocation

0

25

50

75

100

0 50 100 150

+AR

Vector

LNCaP

Intact males

Castrate males

Chen et al, Nature Medicine, 2004

Tran et al, Science, 324: 8 May 2009

Tran et al, Science, 324: 8 May 2009

Waterfall Plot of PercentPSA Change from Baseline

Chemotherapy-Naïve

Post-Chemotherapy

62% (40/65)

51% (38/75)

Circulating Tumor Cells

Pre-Therapy Post-Therapy

UnfavorableUnfavorable

No. > 5 to Favorable

Total 128 51 (32%) 15 (49%)

Pre- 60 16 (23%) 12 (75%)

Post- 68 35 (54%) 13 (37%)Scher et al., ASCO, June 2009

The AR Antagonist MDV3100 is Active in Pre- and Post-Chemotherapy CRPC Based on PSA, Imaging and

CTC Conversion Rates

CTC successfully measured in 128 (92%)of cases in a 5 Center PCCTC Trial

Efficacy-Response #2: Efficacy-Response #2: Phase III Registration Trial of MDV3100 Phase III Registration Trial of MDV3100 in CRPC Post-Chemotherapy in CRPC Post-Chemotherapy (AFFIRM) Also (AFFIRM) Also Includes the

Prospective Evaluation of CTC Number as a Biomarker

Scher H. (North America) and DeBono, J (Europe) Co-PI

R

Medivation 160 mg dailyPrednisone 10 mg daily

Placebo dailyPrednisone 10 mg daily

2

1

STATISTICS

Primary: 25% survival increaseSecondary: CTC numberSample size: Approximately 1200Biomarkers: CTC enumeration

Profiling

1. IRB approved.2. Activation, October, 2009.3. CTC sampling mirrors Cougar 301.4. Associations with clinical outcomes: clinical and

biologic.

Therapy Development: A Multidisciplinary Team

Daniel Danila

David Solit

Dana Rathkopf

Michael Morris

Nicholas Mitsiades

Martin Fleisher

Hans Lilja

Rita Espinosa-

Gonzalez

Aseem Anand

Larry Schwartz

Hedvig

Steven Solomon

Steven Larson

Peter Smith Jones

Charles Sawyers

Yu Chen

Nicola Clegg

Neal Rosen

Adriana Heguy

Margaret Leversha

Jan Hendrix

Oscar Lin

Glenn Heller

Chris Sander

Nikki Schultz

†William Gerald

Anu Gopalan

Victor Reuter

Royal Marsden:

Johann de Bono

Gerhart Attard

U. Miami: Richard Cote

OHSU: Tom Beer

U Washington:

Celestia Higano

Bruce Montgomery

MDACC: Chris Logothetis

Eleni Efstathiou

DFCI: Mary-Ellen Taplin

U Michigan:

Maha Hussain

Ortho Biotechnology (Cougar):

Arturo Molina

Chris Haqq

Medivation: Lynn Seely

Mohammed Hirmand

Veridex: Robert McCormack

CSHL: Richard MacCombie

MGH SU2C: Dan Haber

FDA BQRT: Federico Goodsaid

NIH SPORE; DOD PCCTC

Prostate Cancer Foundation

STARR Foundation ,

FNIH

DeWitt Wallace