Antitumor Activity of MDV3100 in a Phase 1-2 Study of Castration-Resistant

Prostate Cancer

H. I. Scher, T. Beer, C. Higano, M. Taplin, E. Efstathiou, A. Anand, D. Hung, M. Hirmand, M. Fleisher, C. Sawyers

Memorial Sloan-Kettering Cancer Center, New York, NY; Oregon Health and Science University, Portland, OR; University of Washington, Seattle, WA; Dana Farber Cancer Institute, Boston, MA; M.D. Anderson

Cancer Center, Houston, TX; Medivation, San Francisco, CA; and the

Prostate Cancer Clinical Trials Consortium

Disclosure Information Antitumor Activity of MDV3100 in a Phase 1-2 Study of Castration-Resistant Prostate Cancer

Howard I. Scher, M.D.

I have the following financial relationships to disclose:

Consultant for: Medivation (uncompensated)

Grant/Research support from: MedivationVeridex

I will discuss the following off label use and/or investigational use in my presentation:

MDV3100

The Development Landscape For Systemic TherapiesIn Prostate Cancer

Castration resistant:Docetaxel

Deaths From Disease

Diagnoses

Rising PSA

3Clinical

Metastases:Castrate1st Line

DocetaxelStandard

2Clinical

Metastases:Castrate

Pre-

ClinicallyLocalizedDisease

1Rising PSA:

Castrate

ClinicalMetastases:

Non-Castrate

4Clinical

Metastases:Castrate

Post-No Standard

With detectable metastases:deaths from cancer exceed

that from other causes

28,660186, 320

Non-CastrateAndrogen depletion

/blockade (bicalutamide)

Primary Tumors Castration Resistant

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

Androgen Receptor Overexpression is Frequent in Castration Resistant Tumors and is a Target for Therapy

Increased AR proteinAR mRNA overexpressionIncreased AR DNA copy numberIncreased androgen synthesis

o

MDV3100 A Second-Generation Antiandrogen

1. Engineered for activity in prostate cancer cells that overexpress the androgen receptor (AR).

2. Binds the AR more potently than bicalutamide.

3. Unlike bicalutamide, MDV3100 inhibits nuclear translocation of the AR and its binding to DNA.

4. Induces apoptosis in prostate cancer cells.

Ligand

1. AR Binding Affinity• DHT ~ 5nM• Bicalutamide ~160 nM• MDV3100 ~35 nM

2. Nuclear Import• DHT: ++++• Bicalutamide: ++++• MDV3100: ++

3. DNA Binding• DHT: ++++• Bicalutamide: ++• MDV3100: -

4. Coactivator recruitment• DHT: ++++• Bicalutamide: ++• MDV3100: -

The Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide

1

2

Chen, Clegg and Scher

3

4

DNA

POL II

HS

P 9

0

LB

D

HD

DBD

NTD

MDV3100 Is Active Against Bicalutamide Resistant Cell Lines and Xenografts with Overexpressed AR,

And Inhibits AR Nuclear Translocation

Tran et. al. Science [Epub April 9, 2009]

Phase 1-2 Multicenter Trial in CRPC (Prostate Cancer Clinical Trials Consortium)

1. Determine safety

2. Determine pharmacokinetics (PK)

3. Assess antitumor activity: Prostate-specific antigen (PSA) Soft tissue

Bone

4. Exploratory:

Circulating tumor cells

PET: FDG - 18-fluorodeoxyglucose FDHT - 18-fluorodihydrotestosterone

Key Inclusion Criteria

1. Pathologic confirmation of adenocarcinoma of prostate

2. Serum testosterone level <50 ng/dL

3. Progressive disease defined as one or more of:

• 3 rising PSA levels; screening PSA >2 ng/mL

• RECIST

• Two or more new lesions on bone scan

4. No more than 2 prior chemotherapy regimens, at least one of which contained docetaxel

Rising PSAClinicallyLocalizedDisease

MDV3100 Was Evaluated in Pre- and Post-Chemotherapy Treated Patients

1Rising PSA:

Castrate

ClinicalMetastases:

Non-Castrate

3Clinical

Metastases:Castrate1st Line

DocetaxelStandard

2Clinical

Metastases:Castrate

Pre-

4Clinical

Metastases:Castrate

Post-No Standard

“TYPICAL” “ATYPICAL”

Trial Design

SingleDose6 days

Continuous DosingAssess Monthly;Q3 Month Imaging

Long-TermDosingIndefinite

Cohort 1

SingleDose6 days

Continuous DosingAssess Monthly;Q3 Month Imaging

Long-TermDosingIndefinite

Cohort 2After 28Day Safety

Subsequent Dose Levels

Cohort expansion at > 60 mg/day12 pre- and 12 post-chemotherapy Post-chemotherapy only at > 480 mg/day

Demographics/Prior Therapy (N=140)

Med. (range)AGE (years) 68 (44–93)

PSA (ng/mL) 50 (2–2,159)

N (%)PRIOR HORMONE THERAPY 140 (100%)

1 line 32 (23%)2 lines 42 (30%)>3 lines 66 (47%)

CHEMOTHERAPY 75 (54%)

Distribution of Disease (N=140)

Soft tissueSoft tissue 92 (66%) 92 (66%)

Evaluable by PCWG2 59 (42%)

BoneBone 109 (78%)109 (78%)

Rising PSA only:Rising PSA only: 7 7 (5%)(5%)

No detectable metastases:No detectable metastases:

(Bone and soft tissue disease = 68)

Dose Expansions Allowed Rapid Enrollment of 140 Patients Across Dose Levels

Dose (mg/day) Pre-Chemotherapy

Post-Chemotherapy

Total

30 3 - 3

60 15 12 27

150 15 13 28

240 17 12 29

360 15 13 28

480 - 22 22

600 - 3 3

TOTAL 65 75 140

MDV3100 Was Generally Well-Tolerated

Possibly Related Grade 2/3 Adverse Events in >2 Patients

Adverse Event All Doses

(N = 140)

<240 mg/day

(N = 60)

G2 G3 G2 G3

Fatigue

Nausea

Anorexia

Seizure

29 (21%)

11 ( 8%)

4 ( 3%)

12 (9%)

3 (2%)

8 (13%)

2 ( 3%)

3 (5%)

1. Only one subject discontinued treatment due to fatigue which coincided with disease progression

2. There were 2 witnessed seizures (1 each at 600 and 360 mg/day) and a possible unwitnessed seizure (at 480 mg/day). Both patients with witnessed seizures were taking concomitant medications

that can cause seizure3. MTD determined to be 240 mg/day; patients at higher doses were lowered to 240 mg/day

1. Report PSA changes using waterfall plots.2. Assess changes in soft tissue that a 2 cm or greater at baseline.3. Eliminate “overall response” as an outcome measure.4. Focus more on “time to event”, i.e. the treatment is no longer working.

Waterfall Plot of Best Percent PSA Change from Baseline

Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75)

62% (40/65)

>50% Decline

51% (38/75)

>50% Decline

Radiographic Changes in Soft Tissue (N=59) and in Bone (N=109)

Chemotherapy-Naïve Patients (N=65)

Post-Chemotherapy Patients (N=75)

Soft Tissue* (Best Response)

Partial Response

Stable Disease

N=25

36% (9/25)

44% (11/25)

N=34

12% (4/34)

53% (18/34)

Bone Scan (Week 12)

Stable Disease

N=41

63% (26/41)

N=68

51% (35/68)

*59 patients with evaluable soft tissue disease as defined by PCWG2 consensusJ Clin Oncol 2008.

Time to PSA Progression For Pre-and Post-Chemotherapy Treated Patients

Pre (Not reached)

Post (186 days)

Time to Radiographic Progression in Pre- and Post-Chemotherapy Treated Patients

Pre (Not yet reached)

Post (201 days)

Exploratory Biomarker Analyses

1. Circulating Tumor Cells:

Enumeration (CellSearch™ - Veridex, LLC)

AR FISH

AR mutations

2. Positron Emission Tomography:

FDHT - 18-fluorodihydrotesterone

FDG - 18-fluorodeoxyglucose

Circulating Tumor Cell Number is Prognostic for Survival and the Conversion From an Unfavorable (> 5) to a

Favorable (< 5) Count Predicts for an Improved Survival

De Bono Clin Cancer Res; 14:6304, 2008

De Bono, Scher, Montgomery et al. Clin Cancer Res (2008)

Pre- and Post-Treatment CTC Number (N=128/140)

*12 patients with no baseline and/or follow-up CTC count

Total (N=128/140)

Pre-Chemotherapy (N=60/65)

Post-Chemotherapy (N=68/75)

Favorable to Favorable 91% (70/77) 91% (40/44) 91% (30/33)

Favorable to Unfavorable 9% (7/77) 9% (4/44) 9% (3/33)

Unfavorable to Favorable

49% (25/51) 75% (12/16) 37% (13/35)

Unfavorable to Unfavorable

51% (26/51) 25% (4/16) 63% (22/35)

Favorable < 5 CTCs/7.5 ml Unfavorable ≥ 5 CTCs/7.5 ml

PRE- and POST-MDV3100 PET Imaging of Biopsy Proven Metastatic Disease in a Lymph Node

SUV=~

PRE

SUV=3.3 SUV = 8.3

FDHTFDG

POST

SUV = <2SUV = <2AR expression in tumor (IHC)

18F-DHT

Changes In FDG and FDHT Uptake in Tumor by PET and PSA Were Generally Concordant

1. 24* Patients had FDG/FDHT Scans performed at Baseline

2. SUVMaxsum = sum of the hottest SUVs (up to 5 lesions)

SUV Max Decrease from Baseline at 4 Weeks

N=22

SUV Max Decrease from Baseline at 12 Weeks

N=21

FDG 17 (73%) 17 (81%)

FDHT 22 (100%) 21 (100%)

Summary and Conclusions1. MDV3100 is a second-generation antiandrogen engineered for activity in cells that

overexpress AR, unique from bicalutamide.

2. The drug is active in CRPC both before and after chemotherapy as shown by:

declines in PSA, imaging, CTC conversion rates, and PET

3. MDV3100 is generally well-tolerated

4. A Phase 3 placebo-controlled survival trial in post-docetaxel CRPC patients is beginning this year

Dose selected to be 240 mg/day based upon: Significant anti-tumor effects plateau at this dose Few side effects Benefit:risk ratio

AFFIRMAFFIRM

Phase 3 Registration Trial of MDV3100 in Post-Chemotherapy CRPC Patients

R

MDV3100 – 240 mg QD

Placebo QD

2

1

Primary Endpoint:25% survival increase (12 to 15 months)Sample size: ~1170 (780 and 390)Statistics: 85% Power; p=0.05, two-sidedBiomarkers: CTC enumeration and profiling with outcome

Department of Defense Prostate Cancer Clinical Trials Consortium

Prostate Cancer Foundation

Acknowledgments

Daniel Danila

Michael Morris

Susan Slovin

David Solit

Ethan Basch

Aseem Anand

Julie Shelkey

Kin Tse

Ryan Stephenson

Martin Fleisher

Margaret Leversha

Mike Kosczuika

Rita Espinosa-

Gonzalez

Charles Sawyers

Michael Jung

Samedi Ouk

Derek Welsbie

Charlie Chen

Yu Chen

Uma Gopalan

Victor Reuter

Larry Schwartz

Steven Solomon

Steven Larson

Neeta Pandit-Taskar

Heiko Schoder

Peter Smith Jones

OHSU

Tom Beer

Joshi Alumkal

Chris Ryan

Erin LaMaye

U Washington

Celestia Higano

Bruce Montgomery

Evan Y. Yu

MDACC

Christopher Logothetis

Eleni Efstathiou

DFCIMary-Ellen Taplin

Medivation

David Hung

Lynn Seely

Mohammad Hirmand

Beth Spencer

Veridex

Robert McCormack