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

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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: Medivation Veridex I will discuss the following off label use and/or investigational use in my presentation: MDV3100

The Development Landscape For Systemic Therapies In Prostate Cancer Diagnoses Non-Castrate Androgen depletion /blockade (bicalutamide) Castration resistant: Docetaxel Deaths From Disease Rising PSA 3 Clinical Metastases: Castrate 1st Line Docetaxel Standard 2 Pre- Clinically Localized Disease 1 Rising PSA: Non-Castrate 4 Post- No Standard With detectable metastases: deaths from cancer exceed that from other causes 28,660 186, 320

Androgen Receptor Overexpression is Frequent in Castration Resistant Tumors and is a Target for Therapy o Primary Tumors Castration Resistant Increased AR protein AR mRNA overexpression Increased AR DNA copy number Increased androgen synthesis Scher et al. Endocrine-Related Cancer 11:2004;459

MDV3100 A Second-Generation Antiandrogen Engineered for activity in prostate cancer cells that overexpress the androgen receptor (AR). Binds the AR more potently than bicalutamide. Unlike bicalutamide, MDV3100 inhibits nuclear translocation of the AR and its binding to DNA. Induces apoptosis in prostate cancer cells.

The Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ 1 HSP 90 LBD Ligand HD DBD NTD 2 4 POL II 3 DNA Chen, Clegg and Scher

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) Determine safety Determine pharmacokinetics (PK) Assess antitumor activity: Prostate-specific antigen (PSA) Soft tissue Bone Exploratory: Circulating tumor cells PET: FDG - 18-fluorodeoxyglucose FDHT - 18-fluorodihydrotestosterone

Key Inclusion Criteria Pathologic confirmation of adenocarcinoma of prostate Serum testosterone level <50 ng/dL 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 No more than 2 prior chemotherapy regimens, at least one of which contained docetaxel The key inclusion criteria for this trial were: Pathologic confirmation of the adenocarcinoma of the prostate Castrate level of testosterone defined as serum levels <50 ng/dL Progressive disease defined as one or more of the following: Progression by RECIST Minimum of 3 rising PSA levels with an interval of >1 week between each determination with the screening PSA being at least 2 ng/mL Two or more new bone lesions Patients who were previously treated with chemotherapy were also enrolled and these patients had one or two prior chemo regimens with at least one of the regimens containing docetaxel.

MDV3100 Was Evaluated in Pre- and Post-Chemotherapy Treated Patients Clinical Metastases: Castrate 1st Line Docetaxel Standard 2 Pre- 4 Post- No Standard Clinical Metastases: Non-Castrate Clinically Localized Disease Rising PSA 1 Rising PSA: Castrate “TYPICAL” “ATYPICAL”

Trial Design Single Dose 6 days Continuous Dosing Assess Monthly; Q3 Month Imaging Long-Term Dosing Indefinite Cohort 1 Cohort 2 After 28 Day Safety Subsequent Dose Levels After the first six subjects were enrolled into the trial (3 at 30 mg/day and 3 at 60 mg/day), it was noted that PSAs were declining in those six subjects. To gain a better understanding of the antitumor activity of the drug, the sponsor modified the protocol to allow enrollment of 12 chemo-naïve and 12 post-chemotherapy patients at doses of 60 mg/day and higher, once the safey of a dose was established in the dose-escalation cohorts. Cohort expansion at > 60 mg/day 12 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 tissue 92 (66%) Evaluable by PCWG2 59 (42%) Bone 109 (78%) Rising PSA only: 7 (5%) 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 - 60 15 12 27 150 13 28 240 17 29 360 480 22 600 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 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 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 seizure 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) N=41 63% (26/41) N=68 51% (35/68) *59 patients with evaluable soft tissue disease as defined by PCWG2 consensus J 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 Circulating Tumor Cells: Enumeration (CellSearch™ - Veridex, LLC) AR FISH AR mutations 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 N=235 Logrank p < 0.0001 21.4 Months 10.7 Months <5 CTCs n=100 (43%) >5 CTCs n=135 (57%) De Bono, Scher, Montgomery et al. Clin Cancer Res (2008)

Pre-Chemotherapy (N=60/65) Post-Chemotherapy (N=68/75) 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 18F-DHT SUV=~ PRE SUV=3.3 SUV = 8.3 FDHT FDG POST SUV = <2 AR expression in tumor (IHC)

Changes In FDG and FDHT Uptake in Tumor by PET and PSA Were Generally Concordant 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 Conclusions MDV3100 is a second-generation antiandrogen engineered for activity in cells that overexpress AR, unique from bicalutamide. The drug is active in CRPC both before and after chemotherapy as shown by: declines in PSA, imaging, CTC conversion rates, and PET MDV3100 is generally well-tolerated 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

AFFIRM Phase 3 Registration Trial of MDV3100 in Post-Chemotherapy CRPC Patients 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-sided Biomarkers: CTC enumeration and profiling with outcome

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 DFCI Mary-Ellen Taplin Medivation David Hung Lynn Seely Mohammad Hirmand Beth Spencer Veridex Robert McCormack Department of Defense Prostate Cancer Clinical Trials Consortium Prostate Cancer Foundation