1. 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

2. 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

3. 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

4. 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

5. 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.

7. The Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide
AR Binding Affinity
DHT ~ 5nM
Bicalutamide ~160 nM
MDV ~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

8. 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]

9. 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 fluorodeoxyglucose FDHT fluorodihydrotestosterone

10. 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.

11. 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”

12. 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

13. Demographics/Prior Therapy (N=140)
Med. (range)
AGE (years) (44–93)
PSA (ng/mL) (2–2,159)
N (%)
PRIOR HORMONE THERAPY 140 (100%)
1 line (23%)
2 lines (30%)
>3 lines (47%)
CHEMOTHERAPY (54%)

14. 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)

15. 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

16. 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%)
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

17. 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.

18. 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

19. 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.

20. Time to PSA Progression For Pre- and Post-Chemotherapy Treated Patients
Pre (Not reached)
Post (186 days)

21. Time to Radiographic Progression in Pre- and Post-Chemotherapy Treated Patients
Pre (Not yet reached)
Post (201 days)

22. Exploratory Biomarker Analyses
Circulating Tumor Cells:
Enumeration (CellSearch™ - Veridex, LLC)
AR FISH
AR mutations
Positron Emission Tomography:
FDHT fluorodihydrotesterone
FDG fluorodeoxyglucose

23. 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 <
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)

24. 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

25. 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)

26. 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%)

27. 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

28. 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

29. 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