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

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

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

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  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 InformationAntitumor Activity of MDV3100 in a Phase 1-2 Study of Castration-Resistant Prostate CancerHoward 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 Castration resistant: Docetaxel Deaths From Disease Non-Castrate Androgen depletion /blockade (bicalutamide) 28,660 186, 320 3 Clinical Metastases: Castrate 1st Line Docetaxel Standard Clinical Metastases: Non-Castrate 4 Clinical Metastases: Castrate Post- No Standard 2 Clinical Metastases: Castrate Pre- Clinically Localized Disease Rising PSA 1 Rising PSA: Castrate With detectable metastases: deaths from cancer exceed that from other causes Diagnoses

  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.

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

  7. 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]

  8. 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

  9. 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

  10. MDV3100 Was Evaluated in Pre- and Post-Chemotherapy Treated Patients 3 Clinical Metastases: Castrate 1st Line Docetaxel Standard Clinical Metastases: Non-Castrate 4 Clinical Metastases: Castrate Post- No Standard 2 Clinical Metastases: Castrate Pre- Clinically Localized Disease Rising PSA 1 Rising PSA: Castrate “ATYPICAL” “TYPICAL”

  11. Trial Design Cohort 1 Cohort 2 After 28 Day Safety Single Dose 6 days Single Dose 6 days Continuous Dosing Assess Monthly; Q3 Month Imaging Continuous Dosing Assess Monthly; Q3 Month Imaging Long-Term Dosing Indefinite Long-Term Dosing Indefinite Subsequent Dose Levels Cohort expansion at > 60 mg/day 12 pre- and 12 post-chemotherapy Post-chemotherapy only at > 480 mg/day

  12. 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%)

  13. 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)

  14. Dose Expansions Allowed Rapid Enrollment of 140 Patients Across Dose Levels

  15. MDV3100 Was Generally Well-Tolerated • 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

  16. 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.

  17. Waterfall Plot of Best Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 51% (38/75) >50% Decline 62% (40/65) >50% Decline

  18. Radiographic Changes in Soft Tissue (N=59) and in Bone (N=109) *59 patients with evaluable soft tissue disease as defined by PCWG2 consensusJ Clin Oncol 2008.

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

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

  21. Exploratory Biomarker Analyses • Circulating Tumor Cells: Enumeration (CellSearch™ - Veridex, LLC) AR FISH AR mutations • Positron Emission Tomography: FDHT - 18-fluorodihydrotesterone FDG - 18-fluorodeoxyglucose

  22. Circulating Tumor Cell Number is Prognostic for Survival and the Conversion From an Unfavorable (> 5) to aFavorable (< 5) Count Predicts for an Improved Survival N=235 <5 CTCs n=100 (43%) 21.4 Months Logrank p < 0.0001 10.7 Months >5 CTCs n=135 (57%) De Bono, Scher, Montgomery et al. Clin Cancer Res (2008) De Bono Clin Cancer Res; 14:6304, 2008

  23. Pre- and Post-Treatment CTC Number (N=128/140)*12 patients with no baseline and/or follow-up CTC count Favorable < 5 CTCs/7.5 ml Unfavorable ≥ 5 CTCs/7.5 ml

  24. FDG FDHT PRE SUV=3.3 SUV = 8.3 POST SUV = <2 SUV = <2 PRE- and POST-MDV3100 PET Imaging of Biopsy Proven Metastatic Disease in a Lymph Node 18F-DHT SUV=~ AR expression in tumor (IHC)

  25. 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)

  26. 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

  27. AFFIRMPhase 3 Registration Trial of MDV3100 in Post-Chemotherapy CRPC Patients MDV3100 – 240 mg QD 2 R Placebo QD 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

  28. 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

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