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Howard I. Scher, MD Chief, Genitourinary Oncology Service Memorial Sloan Kettering Cancer Center

Advanced Stage Disease: Management of Disease Progression and Emerging Drug Protocols. Howard I. Scher, MD Chief, Genitourinary Oncology Service Memorial Sloan Kettering Cancer Center October 6, 2009. Advanced Stage Disease. Clinical States: A framework for drug development.

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Howard I. Scher, MD Chief, Genitourinary Oncology Service Memorial Sloan Kettering Cancer Center

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  1. Advanced Stage Disease: Management of Disease Progression and Emerging Drug Protocols Howard I. Scher, MD Chief, Genitourinary Oncology Service Memorial Sloan Kettering Cancer Center October 6, 2009

  2. Advanced Stage Disease • Clinical States: A framework for drug development. • Dissecting the lethal phenotype. • Targeting AR signaling: MDV3100. • CTC as a biomarker.

  3. Prostate Cancer Clinical States: A Framework For Clinical Practice, Drug Development and Biomarker Qualification Castration resistant: Deaths From Disease Non-Castrate Androgen depletion /blockade (bicalutamide) Diagnoses 28,660 186, 320 Clinical Metastases: Non-Castrate 2 Clinical Metastases: Castrate Pre- 3 Clinical Metastases: Castrate 1st Line Docetaxel Standard 4 Clinical Metastases: Castrate 2nd Line No Standard Clinically Localized Disease Rising PSA 1 Rising PSA: Castrate

  4. For Castration Resistant Prostate Cancers Q3 Week Docetaxel Can Prolong Life And Is the First Line Standard of Care Median Trial 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 Docetaxel 3 wkly 1.0 0.9 Docetaxel wkly 0.8 Mitoxantrone 0.7 0.6 Probability of Surviving 0.5 0.4 0.3 0.2 0.1 0.0 Tax 327 0 6 12 18 24 30 Petrylak et al., and Tannock et al., NEJM, 2004 –

  5. Clinical Trials Are Experiments Conducted With Therapeutic Intent • Objective: Goals and therapeutic aim. • Patient population: Entry criteria: minimize heterogeneity, or enrich for specific characteristics. • Intervention: Mechanism: cidal, static, targeted. Dose and schedule: safety. • Outcomes: Endpoints: (aka response criteria). Phase 2: ? Signal, if so, how strong? Statistical design. 5. Conclusions: Was the question answered? Is continued development justified?

  6. Outcome Measures Are Biomarkers To be Validated Analytically and Qualified Clinically • Insure a drug is no longer working before stopping therapy. • Report PSA changes using waterfall plots. • Confirm bone scan findings with a second scan. • Eliminate overall response as an outcome: focus on time to event.

  7. Building on Docetaxel As the First-Line Standard of Care 3 Clinical Metastases Castrate 1st Line Docetaxel Standard Clinical Metastases: Non-Castrate 4 Clinical Metastases: Castrate 2nd Line No Standard 2 Clinical Metastases: Castrate Pre- Clinically Localized Disease Rising PSA 1 Rising PSA: Castrate • New agents: many classes: • cytotoxics, biologics, signaling inhibitors, proapoptotic - • microenvironment directed • 2. Combinations:

  8. Drug Development in Castration-Resistant Disease: Clinical Contexts Around Docetaxel As A Standard Clinical Metastases: Non-Castrate 3 Clinical Metastases: Castrate 1st Line Docetaxel 4 Clinical Metastases: Castrate 2nd Line No Standard 2 Clinical Metastases: Castrate Pre- Clinically Localized Disease Rising PSA 1 Rising PSA: Castrate Chemotherapy • Drug Development Contexts: • 1. Rising PSA castrate: • 2 Pre-chemotherapy: 2nd line hormonal agents, biologics. • 1st line: Docetaxel based combinations. • 2nd line: Investigational: e.g. cytotoxics, • targeted / directed agents.

  9. 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!

  10. Targeting the Bidirectional Tumor-Host Interaction in Bone Tu and Lin, The Cancer Journal 14:35, 2008

  11. CALGB 9040: Randomized Double Blinded Placebo controlled Phase III Trial Comparing Docetaxel + Prednisone with or without Bevacizumab in men with CRPC Eligibility Metastatic PC T <50 ng/ml No prior chemo Adequate hem, renal, hepatic function Stratification Halabi nomogram Docetaxel q 3 wks + Prednisone + Placebo Docetaxel q 3 wks + bevacizumab + prednisone RANDOMIZE N = 1020 patients CALGB, ECOG, NCIC • Endpoint: Overall / progression free survival, PSA response rate; • Hazard Ratio = 1.26 (19 months to 24 months), 90% power

  12. Advanced Stage Disease • Clinical States: A framework for drug development. • Dissecting the lethal phenotype. • Targeting AR signaling: MDV3100. • CTC as a biomarker.

  13. Androgen Depletion Produces Declines in PSA and Tumor Shrinkage, Followed by Regrowth as a Castration-Resistant Lesion Castrate “T” < 50 ng/dl • As initial treatment: Androgen • depletion is not curative. • A rising PSA shows the AR • is signaling and a transition to a lethal phenotype.

  14. 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.

  15. Oncogenic Changes in the Androgen Receptor in Castration Resistant Prostate Cancer Are Targets for Therapy o Post-Androgen Depletion Untreated Primary Metastatic Castration Resistant Mutations Increased AR protein AR mRNA overexpression Increased AR DNA copy number Overexpressed androgen synthetic enzymes Scher et al. Endocrine-Related Cancer 11:2004;459

  16. Advanced Stage Disease • Clinical States: A framework for drug development. • Dissecting the lethal phenotype. • Targeting AR signaling: MDV3100. • CTC as a biomarker.

  17. MDV3100 and Abiraterone Acetate Target Specific Alterations in Castration Resistant Prostate Cancer And Show Promising Activity Abiraterone ANDROGEN METABOLISM Adrenal synthesis Cell surface ligand/receptor Androgen precursors Androgens Tumor synthesis AR Abiraterone AR degraded HSP90 DHT Akt SRC MDV-3100 AR AR Receptor Promiscuity: antiandrogens, progestins, mutAR AR AR P P Nuclear Localization + AR AR AR AR Overexpression AmpAR AR AR P P Transcription of TMPRSS-ETS, etcfor growth and survival MDV-3100 Chen et al. Curr Opin Pharm, 2008

  18. MDV3100 For Castration-Resistant Disease: Phase I/II Pre- And Post-Chemotherapy: PSA Based “Go-No Go” 3 Clinical Metastases: Castrate 1st Line Docetaxel Standard Clinical Metastases: Non-Castrate 4 Clinical Metastases: Castrate 2nd Line No Standard 2 Clinical Metastases: Castrate Pre- Clinically Localized Disease Rising PSA 1 Rising PSA: Castrate Are castration resistant prostate cancers sensitive to further androgen depletion? Does the decision to GIVE chemotherapy render the tumor resistant to a hormonal intervention? MDV3100: A Hormonal Therapy

  19. 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

  20. Efficacy Response – 1: The Phase III Registration Trial of Abiraterone Acetate in Post-Chemotherapy (Cougar 301) Includes the Prospective Evaluation of CTC Number STATISTICS Primary: 25% survival increase Secondary: CTC number Statistics: Approximately 1200 Biomarkers: CTC enumeration Profiling Abiraterone 1000 mg daily Prednisone 10 mg daily 2 R Placebo daily Prednisone 10 mg daily 1 • Fully accrued ahead of schedule: Analyses performed blinded and anonymously. • Screening and cycle 1 day 1 samples prior to therapy; monthly post-therapy. • Explore associations with clinical outcomes. • Exploratory molecular/biologic analyses. • Baseline and sequential samples on approximately 1000 patients. DeBono, J (Europe) and Scher, H. (North America) Co-PI, OrthoBiotech Oncology Research And Development (A Unit of Cougar Biotechnology)

  21. Advanced Stage Disease • Clinical States: A framework for drug development. • Dissecting the lethal phenotype. • Targeting AR signaling: MDV3100. • CTC as a biomarker.

  22. MDV3100 and Abiraterone Acetate Target Specific Alterations in Castration Resistant Prostate Cancer And Show Promising Activity Abiraterone ANDROGEN METABOLISM Adrenal synthesis Cell surface ligand/receptor Androgen precursors Androgens Tumor synthesis AR Abiraterone AR degraded HSP90 DHT Akt SRC MDV-3100 AR AR Receptor Promiscuity: antiandrogens, progestins, mutAR AR AR P P Nuclear Localization + AR AR AR AR Overexpression AmpAR AR AR P P Transcription of TMPRSS-ETS, etcfor growth and survival MDV-3100 Chen et al. Curr Opin Pharm, 2008

  23. The AR Antagonist MDV3100 Is Active Against Bicalutamide Resistant Xenografts with Overexpressed AR, And Inhibits AR Nuclear Translocation LNCaP 100 Intact males 75 +AR 50 Castrate males 25 Vector Chen et al, Nature Medicine, 2004 0 0 50 100 150 Tran et al, Science, 324: 8 May 2009 Tran et al, Science, 324: 8 May 2009

  24. Waterfall Plot of PercentPSA Change from Baseline The AR Antagonist MDV3100 is Active in Pre- and Post-Chemotherapy CRPC Based on PSA, Imaging and CTC Conversion Rates Circulating Tumor Cells Pre-Therapy Post-Therapy Unfavorable Unfavorable No. > 5 to Favorable Total 128 51 (32%) 15 (49%) Pre- 60 16 (23%) 12 (75%) Post- 68 35 (54%) 13 (37%) 62% (40/65) 51% (38/75) Chemotherapy -Naïve Post- Chemotherapy CTC successfully measured in 128 (92%) of cases in a 5 Center PCCTC Trial Scher et al., ASCO, June 2009

  25. Efficacy-Response #2: Phase III Registration Trial of MDV3100 in CRPC Post-Chemotherapy (AFFIRM) Also Includes the Prospective Evaluation of CTC Number as a Biomarker STATISTICS Primary: 25% survival increase Secondary: CTC number Sample size: Approximately 1200 Biomarkers: CTC enumeration Profiling Medivation 160 mg daily Prednisone 10 mg daily 2 R Placebo daily Prednisone 10 mg daily 1 • IRB approved. • Activation, October, 2009. • CTC sampling mirrors Cougar 301. • Associations with clinical outcomes: clinical and biologic. Scher H. (North America) and DeBono, J (Europe) Co-PI

  26. 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

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