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

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Presentation on theme: "Howard I. Scher, MD Chief, Genitourinary Oncology Service Memorial Sloan Kettering Cancer Center October 6, 2009 Advanced Stage Disease: Management of."— Presentation transcript:

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

2 Advanced Stage Disease 1.Clinical States: A framework for drug development. 2.Dissecting the lethal phenotype. 3.Targeting AR signaling: MDV CTC as a biomarker.

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

4 Median Trial DrugsNo.SurvivalP= D+E38618 mos.0.02 M+P D M+P D = docetaxel, E = estramustine, M = mitoxantrone, P = prednisone Petrylak et al., and Tannock et al., NEJM, 2004 – Probability of Surviving Docetaxel 3 wkly Docetaxel wkly Mitoxantrone For Castration Resistant Prostate Cancers Q3 Week Docetaxel Can Prolong Life And Is the First Line Standard of Care Tax 327

5 Clinical Trials Are Experiments Conducted With Therapeutic Intent 1. Objective:Goals and therapeutic aim. 2. Patient population:Entry criteria: minimize heterogeneity, or enrich for specific characteristics. 3. Intervention:Mechanism: cidal, static, targeted. Dose and schedule: safety. 4. 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 1.Insure a drug is no longer working before stopping therapy. 2.Report PSA changes using waterfall plots. 3.Confirm bone scan findings with a second scan. 4.Eliminate overall response as an outcome: focus on time to event. Outcome Measures Are Biomarkers To be Validated Analytically and Qualified Clinically

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

8 Rising PSA 3 Clinical Metastases: Castrate 1st Line Docetaxel 2 Clinical Metastases: Castrate Pre- Clinically Localized Disease Drug Development in Castration-Resistant Disease: Clinical Contexts Around Docetaxel As A Standard 1 Rising PSA: Castrate Clinical Metastases: Non-Castrate 4 Clinical Metastases: Castrate 2 nd Line No Standard Chemotherapy Drug Development Contexts: 1.Rising PSA castrate: 2Pre-chemotherapy:2 nd line hormonal agents, biologics. 3.1 st line:Docetaxel based combinations. 4.2 nd line:Investigational: e.g. cytotoxics, targeted / directed agents.

9 A Partial List of Taxotere Combinations Under Evaluation As First-Line Therapy Phase Avastin (anti-VEGF Ab)Genentech (CALGB)- accrued 2.+ AtrasentanAbbott (SWOG) 3.+ ZD4054Astra-Zeneca (ENTHUSE) 4.+ VEGF-trapSanofi-Aventis 5.+dasatinibBMS 6.+ Gossypol (BCL-2)Ascenta 7.+ clusterin antisenseOncogenix 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 RANDOMIZE Docetaxel q 3 wks + Prednisone + Placebo Docetaxel q 3 wks + bevacizumab + prednisone Eligibility Metastatic PC T <50 ng/ml No prior chemo Adequate hem, renal, hepatic function Stratification Halabi nomogram 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 1.Clinical States: A framework for drug development. 2.Dissecting the lethal phenotype. 3.Targeting AR signaling: MDV 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 1.As initial treatment: Androgen depletion is not curative. 2.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 Untreated Primary Metastatic Castration Resistant Scher et al. Endocrine-Related Cancer 11:2004;459 Oncogenic Changes in the Androgen Receptor in Castration Resistant Prostate Cancer Are Targets for Therapy Mutations Increased AR protein AR mRNA overexpression Increased AR DNA copy number Overexpressed androgen synthetic enzymes o Post-Androgen Depletion

16 Advanced Stage Disease 1.Clinical States: A framework for drug development. 2.Dissecting the lethal phenotype. 3.Targeting AR signaling: MDV CTC as a biomarker.

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

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

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 DeclineCTC Conversion > 5 to 4 or less Pre-Chemotherapy Attard (Marsden) (70%) 10/17 (59%) Ryan (UCSF) (53%) --- Post-Chemotherapy Reid (Marsden) (51%) 11/27 (41%) Danila (MSK) (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) Efficacy Response – 1: The Phase III Registration Trial of Abiraterone Acetate in Post-Chemotherapy (Cougar 301) Includes the Prospective Evaluation of CTC Number DeBono, J (Europe) and Scher, H. (North America) Co-PI, OrthoBiotech Oncology Research And Development (A Unit of Cougar Biotechnology) R Abiraterone 1000 mg daily Prednisone 10 mg daily Placebo daily Prednisone 10 mg daily 2 1 STATISTICS Primary:25% survival increase Secondary:CTC number Statistics:Approximately 1200 Biomarkers:CTC enumeration Profiling 1.Fully accrued ahead of schedule: Analyses performed blinded and anonymously. 2.Screening and cycle 1 day 1 samples prior to therapy; monthly post-therapy. 3.Explore associations with clinical outcomes. 4.Exploratory molecular/biologic analyses. Baseline and sequential samples on approximately 1000 patients.

21 Advanced Stage Disease 1.Clinical States: A framework for drug development. 2.Dissecting the lethal phenotype. 3.Targeting AR signaling: MDV CTC as a biomarker.

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

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

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

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

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 Hussa in 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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