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New Clinical Trials in Prostate Cancer

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  1. New Clinical Trials in Prostate Cancer William K. Oh, M.D. Clinical Director, Lank Center for Genitourinary Oncology Dana-Farber Cancer Institute Associate Professor, Harvard Medical School

  2. U.S. Cancer Statistics: Prostate Cancer 2007 • Leading cause of cancer in men (218,890 cases, 29%) • Second leading cause of cancer death in men, after lung (27,050 deaths, 9%) • Cancer-specific survival estimates • 5 years 100% • 10 years 93% • 15 years 77% American Cancer Society 2007

  3. Clinical States of Prostate Cancer 10-15 yrs + Source: figure based on Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232. Pre-Hormone Therapy Hormone Therapy

  4. Clinical States of Prostate Cancer Source: figure based on Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232. Pre-Hormone Therapy Hormone Therapy

  5. “High Risk” Prostate Cancer • High risk of failure with surgery or radiation: • Bulky cancers on prostate exam (T3, T4) • PSA > 20 ng/ml • Gleason score 8-10 • Nomograms also risk stratify • www.nomograms.org

  6. CHEMOTHERAPY? Surgery or Radiation Therapy CHEMOTHERAPY? Hormonal therapy Chemotherapy

  7. Hormones/Radiation +/- Chemotherapy (OPEN) R A N D O M I Z E Radiation therapy Hormone therapy x 6 mo High Risk Prostate Cancer Taxotere (docetaxel) chemotherapy Radiation therapy Hormone therapy x 6 mo n = 350 PI: Dr. D’Amico Primary Endpoint: Survival

  8. Preoperative Chemotherapy Radical Prostatectomy • 6 months of Taxotere before surgery • Monthly PSA, DRE assessments • Prostate MRI at 0, 2, and 6 months • Primary endpoint: Complete eradication of cancer from surgical specimen Febbo Clin Cancer Res 2005

  9. Treatment Response • PSA decline > 50% • 11/19 patients (58%) • Tumor shrinkage > 25% on MRI • 13/19 (68%) • Complete eradication of cancer • 0/16 (0%)

  10. Feasibility • Major side effect: mild-mod fatigue • No nausea, numbness, infection • No surgical complications • After 2 years (avg) since surgery, median PSA <0.1 ng/ml (n=13) • 3 patients started hormones

  11. Chemo-treated Tumors Have Unique Molecular ‘Signatures’

  12. Preoperative Taxotere + Avastin in High Risk Cancer (OPEN) High Risk Prostate Cancer Taxotere x 18 wks Avastin x 15 wks Surgery (RP) Prostate MRI response  n = 42 PI: Dr. Oh

  13. Summary: High Risk Cancer • Multi-modality therapy is the key to improved outcome • Better systemic agents and combinations • Improved understanding of biology • Chemoresistance • New targets

  14. Clinical States of Prostate Cancer Source: figure based on Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232. Pre-Hormone Therapy Hormone Therapy

  15. Failure of Local Therapy • Most men treated for localized prostate cancer are cured • About 1/3 recur, initially as a rising PSA alone (“biochemical failure”) • Little is known about optimal management of rising PSA patients

  16. Natural History of Rising PSA • Patrick Walsh (@Johns Hopkins) • ~15% relapsed after surgery • No hormones until (+) bone scan RP 2 yrs 7.5 yrs 6.5 yrs First Rise in PSA Bone scan (+) Death Eisenberger Proc ASCO 2003

  17. Rapid PSA Doubling Time = More Aggressive Cancer PSADT <2 mo. <3 Percent Dead of Prostate Cancer <4 <6 <12 D’Amico JNCI 2003

  18. Investigational Therapies for Rising PSA • Lifestyle or diet • Pomegranate juice • Novel targeted therapies • Rosiglitazone (Avandia) • Celecoxib (Celebrex) • Thalidomide/Revlimid • Statins • Vaccines • TRICOM-Prostvac

  19. Brief Hormones +/- Avastin for Rising PSA (OPEN SOON) R A N D O M I Z E Hormone therapy x 6 mo Rising PSA No mets Any PSADT Hormone therapy x 6 mo Avastin x 6 mo n = 100 PI: Dr. Taplin Endpoint: PSA > 0.2 ng/ml

  20. Chemohormonal Therapy in Rapid PSADT patients (OPEN) PSADT < 8 mo No mets No chemo Taxotere x 3 mo Avastin x 6 mo Hormones x 18 mo % PSA=0 @ Month 28 n = 40 PI: Dr. Taplin

  21. Conclusions: Rising PSA State • Biochemical failure is heterogeneous • All patients should not be treated alike • PSADT should guide therapeutic decisions • Observation or diet in slow PSADT patients • Hormones alone once PSA ~ 10 ng/ml? • Chemohormonal therapy in rapid PSADT patients?

  22. Clinical States of Prostate Cancer Source: figure based on Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232. Pre-Hormone Therapy Hormone Therapy

  23. Hormone-Refractory Prostate Cancer (HRPC)* *HRPC=CRPC=AIPC

  24. Primary Hormonal Therapy Secondary Hormonal Therapy Chemotherapy

  25. Secondary Hormonal Therapy for HRPC

  26. Testosterone • Testicles: 90% • Adrenal glands: 10% • Prostate cancer cells ?

  27. Can we block testosterone better? • MDV 3100: a better antiandrogen? • Abiraterone: a better adrenal blocker? • Casodex + RAD001: blocking two pathways of cancer growth instead of one

  28. MDV 3100: A Novel Antiandrogen (OPEN SOON) • Blocks androgen receptor (AR) from moving into the nucleus and activating growth genes • Phase I/II trial HRPC pre and post chemotherapy • 7 dose levels tested (24 men each) • Responses at all dose levels • Well tolerated so far PI: Dr. Taplin

  29. Abiraterone (“Abi”) • Blocks testosterone from adrenal gland • Phase I/II trials completed • PSA responses in >60% of patients • Median time to progression ~9 mo • Responses seen even after ketoconazole, chemotherapy

  30. Abiraterone suppresses steroids 6 2 Testosterone Androstenedione 5 4 ng/dl nmol/l Lower limit of sensitivity 3 1 No rise at progression No rise at progression 2 1 0.07 0 0 10 20 60 70 28 56 At progression At progression 1 Start of treatment Start of treatment Days Days 12.5 12.5 DHEA Estradiol 10.0 10.0 7.5 7.5 ρmol/l nmol/l No rise at progression 5.0 5.0 2.5 2.5 0 0 28 56 At progression 10 20 30 40 50 60 Start of treatment Days Days post treatment

  31. Phase III Study: Abiraterone vs Placebo (OPEN SOON) R A N D O M I Z E 1x Placebo HRPC, Prior Chemo Required Abiraterone (daily pill) 2x n = 1158 PI: Dr. Taplin Endpoint: Survival

  32. Phase II Trial of Casodex + RAD001 (OPEN) • mTOR pathway: stimulates cancer growth • RAD001: blocks mTOR, oral therapy • Casodex may synergize with RAD001 • HRPC patients • one prior chemotherapy ok • up to 2 years of prior Casodex ok • PSA > 2.0. • 38 patients to enroll PI: Dr. Taplin

  33. Clinical States of Prostate Cancer Source: figure based on Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232. Pre-Hormone Therapy Hormone Therapy

  34. Taxotere Chemotherapy for HRPC Taxotere every 3 weeks + Prednisone R A N D O M I Z E : Metastatic HRPC Patients Taxotere weekly + Prednisone Mitoxantrone + Prednisone Treatment duration in all 3 arms = 30 weeks

  35. Angiogenesis is Necessary for Tumor Growth ANGIOGENESISINHIBITORS Thalidomide Avastin

  36. Survival: Taxotere +/- Thalidomide Dahut JCO 2004

  37. Taxotere + Avastin in HRPC • PSA response: 77% • Measurable response: 44% • Median time to progression: 10.3 mo

  38. Completed Phase III Trial of Taxotere +/- Avastin in HRPC R A N D O M I Z E Taxotere/Prednisone + Placebo SURV I VAL HRPC Taxotere/Prednisone + Avastin n = 1020

  39. If Taxotere + Avastin is Better for HRPC, Then… Ongoing trials discussed earlier: • Preoperative in high risk patients • Rising PSA, with rapid PSADT

  40. Clinical States of Prostate Cancer Source: figure based on Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232. Pre-Hormone Therapy Hormone Therapy

  41. Therapeutic Options After Taxotere • Traditional options • Chemotherapy (Novantrone, carboplatin) • Radiopharmaceutical (Quadramet, radium) • Active areas of clinical investigation • Chemotherapy (Ixempra, XRP 6258) • Vaccines (Provenge, GVAX, PSMA ADC) • Targeted therapy (IPI-504, Sutent)

  42. Heat Shock Protein-90 Inhibitor: IPI-504 (OPEN) • HSP90 is an important “chaperone” protein that helps other proteins to fold • Client proteins include androgen receptor (AR) degrades AR • Twice weekly IV infusions • Phase II study open nationally PI: Dr. Oh

  43. PSMA ADC (Open Soon) • Antibody directed towards PSMA • “Prostate-specific membrane antigen” • Antibody attached to a toxin called auristatin (ADC) • After attaching to cancer cell, the toxic payload is delivered PI: Dr. Kantoff

  44. Conclusions • Many novel strategies to improve outcome with prostate cancer • Early use of chemotherapy in combination with surgery and radiation • New chemo combinations with angiogenesis inhibitors • More effective hormone blockade • New targeted therapies

  45. Clinical Staff: GU Oncology Jennifer Lowell, RN Stephanie Morrissey, RN Judy Prisby, RN Geoff Buckle David Flanagan Kori Hesse Peggy Inman Jin Kim Matt Lawlor Gina Scibelli Dr. Philip Kantoff Dr. William Oh Dr. Mary-Ellen Taplin Dr. Julia Hayes Dr. Bill Hahn Dr. Mark Pomerantz Dr. Robert Ross Dr. Jonathan Rosenberg Laurie Appleby, NP Sandra Kelly, NP

  46. Contact for Clinical Trials • David Flanagan • Project Manager • 617-632-3466 • David_flanagan@dfci.harvard.edu