XII. Advanced Disease      Richard Lam, MD     Research DirectorProstate Oncology Specialists     Marina del Rey, CA
Advanced Disease
Examples: Advanced Disease
Treatments for Advanced DiseaseAndrogen deprivation therapy--first line therapy.Secondary hormone interventions—older dr...
FDA Approved Treatments for           Advanced Prostate Cancer since 2010Cabazitaxel (Jevtana)Provenge (1st immune treat...
Androgen Deprivation Therapy
Methods to Achieve CastrationSurgicalMedical Lupron, Trelstar, Eligard, Viadur, ZoladexTime
Androgen Deprivation Therapy for            Advanced DiseaseDuration of effectiveness: average 18 months (sometimes up to...
Treatment Options for         Hormone Refractory DiseaseSecondary Hormone Manipulations  Estrogens  Alternative anti-an...
Secondary Hormone-based Therapies    For Hormone Refractory DiseaseNilutamideKetoconazoleEstrogens Vivelle-Dot (Patch)...
FDA-Approved Chemotherapy          Agents until 2010   1980s             1990s               2000s                        ...
TAXOTERE: Study Design     R   Taxotere every 3   Primary endpoint     A    weeks (n=335)     • Overall survival          ...
Taxotere: Overall Survival Benefit                                   1.0Overall Survival Probability (%)                  ...
PSA response does not matter to the FDA (even though itpredicts survival). However, for guiding individual treatment      ...
Taxotere: Side EffectsEffects on Blood  Red blood count can be lowered (Anemia).     Fatigue     Shortness of Breath  ...
Taxotere: Side Effects (Cont.)Effects on Gastrointestinal Tract  Upper Tract     Impaired taste     Mild, if any, naus...
Taxotere: Side Effects (Cont.)Other systems    Hair loss    Numbness in fingers and toes    Tear duct stenosis    Fin...
Promising Taxotere Combinations  How Can We Improve on Taxotere?ThalidomideAvastinXelodaCarboplatinSamarium (Quadrame...
Taxotere Combined with   Platinum DerivativesPrevious                   Response        ReferenceChemo/     Combination   ...
Taxotere & Capecitabine (Xeloda)     # Pts.   Response     Reference                Rate      30        73%       ASCO 200...
Inhibitors of Angiogenesis     Vascular Endothelial Growth Factor (VEGF)1.   Over expression of the COX-2 enzyme stimulate...
Taxotere & Thalidomide                              Taxotere & Thalidomide                                     50 men    7...
Taxotere & Thalidomide Results                          > 50% PSA   18 Month                           Decrease   Survival...
Avastin is an Antibody thatInactivates VEGF Receptor
Taxotere/Avastin/Thalidomide   Ning & Dahut NCI and FDA, ASCO 2008, #500060 men with metastatic diseaseMedians for the g...
PSA Response Rate                             50                             40        Each Vertical Line Represents the P...
Taxotere + Avastin Phase III                  Trial                                         Taxotere, Prednisone & Avastin...
Taxotere + or (-) Avastin: Overall                  Survival Data                                             Median OS,  ...
Rate of Cancer Progression                                                                               Median PFS,      ...
Avastin Significantly Improved        Other Clinical EndpointsOutcome, %                      Bevacizumab Arm   Placebo Ar...
Taxotere and CurstersinCurstersin blocks Clusterin, a cell protein secreted by cancer cells that inhibits the killing eff...
The Cancer Cell Makes Clusterin From RNA   Clusterin    Protein                                  RNA
Curstersin      No Translation,                                          this step fails                                  ...
Taxotere/Curstersin                  Taxotere alone          Taxotere & Curstersin                        (n=41)          ...
Taxotere vs. Taxotere & Curstersin:          Overall Survival                             Further Information             ...
Taxotere Combined with ?     Effective                    Ineffective or Too Toxic                                        ...
Cabazitaxel (Jevtana)                                               Mitoxantrone &     755 patients                       ...
Cabazitaxel: Jevtana
Cabazitaxel: Side Effects Toxicity manageable and similar between    treatment arms Higher incidence of:      grade 3 l...
Immune Approaches to Combat      Advanced Prostate CancerSipuleucel-T (Provenge)Ipilimumab (Yervoy)
Immune SystemMade of cells and antibodies.Underactive: allows cancer to progress (post- transplant, HIV)Overactive: lea...
Immune System is Very Complex!                   Blood
T (Thymus) Cells: The Attack Cells      of the Immune System
Activated Immune Cells Attack and      Kill Cancer Cells Directly
Antigen Presenting Cell (APC)                        T-Cell
Provenge: Sipuleucel-T          Small #4500 ASCO 2005127 men with hormone resistancePlacebo vs. ProvengeOutcome 3x imp...
Provenge, Clinical Trials.                          100    Round 1                                                        ...
Round #2: Larger Provenge Study                                              Sipuleucel-T    Control                      ...
Round #2: Overall Survival                                            HR = 0.759 (95% CI: 0.606, 0.951)                   ...
The Regulatory T-Cells (T-Regs): SuppressImmune Activity, and can Enhance Cancer Activity
“The T-Regs”Treg cells are a subset of T cells that suppresses other T cells  “The Police”Cancer patients have been demo...
Ipilimumab: Antibody against the CTLA-4     receptor on the T-Reg Cell SurfaceCTLA-4                                  CTLA...
Antibody against CTLA-4           (ipilimumab)             Beer et al. ASCO Abstract # 5004, 200826 patients with hormone...
PSA Control is Observed                                                                               100                 ...
Safety Summary            Grade 3/4 Side Effects                  Prostate Cancer                     10 mg/kg            ...
Pre-treatment:   Post-treatment:  PSA 250           PSA <0.1
Randomized Phase III Trial          Ipilimumab                Ipilimumab               wks 1, 4, 7, 10    IpilimumabRadiat...
Novel Anti-testosterone AgentsAbiraterone (Zytiga)MDV-3100 (Enzalutamide)
Abiraterone: Brief ReviewEvidence is accumulating that castration-resistant  prostate cancer frequently remains hormone-d...
.Attard G et al. JCO 2008;26:4563-4571
Abiraterone suppresses steroids            6                                                             2                ...
Abiraterone: Brief ReviewAntitumor demonstrates activity pre-docetaxel and post-docetaxel•PSA, RECIST, bone scans         ...
AbirateronePre-Docetaxel Phase I/II:Maximal PSA Decrements
Abiraterone         Post-docetaxel Phase II (n=34)                            17/34 (50%) pts ≥50% decline                ...
Pre-Abiraterone                   Post-Abiraterone   Massively Enlarge Lymph Node        Lymph Node Resolved
Abiraterone  Post-Chemotherapy Phase III Trial (CB-301)Abiraterone 1000 mg daily (n=797) Prednisone 10 mg daily          ...
Abiraterone-CB-301 Results      (deBono, ASCO June 2011)               PSA       Time to PSA    Overall              respo...
•Binds AR more potently than bicalutamide.•Does not stimulate the AR•Engineered for activity in prostate cancer cells with...
MDV3100 mechanism of action
MDV3100MDV3100 attacks the androgen receptor at multiple levels.Appears effective  In chemo-naïve men (62% likelihood o...
Waterfall Plot of Percent PSA Change from Baseline at12 Weeks for Chemotherapy-Naive Patients Treated at       60, 150, an...
MDV3100 Affirm Study Design
MDV3100 Affirm Study Results  (deBono, ASCO June 2012)            PSA      Time to PSA   Overall          Response   Progr...
Symptoms Commonly Seen in           Advanced DiseaseSkeletal Complications  Bone pain  Spinal cord compression  Low bl...
Quadramet    Samarium Sm 153 Lexidronam Injection    Indicated for relief of pain in patients with confirmed     osteobl...
Pain Reduction         Change in AUPC-VAS in Prostate Cancer             Change from Baseline                             ...
Radium 223 - Alpharadin
Radium 223 - Alpharadin
Radium 223 – Alpharadin      Updated data: June 2012
Hormone Refractory Disease:     Other Options
Successful Warfare:     Attack Multiple FrontsHormone Approaches: Lupron, Casodex Monotherapy, Ketoconazole, Abiraterone,...
Module12 Dr Lam-AdvancedPC
Module12 Dr Lam-AdvancedPC
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  • The role of chemotherapy in prostate cancer has evolved considerably over the last 30 years. In 1981, estramustime was FDA-approved for palliation of metastatic prostate cancer symptoms. In 1996, the FDA approved mitoxantrone and corticosteriods in men with symptomatic androgen-independent prostate cancer for significant reduction in pain. On May 19, 2004, the FDA approved Taxotere® (docetaxel) for injection for use in combination with prednisone for the treatment of patients with androgen-independent (hormone-refractory) metastatic prostate cancer.
  • TAX 327, was a randomized, multicenter global clinical trial designed to evaluate chemotherapy with docetaxel and prednisone in the treatment of men with metastatic, hormone-refractory prostate cancer. 1006 patients were randomized to one of three treatment arms: mitoxantrone (12 mg/m 2 q3w) + prednisone (5 mg bid) weekly docetaxel (30 mg/m 2 ) + prednisone (5 mg bid) docetaxel once every three weeks (75 mg/m 2 ) + prednisone (5 mg bid) The primary efficacy endpoint was overall survival.
  • The initial analysis at 2 years showed that patients in the Taxotere ® q3w arm had a 24% reduced risk of mortality compared to patients in the mitoxantrone arm. Patients in the Taxotere ® q3w arm had a 14.5% median survival advantage and a 27.6% survival advantage at 2 years compared to patients in the mitoxantrone arm.
  • PSA normalization among patients in the TAX 327 study also had independent prognostic significance, but was a weaker surrogate for overall survival. Thus, PSA declines represent a continuum of prognosis and cut-offs are not fully predictive of the survival benefits with chemotherapy.
  • 02/23/13 ISCT FINAL v.2A-- 5-5-09
  • Explain difference between traditional chemo regimens (i.e. 3 weeks per cycle for “x” number of cycles) and the “ipi” format of induction followed by maintenance Emphasize importance of timing between pre-Tx XRT and dose 1, implications for scheduling, need to work closely with RT
  • New Developments for Relapsed Prostate Cancer April 1st 2003 Richard Lam M.D. Prostate Oncology Specialists, Marina del Rey, California
  • New Developments for Relapsed Prostate Cancer April 1st 2003 Richard Lam M.D. Prostate Oncology Specialists, Marina del Rey, California Change from baseline in AUPC-VAS is the primary efficacy of the study. Values shown are mean plus or minus one standard error for each of the first four weeks after administration. Differences are statistically significant at weeks 2, 3 and 4.
  • Module12 Dr Lam-AdvancedPC

    1. 1. XII. Advanced Disease Richard Lam, MD Research DirectorProstate Oncology Specialists Marina del Rey, CA
    2. 2. Advanced Disease
    3. 3. Examples: Advanced Disease
    4. 4. Treatments for Advanced DiseaseAndrogen deprivation therapy--first line therapy.Secondary hormone interventions—older drugs.  Ketoconazole  Estrogen  NilutamideImmune approachesNovel anti-testosterone agents  Abiraterone  MDV-3100Chemotherapy (Taxotere, Jevtana)Bone targeted therapy
    5. 5. FDA Approved Treatments for Advanced Prostate Cancer since 2010Cabazitaxel (Jevtana)Provenge (1st immune treatment)AbirateroneMDV-3100 (very soon!)Alpha-radin (very soon!)
    6. 6. Androgen Deprivation Therapy
    7. 7. Methods to Achieve CastrationSurgicalMedical Lupron, Trelstar, Eligard, Viadur, ZoladexTime
    8. 8. Androgen Deprivation Therapy for Advanced DiseaseDuration of effectiveness: average 18 months (sometimes up to 10 years though)Prognostic indicators PSA PSA doubling time Gleason score Small cell histology Extent of disease Addition of anti-androgens, such as bicalutamide PSA nadir
    9. 9. Treatment Options for Hormone Refractory DiseaseSecondary Hormone Manipulations Estrogens Alternative anti-androgens, ie nilutamide, flutamide KetoconazoleChemotherapy Taxotere Cytoxan, Mitoxantrone, Xeloda, Avastin, Carboplatin JevtanaNovel agents Abiraterone MDV-3100 Provenge
    10. 10. Secondary Hormone-based Therapies For Hormone Refractory DiseaseNilutamideKetoconazoleEstrogens Vivelle-Dot (Patch) DES Ethinyl estradiol
    11. 11. FDA-Approved Chemotherapy Agents until 2010 1980s 1990s 2000s Taxotere® (docetaxel) Estramustine Mitoxantrone with injection concentratephosphate (EMP) corticosteroids with prednisone
    12. 12. TAXOTERE: Study Design R Taxotere every 3 Primary endpoint A weeks (n=335) • Overall survival (OS) N D Secondary endpoints O • Pain response • 50% PSA decline M • Response rates I • Quality of life Z Mitoxantrone every 3 weeks E (n=337)
    13. 13. Taxotere: Overall Survival Benefit 1.0Overall Survival Probability (%) 0.8 0.6 Taxotere ® Mitoxantrone 27.6% 2-year survival advantage 0.4 0.2 P=0.009 0 0 3 6 9 12 15 18 21 24 27 30 Overall Survival Time (months )
    14. 14. PSA response does not matter to the FDA (even though itpredicts survival). However, for guiding individual treatment decisions, PSA response is extremely useful. 1.00 PSA normalized (n=115) Proportion surviving PSA not normalized (n=743) 0.75 0.50 (%) 0.25 p<0.0001 0 0 5 10 15 20 25 30 35 40 45 50 Survival time (months)
    15. 15. Taxotere: Side EffectsEffects on Blood Red blood count can be lowered (Anemia).  Fatigue  Shortness of Breath  Transfusions White blood count.  Fever  Infection
    16. 16. Taxotere: Side Effects (Cont.)Effects on Gastrointestinal Tract Upper Tract  Impaired taste  Mild, if any, nausea  Loss of appetite Lower Tract  Diarrhea Liver  Inflammation
    17. 17. Taxotere: Side Effects (Cont.)Other systems  Hair loss  Numbness in fingers and toes  Tear duct stenosis  Finger nail discoloration, pain, discharge
    18. 18. Promising Taxotere Combinations How Can We Improve on Taxotere?ThalidomideAvastinXelodaCarboplatinSamarium (Quadramet)Custersin
    19. 19. Taxotere Combined with Platinum DerivativesPrevious Response ReferenceChemo/ Combination Rate # Pts. 2/34 Carboplatin 18% ASCO 2007 Abst. # 238 1/40 Carboplatin 95% Eur Urol Emcyt 51:1252 1/40 Carboplatin 68% Cancer Emcyt 98:2592 2/34 Oxaliplatin 64% GUCS 2008 Abst. # 155 Obtaining good results in men previously treated with chemotherapy indicates a more powerful and active regimen
    20. 20. Taxotere & Capecitabine (Xeloda) # Pts. Response Reference Rate 30 73% ASCO 2007 Abst. #5121 77 41% Clin. GU Cancer 5:155 50 68% Cancer 107:738
    21. 21. Inhibitors of Angiogenesis Vascular Endothelial Growth Factor (VEGF)1. Over expression of the COX-2 enzyme stimulates production of VEGF. COX-2 inhibitors (Celebrex ®) reduce VEGF (Fujita et al. The Prostate 2002).2. Thalidomide blocks VEGF and basic fibroblastic growth factor (D’Amato Proc Natl Acad Sci 1994).3. Avastin® is a synthetic monoclonal antibody that blocks VEGF directly (FDA approved for colon, lung, kidney and brain cancer).
    22. 22. Taxotere & Thalidomide Taxotere & Thalidomide 50 men 75 Men Metastatic Disease Taxotere Alone 25 menJournal of Clinical Oncology Vol. 22:2532
    23. 23. Taxotere & Thalidomide Results > 50% PSA 18 Month Decrease Survival Taxotere 37% 43% Taxotere & Thalidomide 53% 68%
    24. 24. Avastin is an Antibody thatInactivates VEGF Receptor
    25. 25. Taxotere/Avastin/Thalidomide Ning & Dahut NCI and FDA, ASCO 2008, #500060 men with metastatic diseaseMedians for the group: PSA was 99 Gleason was 8 PSA doubling time was 1.6 month
    26. 26. PSA Response Rate 50 40 Each Vertical Line Represents the Percentage 30 Drop in PSA in An Individual Patient 20 10 % of PSA at Enrollment 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 -10 -20 -30 -4050% Decline -50 -60 -70 -80 -90 -100 Patients
    27. 27. Taxotere + Avastin Phase III Trial Taxotere, Prednisone & Avastin (n = 524)1050 Patients Docetaxel & Prednisone (n = 526)Kelly WK, et al. ASCO 2010. Abstract LBA4511.
    28. 28. Taxotere + or (-) Avastin: Overall Survival Data Median OS, 1.0 Mos (Range) Bevacizumab + CT 22.6 (21.1-24.5) 0.8 Placebo + CT 21.5 (20.0-23.0) HR: 0.91 (95% CI: 0.78-1.05) Probability 0.6 Log rank P = .181 0.4 0.2 0 0 6 12 18 24 30 36 42 Mos Patients at Risk, n Placebo + CT 526 480 390 305 199 100 44 22 Bev + CT 524 484 417 327 217 117 52 23Kelly WK, et al. ASCO 2010. Abstract LBA4511.
    29. 29. Rate of Cancer Progression Median PFS, 1.0 Mos (Range) Bevacizumab + CT 9.9 (9.1-10.6) 0.8 Placebo + CT 7.5 (6.7-8.0) HR: 0.77 (95% CI: 0.68-0.88) Probability 0.6 Log rank P < .0001 0.4 0.2 0 0 6 12 18 24 30 36 42 Mos Patients at Risk, n Placebo + CT 526 303 134 75 34 8 4 0 Bev + CT 524 381 194 97 44 15 5 1Kelly WK, et al. ASCO 2010. Abstract LBA4511.
    30. 30. Avastin Significantly Improved Other Clinical EndpointsOutcome, % Bevacizumab Arm Placebo Arm P Value (n = 524) (n = 526)≥ 50% decline in PSA 69.5% 57.9% .0002Scan response rate 53.2% 42.1% .0113 The Marginal Advantages Seen with Avastin & Taxotere in this Study May Possibly Be Explained by the Failure to Incorporate Thalidomide (or Revlimid) in the RegimenKelly WK, et al. ASCO 2010. Abstract LBA4511.
    31. 31. Taxotere and CurstersinCurstersin blocks Clusterin, a cell protein secreted by cancer cells that inhibits the killing effect of chemotherapyCurstersin is anti-sense oligonucleotide that reduces Clusterin production Chi, Kim. Proc. ASCO 2009, abs #5012.
    32. 32. The Cancer Cell Makes Clusterin From RNA Clusterin Protein RNA
    33. 33. Curstersin No Translation, this step fails Clusterin not Created RNA of ClusterinRNA Exploded view: Transcription
    34. 34. Taxotere/Curstersin Taxotere alone Taxotere & Curstersin (n=41) (n=41)50% PSA 54% 58%DropAny PSA 68% 87%DropOverall 16.9 months 23.8 monthsSurvival Chi, Kim. Proc. ASCO 2009, abs #5012.
    35. 35. Taxotere vs. Taxotere & Curstersin: Overall Survival Further Information on a Clinical Trial of Taxotere & Curstersin Is Available by Calling Jennifer at (310) 827-7707 Ext #32
    36. 36. Taxotere Combined with ? Effective Ineffective or Too Toxic CisplatinCarboplatin with Mitoxantrone Emcyt AdriamycinCapecitabine Vinorelbine (Velban)Avastin and Revlimid Vitamin D (Calcitriol)Curstersin * ?Avastin/Revlimid? *Available on trial and final results are still pending
    37. 37. Cabazitaxel (Jevtana) Mitoxantrone & 755 patients Prednisone whose cancer (n = 377) is Progressing Cabazitaxel & on Taxotere Prednisone 10 (n = 378) Obtaining Results in Taxotere Resistant Patients Would Constitute a Notable AccomplishmentDe Bono JS, et al. ASCO 2010. Abstract 4508.
    38. 38. Cabazitaxel: Jevtana
    39. 39. Cabazitaxel: Side Effects Toxicity manageable and similar between treatment arms Higher incidence of:  grade 3 low blood counts (82% vs 58%)  fevers from low blood counts (7.5% vs 1.3%) diarrhea (46.6% vs. 10.5%)De Bono JS, et al. ASCO 2010. Abstract 4508.
    40. 40. Immune Approaches to Combat Advanced Prostate CancerSipuleucel-T (Provenge)Ipilimumab (Yervoy)
    41. 41. Immune SystemMade of cells and antibodies.Underactive: allows cancer to progress (post- transplant, HIV)Overactive: leads to autoimmune illness. Control cancer?
    42. 42. Immune System is Very Complex! Blood
    43. 43. T (Thymus) Cells: The Attack Cells of the Immune System
    44. 44. Activated Immune Cells Attack and Kill Cancer Cells Directly
    45. 45. Antigen Presenting Cell (APC) T-Cell
    46. 46. Provenge: Sipuleucel-T Small #4500 ASCO 2005127 men with hormone resistancePlacebo vs. ProvengeOutcome 3x improvement in 3 year survivalToxicity very mild
    47. 47. Provenge, Clinical Trials. 100 Round 1 Median Survival Benefit = 4.5 months 75 Percent Survival Sipuleucel-T (n=82) Median Survival: 25.9 months 50 Control (n=45) 34% 25 Median Survival: 21.4 months 11% 0 0 10 20 30 40 Survival (months)Small EJ, Schellhammer PF, Higano CS, et. al. J Clin Oncol 24:3089-3094, 2006/Data on file,Dendreon Corp.
    48. 48. Round #2: Larger Provenge Study Sipuleucel-T Control (N = 341) (N = 171) Serum PSA median, ng/mL 51.7 47.2 Serum PAP median, U/L 2.7 3.2Kantoff, IMPACT manuscript, submitted, 2010
    49. 49. Round #2: Overall Survival HR = 0.759 (95% CI: 0.606, 0.951) p = 0.017 (Cox model) Median Survival Benefit = 4.1 months Sipuleucel-T (n = 341) Median Survival: 25.8 mo. 36 mo. survival: 32.1% Control (n = 171) Median Survival: 21.7 mo. 36 mo. survival: 23.0% No. at Risk Sipuleucel-T 341 274 142 56 18 3 Control 171 123 59 22 5 2Kantoff, ASCO-GU March 2010
    50. 50. The Regulatory T-Cells (T-Regs): SuppressImmune Activity, and can Enhance Cancer Activity
    51. 51. “The T-Regs”Treg cells are a subset of T cells that suppresses other T cells “The Police”Cancer patients have been demonstrated to have an increased levels of Treg cells in the bloodStudies show that higher levels of Treg cells in the blood predict shorter survivalCTLA is an important receptor on the surface.
    52. 52. Ipilimumab: Antibody against the CTLA-4 receptor on the T-Reg Cell SurfaceCTLA-4 CTLA-4 Cell Surface
    53. 53. Antibody against CTLA-4 (ipilimumab) Beer et al. ASCO Abstract # 5004, 200826 patients with hormone refractory, end stage, metastatic prostate cancer treated with escalating doses (phase I) with or without radiation to a metastatic site.6 men had greater than 50% decline in PSA.2 men had PSA drop to zero.Side effects were diarrhea, liver inflammation and rash
    54. 54. PSA Control is Observed 100 Best PSA Change From Baseline (%) 50 100 aBest PSA Change From Baseline (%) 50 0 0 a a -50 -50 11/43 responses (26%) 25/43 PSA control (58%) -100 -100 a 10 mg/kg +XRT Chemotherapy- +XRT Prior a Prior Chemotherapy Naïve Chemotherapy
    55. 55. Safety Summary Grade 3/4 Side Effects Prostate Cancer 10 mg/kg Combo (n = 31) XRTb (n = 29) Skin 4 (13%) – GI 9 (29%) 4 (12%) Liver 4 (13%) 2 (12%)Endocrine 2 (6.4%) –
    56. 56. Pre-treatment: Post-treatment: PSA 250 PSA <0.1
    57. 57. Randomized Phase III Trial Ipilimumab Ipilimumab wks 1, 4, 7, 10 IpilimumabRadiation to every 12 wks a bonemetastasis Placebo Placebo every 12 wks wks 1, 4, 7, 10
    58. 58. Novel Anti-testosterone AgentsAbiraterone (Zytiga)MDV-3100 (Enzalutamide)
    59. 59. Abiraterone: Brief ReviewEvidence is accumulating that castration-resistant prostate cancer frequently remains hormone-driven by using adrenal hormones or through intracrine synthesis.CYP17A1 (or 17-a-hydroxylase or 17,20-lyase) is a cytochrome P450 enzyme responsible for androgen and estrogen synthesis from adrenal hormones.Abiraterone is a potent, selective, and irreversible inhibitor of CYP17A1
    60. 60. .Attard G et al. JCO 2008;26:4563-4571
    61. 61. Abiraterone suppresses steroids 6 2 Testosterone Androstenedione 5 4 nmol/l ng/dl Lower limit of 3 sensitivity 1 No rise at 2 progression No rise at progression 1 0.07 0 01 Start of 10 20 60 70 At Start of 28 56 At treatment Days progression Days progression treatment 12.5 12.5 DHEA Estradiol 10.0 10.0 ρmol/lnmol/l 7.5 7.5 No rise at 5.0 progression 5.0 2.5 2.5 0 0 28 56 At 10 20 30 40 50 60 Start of treatment Days progression Days post treatment
    62. 62. Abiraterone: Brief ReviewAntitumor demonstrates activity pre-docetaxel and post-docetaxel•PSA, RECIST, bone scans ••Confirmed in Multiple phase II studies •Pre-docetaxel: 60-80% PSA response rate •Post-docetaxel: 40-50% PSA response rate•Phase III studies •Post-docetaxel: Completed accrual first quarter ’09 •Pre-docetaxel: Completed accrual first quarter ‘10
    63. 63. AbirateronePre-Docetaxel Phase I/II:Maximal PSA Decrements
    64. 64. Abiraterone Post-docetaxel Phase II (n=34) 17/34 (50%) pts ≥50% decline 22/34 (65%) pts ≥30%decline 24/34 (71%) pts had a PSA decline3 pts did not reach 12-weeks but are included
    65. 65. Pre-Abiraterone Post-Abiraterone Massively Enlarge Lymph Node Lymph Node Resolved
    66. 66. Abiraterone Post-Chemotherapy Phase III Trial (CB-301)Abiraterone 1000 mg daily (n=797) Prednisone 10 mg daily OrPlacebo daily (n=398) Prednisone 10 mg daily
    67. 67. Abiraterone-CB-301 Results (deBono, ASCO June 2011) PSA Time to PSA Overall response progression SurvivalAbiraterone 38% 11 months 15.8 months Placebo 10% 6.6 months 11.2 months
    68. 68. •Binds AR more potently than bicalutamide.•Does not stimulate the AR•Engineered for activity in prostate cancer cells with acommon and specific molecular defect: OverexpressedAR•Inhibits movement of the androgen receptor to thenucleus where it binds to DNA and triggers a signallingcascade leading to tumor growth
    69. 69. MDV3100 mechanism of action
    70. 70. MDV3100MDV3100 attacks the androgen receptor at multiple levels.Appears effective In chemo-naïve men (62% likelihood of 50% PSA decline). Post-chemotherapy disease (50% PSA response rate). Scher, H. PASCO 2009, abs 5011.Preliminary Phase III results 2012
    71. 71. Waterfall Plot of Percent PSA Change from Baseline at12 Weeks for Chemotherapy-Naive Patients Treated at 60, 150, and 240 mg/day of MDV3100 7 pt off N=42 Chemo-naïve study <12 weeks >50% Decline: 23/42 (55%)
    72. 72. MDV3100 Affirm Study Design
    73. 73. MDV3100 Affirm Study Results (deBono, ASCO June 2012) PSA Time to PSA Overall Response Progression SurvivalMDV- 54% 8.3mo 18.43100 monthsPlacebo 1.5% 2.9mo 13.6 months
    74. 74. Symptoms Commonly Seen in Advanced DiseaseSkeletal Complications Bone pain Spinal cord compression Low blood counts Fatigue Infections
    75. 75. Quadramet Samarium Sm 153 Lexidronam Injection Indicated for relief of pain in patients with confirmed osteoblastic metastatic bone lesions. Controlled studies included patients with prostate cancer, breast cancer, and others. Administered intravenously, usually as an outpatient procedure. Repeat administrations are safe and effective.1Quadramet (samarium Sm 153 lexidronam injection) prescribing information. September 2003.2Resche I, et al. Eur J Cancer. 1997;33:1583–1591.3Serafini AN, et al. J Clin Oncol. 1998;16:1574–1581.
    76. 76. Pain Reduction Change in AUPC-VAS in Prostate Cancer Change from Baseline 2 Placebo 0 1.0 mCi/kg -2 -4 -6 * * * -8 -10 0 1 2 3 4AUPC: area under the pain curve.VAS: visual analog scale; Week NumberPDS: pain descriptor scale.*P≤0.05 vs placebo.Sartor O, et al. Urology. 2004;63:940-945.
    77. 77. Radium 223 - Alpharadin
    78. 78. Radium 223 - Alpharadin
    79. 79. Radium 223 – Alpharadin Updated data: June 2012
    80. 80. Hormone Refractory Disease: Other Options
    81. 81. Successful Warfare: Attack Multiple FrontsHormone Approaches: Lupron, Casodex Monotherapy, Ketoconazole, Abiraterone, MDV3100Immune Mechanisms: Provenge, IpilimumabAnti-VEGF Targetting: Revlimid, AvastinChemotherapy: Taxotere, JevtanaNew Approaches: Alpha-radin, XL-184 (in studies)

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