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“Fighting Cancer: It’s All We Do.” ™

“Fighting Cancer: It’s All We Do.” ™. Therapies in Androgen Resistant Prostate cancer and non metastatic prostate cancer. Ulka Vaishampayan M.D. Chair, GU Multidisciplinary team Associate Professor Of Medicine Detroit Medical Center

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“Fighting Cancer: It’s All We Do.” ™

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  1. “Fighting Cancer: It’s All We Do.”™

  2. Therapies in Androgen Resistant Prostate cancer and non metastatic prostate cancer Ulka Vaishampayan M.D. Chair, GU Multidisciplinary team Associate Professor Of Medicine Detroit Medical Center Wayne State University/ Karmanos Cancer Institute, Detroit MI.

  3. TAX 327 Trial Results-1006 Pts Eisenberger et al. ASCO 2004, abstr#4

  4. TAX 327: Docetaxel/Prednisone vs. Mitoxantrone/Prednisone in AIPC De Wit et al. Presented at the Annual Meeting of the American Society for Clinical Oncology, 2004. Plenary Session [abstract 4] Eisenberger MA et al. J Clin Oncol. 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 suppl), 2004:4 [Kathy to style refs]

  5. Novel Agents Under Investigation in Androgen-Independent Metastatic Prostate Cancer Chemobiologic combinations Vaccines Novel hormone agents: abiraterone, Kinex, TAK-700 Androgen receptor blockers- MDV-3100 Integrin inhibitors: EMD525797

  6. Docetaxel based combinations:Disappointing!! • Docetaxel and calcitriol (Vit D)- Showed increased death rate with the combination. • Docetaxel and Avastin:No benefit with combination • Docetaxel and G Vax (vaccine made from prostate cancer cells) Trial completed, again increased risk of death with combination as compared to docetaxel alone. • So far no therapy has proven benefit when added to docetaxel alone.

  7. Provenge/Dendritic cell therapy[Small E. et al.JCO 2008] • Peripheral stem cells collected and pulsed with prostatic acid phosphatase antigen and GMCSF • Antigen loaded, dendritic cells enriched preparation infused to patients • Patients with asymptomatic CRPC randomized to Provenge versus placebo in a 2:1 ratio • Administration was IV infusion every 2 weeks for 3 doses

  8. Sipuleucel-T Immunotherapy for Advanced Prostate Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial Penson et al. IMPACT Study Investigators Presented at American Urological Association Annual Meeting April 28, 2009 IMPACT STUDY

  9. Randomized Phase 3 IMPACT Trial(IMmunotherapy Prostate AdenoCarcinoma Treatment) P R O G R E S S I O N S U R V I V A L Treated at Physician discretion Sipuleucel-T Q 2 weeks x 3 Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512) 2:1 Treated at Physician discretion and/or Salvage Protocol Placebo Q 2 weeks x 3 Primary endpoint: Overall Survival Secondary endpoint: Time to Objective Disease Progression

  10. Sipuleucel-T: Patient-Specific Therapy Day 1 Leukapheresis sipuleucel-T is manufactured Day 3-4 Patient is infused Apheresis Center Dendreon Doctor’s Office COMPLETE COURSE OF THERAPY: Weeks 0, 2, 4

  11. Provenge Summary First active immunotherapy to demonstrate improvement in overall survival for prostate cancer Favorable benefit to risk profile Short duration of therapy Problems: Compared to placebo and not to chemotherapy, (docetaxel was compared to mitoxantrone). Easier to show benefit. Fairly cumbersome, with pheresis. No data regarding palliation, and worrisome that no improvement in time to objective progression. Represents another therapy in the armamentarium against prostate cancer.

  12. What Next After Docetaxel Failure? • Usually treat for symptom progression and not by PSA • Look for clinical trials of novel agents • Cabazitaxel prolongs life span after docetaxel therapy • FDA approved for use after docetaxel therapy. • Side effects similar to docetaxel therapy with infection, tiredness, nausea, being the most likely. • Long term benefit is being evaluated.

  13. Persistent hormone sensitivity • 10% of circulating testosterone remains after conventional hormone therapy • Conversion of adrenal hormones to testosterone • Testosterone persists in prostate cancer microenvironment • Androgen receptor upregulation • Cyp17A, the enzyme that converts adrenal steroids to androgen is overexpressed in advanced prostate cancer and in bone biopsies from metastatic sites. • Hence cancer remains androgen dependent.

  14. Abiraterone • Oral Cyp-17 A inhibitor • Efficacy noted in phase I and II trials with responses in pretreated metastatic CRPC. • Tolerable medication. • Phase III study almost completed, of abiraterone vs placebo in patients with met CRPC after chemotherapy. • Proposed trial is evaluating the role of abiraterone in metastatic CRPC, prior to chemo, asymptomatic or mildly symptomatic.

  15. Study Design • 1:1 randomization of abiraterone + prednisone vs prednisone + placebo. • Progression based on scans, symptoms and PSA. • Primary endpoint is OS • Secondary is rPFS, toxicity, correlates such as Circulating tumor cells and TMPRSS-2 gene. • Time to opiate administration, time to chemo will also be evaluated. • Sample size:1000 pts nationwide, study complete

  16. 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 3 Chen, Clegg and Scher DNA

  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. AFFIRMPhase 3 Registration Trial of MDV3100 in Post-Chemotherapy CRPC Patients MDV3100 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 Scher, H. (North America) and De Bono, J. Co-PI, Medivation

  19. Managing Hormone Sensitive, Non-Metastatic Prostate Cancer No standard approved therapy Clinical trials offer the best therapy in this setting. Consider very carefully the risks vs benefits

  20. PSA Relapse Non-metastatic Prostate Cancer • Rapidly growing population • Guidelines for therapy not completely established • Based on patient age, comorbid conditions, prior therapy etc. • Start hormone therapy early but not too early! • Retrospective study reveals that patients with PSA doubling time <12 months and high Gleason score have longer survival if hormones started when PSA<5ng/ml • Studies of adding chemotherapy early for high-risk patients are ongoing Moul et al. Urologic Oncology:Sem and Original Investigations, 21; 292-304, 2003

  21. Non metastatic PSA only prostate cancer: Principles of management • PSA rising • No spread visualized on CT scans and bone scan. • Consider multiple PSA levels and the rate of rise over time. • The actual value of PSA is not as important as the rate of rise; for instance a PSA rise from 38 to 40 to 45 in 6 months is less worrisome than a rise from 5 to 10 to 20 in 6 months. • PSA produces “Prostate Specific Anxiety” but otherwise the disease is not bothersome. • No therapy has proven benefit.

  22. Non metastatic PSA only prostate cancer: Principles of management • Secondary hormone therapies sometimes work, even for long periods of time; that would be standard therapy. • Caution about doing chemotherapy since: • Risks are higher • No proven benefit • Considering clinical trials • Look at side effects very carefully • Look at how much this will impact your daily life • Consider some of the background research done on the agent

  23. Conclusions • Metastatic disease: Back to hormone therapy with androgen receptor antagonist agents. • Immunotherapy such as Provenge is showing promise but cumbersome and expensive. • More chemotherapy options to prolong life and improve quality of life and pain control.

  24. “Fighting Cancer: It’s All We Do.”™

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