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Managing Castrate-Resistant Metastatic Prostate Cancer

Managing Castrate-Resistant Metastatic Prostate Cancer. Elisabeth I. Heath, MD Associate Professor of Medicine and Oncology Wayne State University/Karmanos Cancer Institute August 28, 2010. Clinical States of Prostate Cancer. Under the care of ONCOLOGIST. Denosumab. Provenge.

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Managing Castrate-Resistant Metastatic Prostate Cancer

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  1. Managing Castrate-Resistant Metastatic Prostate Cancer Elisabeth I. Heath, MD Associate Professor of Medicine and Oncology Wayne State University/Karmanos Cancer Institute August 28, 2010

  2. Clinical States of Prostate Cancer Under the care of ONCOLOGIST Denosumab Provenge AR Modulators Androgen Deprivation Death Therapies After LHRH Agonists and AA Local Therapy Chemotherapy Postchemo Cabazitaxel Symptomatic Asymptomatic Non Metastatic Metastatic Castrate Sensitive Castrate Resistant • Typical presentation of patient as they move through the different stages. The line represents level burden of disease. Time is not proportional Abbreviations: AA = antiandrogen; LHRH=luteinizing hormone-releasing hormone.

  3. Definition of Castrate-Resistant Disease • Prostate Cancer Working Group 2 (PCWG2) • PSA 2.0 ng/mL • Rising PSA minimum 1 week apart • LN > 2 cm used for assessment • Bone scan: 2 more new lesions Howard Scher et al. Design and End Points of Clinical Trials for Patients With Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group J Clin Oncol 26:1148-1159.

  4. Radiology April 2007 vol 243 no 1, 28-53.

  5. Androgen Deprivation Therapy • Maintain castrate levels of testosterone • ADT important in controlling castrate-sensitive population • Supportive therapy for bone health including calcium and vitamin D still indicated • Supportive therapy for symptoms of androgen suppression also indicated

  6. Therapy for Bone Metastasis • Zoledronic acid administered IV q 4 weeks • Monitor renal function and perform close evaluations for osteonecrosis of the jaw • Prevent disease related skeletal complications including • Pathological fractures • Spinal cord compression • Radiation therapy • Surgery

  7. Secondary Hormonal Therapy • Add anti-androgen • Subtract anti-androgen • Add ketoconazole • Add steroid • Add Diethylstilbesterol (DES) • Consider clinical trial

  8. Immunotherapy • Sipuleucel-T (Provenge)(Dendreon) FDA approved on April 29, 2010 • Approval for treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer • Provenge designed to induce an immune response against prostate cancer • First in class to be approved

  9. Sipuleucel-T (Provenge)(Dendreon) • Sipuleucel-T is composed of autologous antigen presenting cells (APCs) cultured with a fusion protein (PA2024) consisting of prostatic acid phosphatase (PAP) linked to GM-CSF • Sipuleucel-T is designed to stimulate T-cell immunity to PAP • PAP is expressed in the vast majority of prostate cancers but not in non-prostate tissue • PA2024 provides efficient loading and processing of antigens by APCs

  10. Cellular Immunotherapy Recombinant Prostatic Acid Phosphatase (PAP) antigen combines with resting antigen presenting cell (APC) APC takes up the antigen Fully activated, the APC is now sipuleucel-T Antigen is processed and presented on surface of the APC INFUSE PATIENT Active T-cell Inactive T-cell T-cells proliferate and attack cancer cells Sipuleucel-T activates T-cells in the body The precise mechanism of sipuleucel-T in prostate cancer has not been established.

  11. Sipuleucel-T Manufacturing Day 1 Leukapheresis Day 1-2 Sipuleucel-T is manufactured Day 2 Patient is infused Apheresis Center 1.5 – 2.0 ml mononuclear cells Dendreon Doctor’s Office COMPLETE COURSE OF THERAPY: 3 CYCLES WEEKS 0, 2, and 4 • # cells infused was the maximum # of cells that could be prepared from the leukapheresis product. Median # of nucleated cells per infusion = 3.65 x 109 and median # of CD54+ bright cells per infusion = 7.45 x 108. Patients premedicated 30 minutes before each infusion with Tylenol (650 mg) and Benadryl (50 mg). Sipuleucel-T or placebo administered IV over 30 minutes, and patients observed 30 minutes

  12. IMPACT Study • Phase 3 clinical trial or Provenge compared to patient’s non-activated immune cells • 512 patients in 2:1 randomization • Administered IV q 2 weeks for a total of 3 infusions • Primary endpoint: overall survival Philip W. Kantoff et al for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363:411-422.

  13. IMPACT Study • Men who received Provenge lived an average of 4.1 months longer and had a 22.5% reduction in the risk of death compared to men in control group (P=0.032, HR=0.77, [95% CI: 0.614,0.979])

  14. IMPACT Study Philip W. Kantoff et al for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363:411-422.

  15. Current Challenges • Leukopheresis • Venous access • Location of center • Increasing public demand • First year only in select sites • Manufacturing centers being developed

  16. Biologic Targets for Cancer Therapy Tumor Cell 1. Growth Factors andGrowth-Factor Receptors (HER family, VEGFR, c-kit/SCFR) 2. Signal Transduction Pathways (Ras, raf, MAPK, MEK, ERK PKC, P13K) 3. Tumor-AssociatedAntigens/Markers (gangliosides, CEA, MAGE, CD20, CD22) 6. Extracellular Matrix/Angiogenic Pathways (MMPs, VEGF, integrins) 4. Proteasome 5. Cell-Survival Pathways (cyclin-dependent kinases, mTOR, cGMP, COX-2, p53, Bcl-2) HER = human epidermal growth factor receptor; MMPs = matrix metalloproteinases; SCFR = stem cell growth factor receptor. Adapted with permission from Perez-Soler R, Miller V. Presented at: New Advances in the Management of Advanced NSCLC: the Expanding Role of Targeted Therapies [live Web conference]; April 20, 2005.

  17. Targeted Agents • Compounds that target cellular pathways abnormal in cancer cells, not in normal cells • Potentially more effective and less toxic • Better understanding of genetic and biologic changes underlying prostate cancer progression has led to growing research and development of rational prostate-specific drug targets1 1 Heath EI, Carducci MA. Hematol Oncol Clin North Am 2006 Aug;20(4):985-999.

  18. Novel Agents • VEGF inhibitors • Src inhibitors • HSP90 inhibitors • AKT inhibitors • PI3 kinase inhibitors • MTOR inhibitors • Jak/Stat inhibitors • Encourage enrollment into clinical trials

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