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

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

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:

Radiology April 2007 vol 243 no 1,

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

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

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

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

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

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

Sipuleucel-T Manufacturing COMPLETE COURSE OF THERAPY: 3 CYCLES WEEKS 0, 2, and 4 Day 1 Leukapheresis Day 1-2 Sipuleucel-T is manufactured Day 2 Patient is infused Apheresis Center 1.5 – 2.0 ml mononuclear cells DendreonDoctor’s Office # cells infused was the maximum # of cells that could be prepared from the leukapheresis product. Median # of nucleated cells per infusion = 3.65 x 10 9 and median # of CD54+ bright cells per infusion = 7.45 x 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

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:

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])

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:

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

Biologic Targets for Cancer Therapy 1. Growth Factors and Growth-Factor Receptors (HER family, VEGFR, c-kit/SCFR) 2. Signal Transduction Pathways (Ras, raf, MAPK, MEK, ERK PKC, P13K) 3. Tumor-Associated Antigens/Markers (gangliosides, CEA, MAGE, CD20, CD22) 4. Proteasome 6. Extracellular Matrix/ Angiogenic Pathways (MMPs, VEGF, integrins) 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, Tumor Cell

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 targets 1 1 Heath EI, Carducci MA. Hematol Oncol Clin North Am 2006 Aug;20(4):

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