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Managing Castrate-Resistant Metastatic Prostate Cancer

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Managing Castrate-Resistant Metastatic Prostate Cancer ... Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363:411-422. – PowerPoint PPT presentation

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Title: Managing Castrate-Resistant Metastatic Prostate Cancer


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

Provenge
AR Modulators
Denosumab
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
LHRHluteinizing 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 gt 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
261148-1159.
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
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
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
Doctors 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
    patients non-activated immune cells
  • 512 patients in 21 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 363411-422.
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
    (P0.032, HR0.77, 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 363411-422.
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 (ganglioside
s, 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 Aug20(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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