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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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Managing castrate resistant metastatic prostate cancer l.jpg

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

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Clinical States of Prostate Cancer

Under the care of ONCOLOGIST



AR Modulators




Therapies After LHRH Agonists and AA








Non 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.

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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.

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

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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

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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

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Secondary Hormonal Therapy

  • Add anti-androgen

  • Subtract anti-androgen

  • Add ketoconazole

  • Add steroid

  • Add Diethylstilbesterol (DES)

  • Consider clinical trial

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  • 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

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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

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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


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.

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Sipuleucel-T Manufacturing

Day 1


Day 1-2

Sipuleucel-T is manufactured

Day 2

Patient is infused

Apheresis Center

1.5 – 2.0 ml mononuclear cells


Doctor’s Office



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

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  • 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.

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  • 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])

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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.

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Current Challenges

  • Leukopheresis

    • Venous access

    • Location of center

  • Increasing public demand

  • First year only in select sites

  • Manufacturing centers being developed

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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.

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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.

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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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