Managing castrate resistant metastatic prostate cancer
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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

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

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.


Definition of castrate resistant disease

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.


Managing castrate resistant metastatic prostate cancer

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


Androgen deprivation therapy

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

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

Secondary Hormonal Therapy

  • Add anti-androgen

  • Subtract anti-androgen

  • Add ketoconazole

  • Add steroid

  • Add Diethylstilbesterol (DES)

  • Consider clinical trial


Immunotherapy

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 (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

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.


Sipuleucel t manufacturing

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


Impact study

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.


Impact study1

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 study2

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.


Current challenges

Current Challenges

  • Leukopheresis

    • Venous access

    • Location of center

  • Increasing public demand

  • First year only in select sites

  • Manufacturing centers being developed


Managing castrate resistant metastatic prostate cancer

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.


Targeted agents

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.


Novel agents

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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