Managing CastrateResistant 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
Androgen
Deprivation
Denosumab
Provenge
AR Modulators
Death
Therapies After
LHRH Agonists
and AA
Local
Therapy
Chemotherapy Postchemo
Cabazitaxel
Symptomatic
Under
the care of
ONCOLOGIST
Asymptomatic
Non Metastatic
Castrate Sensitive
Metastatic
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 CastrateResistant 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.
Radiology April 2007 vol 243 no 1, 28-53.
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
Recombinant
Prostatic Acid
Phosphatase (PAP)
antigen combines
with resting antigen
presenting cell (APC)
T-cells
proliferate and
attack
cancer cells
APC takes
up the
antigen
Antigen is
processed and
presented on
surface of the APC
Active
T-cell
Sipuleucel-T
activates Tcells in the
body
The precise mechanism of sipuleucel-T in prostate cancer has not been established.
Fully activated, the
APC is now
sipuleucel-T
INFUSE PATIENT
Inactive
T-cell
Sipuleucel-T Manufacturing
Day 1
Day 1-2
Day 2
Leukapheresis
Sipuleucel-T is
manufactured
Patient is infused
Dendreon
Doctor’s Office
Apheresis Center
1.5 – 2.0 ml mononuclear cells
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
 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 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; 363:411-422.
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
Tumor Cell
1. Growth Factors and
Growth-Factor Receptors
(HER family, VEGFR, c-kit/SCFR)
6. Extracellular Matrix/
Angiogenic Pathways
(MMPs, VEGF, integrins)
5. Cell-Survival Pathways
2. Signal Transduction Pathways
(Ras, raf, MAPK, MEK, ERK PKC, P13K)
3. Tumor-Associated
Antigens/Markers
(gangliosides, CEA, MAGE,
CD20, CD22)
4. Proteasome
(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
 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
 VEGF inhibitors
 Src inhibitors
 HSP90 inhibitors
 AKT inhibitors
 PI3 kinase inhibitors
 MTOR inhibitors
 Jak/Stat inhibitors
 Encourage enrollment into clinical trials