Treatment of
Advanced Disease
Elisabeth I. Heath, MD
Associate Professor of Medicine and
Oncology
Wayne State University/Karmanos Cancer
Institute
August 28, 2010
Prostate Cancer

Annual incidence in the USA slowly
increasing




Longer life expectancy
Widespread use of PSA leading to early
detection
15% present with advanced disease
20-30% of localized disease eventually
progress to metastatic disease
Clinical States of Prostate
Cancer
Androgen
Deprivation
Death
Therapies After
LHRH Agonists
and AA
Local
Therapy
Chemotherapy
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.
Postchemo
Definition of Advanced
Disease
 Locally advanced



Extracapsular extension
Seminal vesicles
Lymph nodes
 Castration sensitivity


Orchiectomy
LHRH suppression
 Prior therapy



Surgery
Radiation therapy
Chemotherapy
Multimodality Therapy
 Urology
 Radiation Oncology
 Medical Oncology
 Pathology
 Radiology
Hormone Therapy
 Male menopause
 Lutenizing Hormone Releasing Hormone
(LHRH) Agonist


Leuprolide acetate (Lupron)
Goserelin acetate (Zoladex)
 Decrease testosterone level
 Not permanent, although testosterone
recovery may take months depending on
length of hormone therapy and age
Side Effects of Hormonal
Therapy
 Hot flashes
 Sweats
 Weight gain
 Change in mood
 Sexual dysfunction
 Bone metabolism changes
Length of Hormonal Therapy
 Continuous versus intermittent therapy
 Clinical trials not definitive as of yet
 Discuss with your physician pros/cons of
both approaches
 Issues for discussion include short and
long term side effects of therapy
Radiology April 2007 vol 243 no 1, 28-53.
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
Denosumab (Amgen)
 Another bone strengthening compound
in advanced clinical trials
 Monoclonal antibody targeting and
binding against anti-RANK ligand
 Given subcutaneously
 Increases bone mineral density and
reduces risk of fractures in men who
received androgen-deprivation therapy
for non-metastatic prostate cancer
Smith MR, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer.
NEJM 2009 Aug 20: 361(8): 745-55.
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 of 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])
Current Challenges
 Leukopheresis


Venous access
Location of center
 Increasing public demand
 First year only in select sites
 Manufacturing centers being developed
Cabazitaxel
(Jevtana)(Sanofi-Aventis)
 FDA approved on June 17, 2010 in
combination with prednisone for the
treatment of patients with metastatic
castrate-resistant prostate cancer
 Phase 3 TROPIC study


755 patients previously treated with docetaxel
30% risk reduction in risk of death from
cabazitaxel/prednisone versus
mitoxantrone/prednisone (P<0.0001)
Sartor AO, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castrationresistant prostate cancer (mCRPC) previously treated with docetaxel: Final results of a multinational
phase III trial (TROPIC). GU ASCO 2010, #9.
Androgens Synthesized Within
the Tumor Itself
 Tumor cells use androgen along with androgen precursors from their
microenvironment to convert them into testosterone and
dihydrotestosterone
 In this way, the tumor produces androgen de novo to fuel its own
growth and proliferation
Prostate Tumor Cell Activates
Itself
 In CRPC, it is believed that the tumor itself is capable of synthesizing
its own source of androgen growth factors, while circulating levels of
testosterone remain low
 This, in combination with hypersensitivity of the androgen receptor,
could result in “self-activation” of the tumor
Abiraterone
 Molecular modeling was used to
design a compound that could act
as a substrate for CYP17

Inhibition of CYP17 has been
shown to block production of
androgens from all sources in the
body—testes, adrenal glands, and
the CaP tumor
 Dehydroepiandrosterone-acetate
3β-Acetoxy-17-(3pyridyl)androsta-5,16-diene
Molecular Weight=391.55
converted into a pyridyl analog of
pregnenolone, which is the
preferred substrate for the
CYP17 enzyme
 The resulting analog, abiraterone,
was not only highly specific for
CYP17, but also was extremely
potent
Androgenic Steroidogenesis
-
• Abiraterone is a
selective and
potent inhibitor of
CYP17 enzymes
• Blocks production
of androgens,
including
testosterone and
DHT
Abbreviations: ACTH=adrenocorticotropic hormone; DHEA=dehydroepiandrosterone; DHT=dihydrotestosterone.
Abiraterone Blocks Androgen
Production at All 3 Sources
•
•
Blocks androgen
production at all
3 sources
Inhibits
production of
androgens
needed to fuel
prostate tumor
cell growth
Other Novel AR Modulators
 MDV3100 (Medivation)
 TAK700 (Millenium)
 TOK-001 (Tokia Pharmaceuticals)
Treatment Advancements
 Sipuleucel-T (Provenge)
 Cabazitaxel (Jevtana)
 Denosumab
 AR modulators




Abiraterone
MDV3100
TAK700
TOK-001
Treatment Advancements
 Recognition of importance of
multidisciplinary care in treatment of
advanced stage prostate cancer
 Role of hormonal therapy being optimized
 Immunotherapy for treatment of advanced
disease
 Second-line therapy for patients who fail
docetaxel
 Encourage enrollment in clinical trials