Transcript Slide 1

MANAGEMENT OF ADVANCED PROSTATE
CANCER
Daniel Shevrin, MD
Division Hematology/Oncology
Northshore University Healthsystem
Pritzker School of Medicine
University of Chicago
ARS
1-G
Androgen Ablation
Androgen Ablation & Prostate Ca
• The androgen receptor is the most important
therapeutic target in PCa
– Targeting AR is effective in >90%
– The AR is critical even in the “hormone refractory” state
– Targeting AR is not curative
• Androgen ablation has toxicity
– Bone, muscle, sex
– Toxicity minimal in comparison to other cancer therapies
Prostate Ca System Therapy Philosophy
• Natural history can be very long
– Chronic disease management
– Competing mortality/morbidity
– Therapy toxicity can have significant functional signficance
• Natural history is highly variable
– Some patients have rapid disease progression
– Disease mortality and morbidity not insignificant
• Care is often fragmented
– Urologists
– Medical oncologists
– Primary care
ANDROGEN DEPRIVATION THERAPY FOR ADVANCED
DISEASE
• LHRH agonist + casodex
• Degaralix (antagonist) or orchiectomy for
immediate drop in testosterone
• PSA nadir prognostic
• Time to progression varies greatly
– Depends on biology: grade, bone vs visceral
– Favorable biology: 3 – 5+ years
– Unfavorable biology: 1-3 years
Intermittent vs. Continuous
• Phase II and early phase III data
– Intermittent therapy better tolerated and not associated with
worse outcome
– Fixed on-phase (6-8 months) of ADT
– Variable off-phase depends on recovery of testosterone and
biologic behavior of cancer
– Must monitor T and PSA levels and clinical
– Data for less bone density loss
– Suggestion of improved sexual function and QOL
– Intermittent therapy is a reasonable option for patients requiring
androgen deprivation
Castrate Resistant Disease
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Not really “hormone refractory”
Disease actually “hormone hypersensitive”
AR still a relevant target
Mechanisms of castrate resistance
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AR amplification
AR mutation
AR modification
Ligand availability
AR interactions
What we know…
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Prostate cancer requires AR signaling for development and
sustenance.
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AR activation is required throughout the natural history of
prostate cancer.
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AR activation in CRPC occurs via many mechanisms.
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Successful blockade of the receptor pathways will confer
greater therapeutic control on metastatic prostate cancer.
Second-Line Hormonal Agents
• Anti-androgen addition
– Casodex®
– Flutamide®
– Nilutamide®
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Anti-androgen withdrawal
Ketoconazole
17,20-lyase inhibitors
Estrogen
Corticosteroids
Small and Vogelzang, JCO, 1997
Ketoconazole
• Inhibits cytochrome P-450 enzymes
– Blocks testicular and adrenal androgenesis
• 200 - 400 mg TID
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Acid environment improves absorption
Expensive
Replacement hydrocortisone required
20 mg in morning, 10 mg evening
• PSA response rate  40%
• Nausea, LFT abnormalities, rash (rare)
• Drug interactions – statins, coumadin
Abiraterone/TAK-700
NEW INHIBITORS OF ADRENAL
ANDROGENS
• Abiraterone and TAK700 more potent and
selective inhibitors of CYP17lyase
• Further inhibition of T levels in blood
• Reduction in intra-tumoral T levels
• No cortisone requirement
• No drug-drug interactions
• Nausea, rash, fatigue
Castrate Resistant Disease
Non-Hormonal Treatment Options
• Good prognosis (asymptomatic, “low volume”)
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Standard Taxotere® chemotherapy
Antiandrogens, ketoconazole
Immunotherapy (Provenge, sipuleucel-T)
Investigational therapy
• Poor prognosis
– Standard Taxotere® chemotherapy
– Investigational chemotherapy combinations
WHAT ABOUT TAXOTERE®?
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Treatment improves survival (22 vs 18 months)
Treatment improves symptoms
Treatment usually decreases PSA
Side-effects are manageable
– Low WBC, anemia
– Hair loss, fatigue, neuropathy
• Infusion q 3 weeks for 6-10 cycles
• Necessary if disease is aggressive and symptomatic
Sipuleucel-T: Autologous APCs Cultured with
Antigen Fusion Protein
Recombinant Prostatic
Acid Phosphatase
(PAP) fusion antigen
combines with resting
antigen presenting cell
(APC)
APC takes up
the antigen
Antigen is
processed and
presented on
surface of the APC
Fully activated, the
APC is now
sipuleucel-T
INFUSE PATIENT
Inactive
T-cell
Active
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: Logistics of Therapy
Day 1
Leukapheresis
Apheresis Center
Day 2-3
sipuleucel-T is manufactured
Central Processing
Day 3-4
Patient is infused
Doctor’s Office
COMPLETE COURSE OF THERAPY:
Weeks 0, 2, 4
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Randomized Phase 3 IMPACT Trial
(IMmunotherapy Prostate AdenoCarcinoma Treatment)
Asymptomatic or
Minimally
Symptomatic
Metastatic
Castration
Resistant
Prostate Cancer
(N=512)
Sipuleucel-T
Q 2 weeks x 3
2:1
Placebo
Q 2 weeks x 3
P
R
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G
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E
S
S
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O
N
Treated at
Physician
Discretion
S
U
R
V
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V
A
L
Treated at
Physician
Discretion
and/or Salvage
Protocol
Primary Endpoint: Overall Survival
Secondary Endpoint: Objective Disease Progression
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IMPACT Overall Survival
Final Analysis (349 events)
36.5 mo median f/u
HR = 0.759 (95% CI: 0.606, 0.951)
p = 0.017 (Cox model)
Sipuleucel-T (n = 341)
Median Survival: 25.8 mo.
36 mo. survival: 32.1%
Placebo (n = 171)
Median Survival: 21.7 mo.
36 mo. survival: 23.0%
No. at Risk
Sipuleucel-T
341
274
142
56
18
3
Placebo
171
123
59
22
5
2
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Adverse Events More Commonly1 Reported in
Sipuleucel-T Group
Sipuleucel-T
N = 338
%
Placebo
N = 168
%
Chills
54.1
12.5
Pyrexia
29.3
13.7
Headache
Influenza-Like Illness
Myalgia
Hypertension
Hyperhidrosis
Groin Pain
16.0
9.8
9.8
7.4
5.3
5.0
4.8
3.6
4.8
3.0
0.6
2.4
Preferred Term
1 Reported
by ≥ 5% of sipuleucel-T patients and having a ≥ 2-fold difference from placebo.
The majority of the most common AEs were mild or moderate in severity.
Safety results obtained from primary analysis did not substantively change with additional
data obtained after study closure.
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Challenges
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Why no effect on prostate cancer progression?
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Ability to measure disease progression limited
Effect on tumor growth “takes time”
Minimal effect on PSA or symptoms
Cost
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$93,000 not include all apheresis and infusion costs
Logistics
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Limited apheresis capacity
Limited processing capacity
IS THERE ANYTHING AFTER TAXOTERE®?
• Cabazitaxel (Jevtana®)
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A novel drug designed for Tax resistance
TROPIC study: Jevtana vs Mitoxantrone
Infusion every 3 weeks for ~ 6 cycles
Improvement in survival (15.1 vs 12.7 months)
Much greater decrease in PSA
Neutropenia (low WBC) most frequent serious side-effect
FDA-approved
An important new weapon for advanced prostate cancer
Conclusions
• Advanced prostate cancer pts can have a long
history
– Opportunity for multiple therapies
– Toxicities and quality of life important
– Issues of co-morbid disease and aging
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Philosophy of chronic disease management
Androgen receptor pathway targeting is key
DNA targeted chemotherapy plays a role
Immunotherapy may play a role
New therapies need to be identified
MANAGEMENT OF ADVANCED PROSTATE
CANCER
Daniel Shevrin, MD
Division Hematology/Oncology
Northshore University Healthsystem
Pritzker School of Medicine
University of Chicago