MANAGEMENT OF ADVANCED PROSTATE CANCER

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MANAGEMENT OF ADVANCED PROSTATE CANCER

• Daniel Shevrin, MD
• Division Hematology/Oncology
• Northshore University Healthsystem
• Pritzker School of Medicine
• University of Chicago

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ARS
?1-G
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Androgen Ablation
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Androgen Ablation Prostate Ca

• The androgen receptor is the most important
  therapeutic target in PCa
• Targeting AR is effective in gt90
• 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

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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

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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

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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

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Castrate Resistant Disease

• Not really hormone refractory
• Disease actually hormone hypersensitive
• AR still a relevant target
• Mechanisms of castrate resistance
• AR amplification
• AR mutation
• AR modification
• Ligand availability
• AR interactions

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What we know

• Prostate cancer requires AR signaling for
  development and sustenance.
• AR activation is required throughout the natural
  history of prostate cancer.
• AR activation in CRPC occurs via many mechanisms.
• Successful blockade of the receptor pathways will
  confer greater therapeutic control on metastatic
  prostate cancer.

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Second-Line Hormonal Agents

• Anti-androgen addition
• Casodex
• Flutamide
• Nilutamide
• Anti-androgen withdrawal
• Ketoconazole
• 17,20-lyase inhibitors
• Estrogen
• Corticosteroids

Small and Vogelzang, JCO, 1997
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Ketoconazole

• Inhibits cytochrome P-450 enzymes
• Blocks testicular and adrenal androgenesis
• 200 - 400 mg TID
• 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

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Abiraterone/TAK-700
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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

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Castrate Resistant Disease Non-Hormonal
Treatment Options

• Good prognosis (asymptomatic, low volume)
• Standard Taxotere chemotherapy
• Antiandrogens, ketoconazole
• Immunotherapy (Provenge?, sipuleucel-T)
• Investigational therapy
• Poor prognosis
• Standard Taxotere chemotherapy
• Investigational chemotherapy combinations

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WHAT ABOUT TAXOTERE?

• 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

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Sipuleucel-T Autologous APCs Cultured with
Antigen Fusion Protein
APC takes up the antigen
Recombinant Prostatic Acid Phosphatase (PAP)
fusion antigen combines with resting antigen
presenting cell (APC)
Fully activated, the APC is now sipuleucel-T
Antigen is processed and presented on surface of
the APC
Inactive T-cell
INFUSE PATIENT
Active T-cell
T-cells proliferate and attack cancer cells
sipuleucel-T activates T-cells in the body
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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
Day 2-3 sipuleucel-T is manufactured
Day 3-4 Patient is infused
Apheresis Center
Central Processing
Doctors Office
COMPLETE COURSE OF THERAPY Weeks 0, 2, 4
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Randomized Phase 3 IMPACT Trial (IMmunotherapy
Prostate AdenoCarcinoma Treatment)
P R O G R E S S I O N
SURVIVAL
Sipuleucel-T Q 2 weeks x 3
Treated at Physician Discretion
Asymptomatic or Minimally Symptomatic Metastatic
Castration Resistant Prostate Cancer (N512)
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Treated at Physician Discretion and/or Salvage
Protocol

Placebo Q 2 weeks x 3
Primary Endpoint Overall Survival Secondary
Endpoint Objective Disease Progression
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IMPACT Overall SurvivalFinal 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
Preferred Term Sipuleucel-T N 338 Placebo N 168
Chills 54.1 12.5
Pyrexia 29.3 13.7
Headache 16.0 4.8
Influenza-Like Illness 9.8 3.6
Myalgia 9.8 4.8
Hypertension 7.4 3.0
Hyperhidrosis 5.3 0.6
Groin Pain 5.0 2.4
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

• Why no effect on prostate cancer progression?
• Ability to measure disease progression limited
• Effect on tumor growth takes time
• Minimal effect on PSA or symptoms
• Cost
• 93,000 not include all apheresis and infusion
  costs
• Logistics
• Limited apheresis capacity
• Limited processing capacity

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IS THERE ANYTHING AFTER TAXOTERE?

• Cabazitaxel (Jevtana)
• 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

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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
• 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

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MANAGEMENT OF ADVANCED PROSTATE CANCER

• Daniel Shevrin, MD
• Division Hematology/Oncology
• Northshore University Healthsystem
• Pritzker School of Medicine
• University of Chicago