Expert Video Viewpoints on Castration-Resistant Prostate Cancer: Care Across the Continuum

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and readers should verify the prescribing information and all data before treating
patients or employing any therapeutic products described in this educational activity.

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DISCLAIMER
Participants have an implied responsibility to use the newly acquired information
to enhance patient outcomes and their own professional development. The
information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis
or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patients’ conditions and possible
contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.

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This activity may contain discussion of published and/or investigational uses of
agents that are not indicated by the FDA. JHU and IMER do not recommend the
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The opinions and recommendations expressed by faculty and other experts
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University School of Medicine name implies review of educational format design
and approach. Please review the complete prescribing information of specific
drugs or combination of drugs, including indications, contraindications, warnings,
and adverse effects before administering pharmacologic therapy to patients.

Disclosure of Conflicts of Interest
Emmanuel S. Antonarakis, MD, reported a financial
interest/relationship or affiliation in the form of: Consultant: sanofi-
aventis
Leonard G. Gomella, MD, FACS, reported a financial
interest/relationship or affiliation in the form of: Consultant: Astellas
Pharma US, Inc. , Centocor Ortho Biotech Services, LLC, Dendreon
Corporation, Ferring Pharmaceuticals, Inc.; Grant/Research Funding:
Centocor Ortho Biotech Services, LLC; Data/Safety Monitoring Board:
sanofi-aventis U.S.
A. Oliver Sartor, MD, reported a financial interest/relationship or
affiliation in the form of: Advisory Board: Algeta ASA, Bristol-Myers
Squibb Company, Centocor Ortho Biotech Services, LLC, Dendreon
Corporation, Medivation, Inc., sanofi-aventis U.S., Takeda
Pharmaceutical Company; Grant/Research Funding: AstraZeneca
Pharmaceuticals LP, Centocor Ortho Biotech Services, sanofi-aventis
U.S., Takeda Pharmaceutical Company, Algeta ASA

Learning Objectives
L
Upon completion of this activity, participants
should demonstrate the ability to:
 Identify characteristics of a patient with CRPC and the
implications those factors have on treatment options
 Outline the appropriate treatment choices for patients
with non-metastatic, metastatic, asymptomatic, and
symptomatic disease based upon treatment guidelines
 Define the optimal initiation of treatment and
management of a patient who progresses
 Identify future treatments for patients with CRPC and
their potential effect on treatment decisions
 Review novel and emerging bone targeted therapies for
use in patients with CRPC

Expert Video Viewpoints on
Castration-Resistant Prostate Cancer:
Care Across the Continuum

Section I:

Identification and Initial
Treatment of CRPC

CRPC = castration-resistant prostate cancer.

Testing and Monitoring
for CRPC
 How do you identify patients with CRPC?

Prostate Cancer Clinical States
Non-metastatic,
Non-
Hormone-responsive
>200,000 60,000 Prostate cancer
metastatic
CRPC
Clinically Biochemically
Localized Relapsed
Prostate cancer Prostate cancer >30,000
Prostatectomy Salvage Metastatic,
Radiation ± ADT Radiation Metastatic Chemo-refractory
Brachytherapy
Hormone-responsive
CRPC CRPC
Primary ADT Prostate cancer
Active Surveillance

Prostate cancer-
specific death
Death from co-morbidities

10 - 15 years +

ADT = androgen deprivation therapy.
Scher et al, 2008; Jemal et al, 2010.

CRPC
 Almost all patients with prostate cancer treated with ADT
eventually experience progression in the setting of castrate
serum testosterone levels (< 50 ng/dL)
– Rising PSA, new symptoms, or radiographic findings

 Several “secondary” hormonal therapies are used in this
setting
– Anti-androgens (eg, bicalutamide, nilutamide, flutamide)
– Ketoconazole
– Estrogens (eg, DES, megestrol)
– Steroids (eg, prednisone, dexamethasone)

PSA = prostate specific antigen; DES = diethylstilbestrol.
Gelmann, 2002; Hussain et al, 2006.

CRPC: An Evolving Paradigm
 AR signaling is a key factor in prostate cancer growth
despite castrate serum testosterone (< 50 ng/dL)
– Promoted by a number of different factors
• AR overexpression/amplification
• AR mutations
• Increased AR ligand expression
• AR coactivators
• Ligand-independent AR activation
 Persistent AR signaling leads to tumor growth and
proliferation

AR = androgen receptor.
Gelmann, 2002; Debes et al, 2004.

Initial Treatment of CRPC
 Non-metastatic CRPC
– Treatment options
– How do we manage?
 What
treatment choices do patients with
CRPC have?
– Asymptomatic/minimally symptomatic

4 New FDA Approved Drugs
 Sipuleucel-T (4/29/10)
– Asymptomatic or minimally symptomatic mCRPC
 Cabazitaxel (6/17/10)
– mCRPC, after failure of a docetaxel-containing regimen
 Denosumab (11/18/10)
– Prophylaxis against SREs for bone mCRPC
 Abiraterone (4/28/11)
– mCRPC, after receipt of docetaxel-containing chemotherapy

mCRPC = metastatic CRPC; SREs = skeletal-related events.
Provenge® prescribing information, 2011; Jevtana® prescribing information, 2011;
Xgeva® prescribing information, 2010; Zytiga® prescribing information, 2011.

New Therapies: Where Do They Fit In?
Non-metastatic,
Non-
Hormone-responsive
metastatic
Prostate cancer
CRPC
Clinically Biochemically
Localized Relapsed
Prostate cancer Prostate cancer

Prostatectomy Salvage Metastatic,
Radiation ± ADT Radiation Metastatic Chemo-refractory
Brachytherapy
Hormone-responsive
CRPC CRPC
Primary ADT Prostate cancer
Active Surveillance

Observation  Androgen Deprivation Therapy (ADT)  Secondary hormonal therapies

Zoledronic Acid or Denosumab

Abiraterone,
Docetaxel Cabazitaxel,
Mitoxantrone
Sipuleucel-T

NCCN, 2011.

Sipuleucel-T
 Autologous APC vaccine
 Leukapheresis product collected
 APCs primed with GM-CSF–PAP fusion protein
 Reinfused back into patient
 Mature APCs present PAP peptide to CD8 T cells
 T cells initiate lytic antitumor response

APCs = antigen-presenting cells; GM-CSF = granulocyte-macrophage/colony stimulating factor; PAP = prostatic acid phosphatase.
Drake, 2010; Higano et al, 2010.

Sipuleucel-T: Phase III IMPACT Trial
P
R
Treated at
Sipuleucel-T O Physician’s
S
Q 2 weeks x 3
G Discretion U
Asymptomatic R R
or minimally
2:1 E Cross-over V
symptomatic
mCRPC S I
(N=512) S V
Treated at
Placebo I Physician’s
A
Q 2 weeks x 3
O Discretion L
N

Primary endpoint: Overall survival
Secondary endpoint: Progression-free survival

Kantoff, Higano, et al, 2010.

IMPACT Trial: Overall Survival
100
HR = 0.78 [95% CI 0.61 - 0.98]
P = 0.03 (Cox model)
75
Median Survival Benefit = 4.1 mo
Percent Survival

50
Sipuleucel-T (n = 341)
Median survival: 25.8 mo

25 BUT, no difference in
Placebo (n = 171) PFS (median 14.6 vs
Median survival: 21.7 mo 14.4 wk compared to
placebo; P = 0.648)
0
0 6 12 18 24 30 36 42 48 54 60 66

Survival (Months)
FDA-Approved in April 2010

Kantoff, Schuetz, et al, 2010.

Sipuleucel-T: Adverse Events
 All grades
– Chills (53%)
– Fever (31%)
– Back pain (30%)
– Headache (18%)
– Flu-like illness (10%)

Provenge® prescribing information, 2011.

Treatments Post Sipuleucel-T
Progression
OS Following DP

OS = overall survival; DP = disease progression.
Gomella et al, 2011.

 What
treatment choices do patients with
CRPC have?
– Symptomatic (docetaxel is not label-restricted to
symptomatic patients)

Docetaxel for mCRPC
 The standard of care for mCRPC changed from
mitoxantrone to docetaxel based on data from 2
randomized phase III studies
– SWOG 9916: Docetaxel/estramustine improved
median survival vs. mitoxantrone/prednisone
– TAX-327: Docetaxel/prednisone improved survival as
well as pain responses, PSA responses, and QOL vs.
mitoxantrone/prednisone

SWOG = Southwest Oncology Group; QOL = quality of life.
Petrylak et al, 2004; Tannock et al, 2004.

5 on; 1 off x 6 cycles
N = 1006
Docetaxel 75 mg/m2

m
R
o
d
n
e
a
z
Prednisone 10 mg q day

i
Docetaxel for mCRPC (cont.)Q 21 days up to 10 cycles

Mitoxantrone 12 mg/m2
SWOG 9916 Prednisone 5 mg bid
Q 21 days

N = 770 Docetaxel 60 mg/m2 d 2
Estramustine 280 mg d1-5
Dexamethasone 20 mg, tid d 1 & 2
m
R
o
d
n
e
a
z
i

Mitoxantrone 12 mg/m2
Q 21 days up to 10 cycles
TAX 327 Docetaxel 30 mg/m2/wk
5 on; 1 off x 6 cycles
N = 1006
Docetaxel 75 mg/m2
m
R
o
d
n
e
a
z

i

Q 21 days up to 10 cycles

Petrylak et al, 2004; Tannock et al, 2004. 2

Docetaxel for mCRPC (cont.)
SWOG 9916 TAX-327

HR: 0.83, P=0.03

Petrylak et al, 2004; Tannock et al, 2004.

Docetaxel: The Pivot Point
 Docetaxel became a pivot point for the
treatment of patients and the design of
clinical trials
– Before docetaxel
– With docetaxel
– After docetaxel

Docetaxel Plus Phase III Studies
 Docetaxel +/- VEGF Trap (VENICE)
 Docetaxel +/- lenalidomide (MAINSAIL)
 Docetaxel +/- custirsen (SYNERGY)
 Docetaxel +/- zibotentan (ENTHUSE)
 Docetaxel +/- dasatinib (READY)
 Others

VEGF = vascular endothelial growth factor.

 What are the consensus-based treatment
guidelines for mCRPC?

NCCN Guidelines for
Systemic Therapy
 Negative for metastases
– Clinical trial (preferred)
– Observation
– Antiandrogen
– Antiandrogen withdrawal
– Ketoconazole
– Steroids
– DES or other estrogen

NCCN = National Comprehensive Cancer Network.
NCCN, 2011.

NCCN Guidelines for
Systemic Therapy (cont.)
 Positive for metastases
– Symptomatic, visceral disease
• Docetaxel (category 1)
• Mitoxantrone
• Abiraterone acetate (category 2B)
• Palliative RT or radionucleide for symptomatic bone
metastases
• Clinical trial

RT = radiotherapy.
NCCN, 2011.

NCCN Guidelines for
Systemic Therapy (cont.)
 Positive for metastases
– Asymptomatic
• Sipuleucel-T (category 1)
• Secondary hormone therapy
– Antiandrogen
– Antiandrogen withdrawal
– Ketoconazole or abiraterone acetate (category 2B)
– Steroids
– DES or other estrogen
• Clinical trial

NCCN, 2011.

 Discussion:
The optimal initiation of
chemotherapy for patients with mCRPC

Key Takeaways
 Active surveillance involves actively monitoring course of
disease with the expectation to intervene with curative
intent if the cancer progresses
 There is no standard of care for the treatment of non-
mCRPC, but reasonable options include observation,
secondary hormones, ketoconazole
 Sipuleucel-T is indicated for men with mCRPC and
no/minimal symptoms
 Docetaxel chemotherapy is the first-line standard for
symptomatic mCRPC; FDA label should be adhered to

Section II:

mCRPC Progression

Identifying and Treating
CRPC Progression
 What parameters define CRPC progression?

CRPC Progression
 Parameters that define CRPC progression:
– Two consecutive rises in PSA
– Progressive disease in measurable (soft tissue,
visceral) radiographic lesions defined by RECIST
– Two or more new bone lesions on 99mTc-bone scan

… in the setting of persistent castrate levels of serum
testosterone (<50 ng/dl)

Scher et al, 2008.

CRPC Progression(cont.)
 What are the treatment options for patients
with mCRPC who progress after docetaxel?
– Cabazitaxel
– Abiraterone

Cabazitaxel: Next Generation Taxane

 Novel semi-synthetic taxane that stabilizes
microtubules and may overcome taxane resistance
 Preclinical data show activity against taxane-
sensitive and -resistant cell lines and tumor models
 In phase I trials, antitumor activity seen in mCRPC,
including in men with docetaxel-refractory disease
 DLT was neutropenia

DLT = dose limiting toxicity.
Attard et al, 2006; Pivot et al, 2008; Mita et al, 2009.

TROPIC: Cabazitaxel Phase III Trial
Patients with mCRPC and progression during/after
treatment with a docetaxel-containing regimen
(N=755) – 146 sites in 26 countries

Stratification factors
ECOG PS (0, 1 vs. 2) and measurable vs. non-measurable disease

Cabazitaxel 25 mg/m² q 3 wk + Mitoxantrone 12 mg/m² q 3 wk +
prednisone 10mg QD for 10 cycles prednisone 10mg QD for 10 cycles
(n=378) (n=377)

Primary endpoint: OS
Secondary endpoints: PFS, RR, safety

PFS = progression-free survival; RR = response rate; ECOG = Eastern Cooperative Oncology Group;
PS = performance status.
De Bono et al, 2010.

TROPIC Primary End Point: Survival
100

MP CBZP
Median OS (months) 12.7 15.1
80
HR 0.70
Proportion Surviving (%)

95% CI 0.59–0.83
p Value < .0001
60

Cabazitaxel
40

20 Mitoxantrone

0
0 months 6 months 12 months 18 months 24 months 30 months

MP = mitoxantrone, prednisone; CBZP = carbazitxel;
FDA Approved in June 2010
HR = hazard ratio; CI = confidence interval.

TROPIC: Secondary End Points

TTP = time to progression; NR = no response.

TROPIC: Adverse Events


Cabazitaxel: Prescribing Information
 Dose: 25 mg/m2 IV (over 1 hr) q21days
 Combine with prednisone 5 mg po bid
 Premeds
– Diphenhydramine 25, dexamethasone 10, ranitidine 50

 Caution in liver impairment (hepatic excretion)
 Consider primary GCSF prophylaxis for men ≥ 65 yrs old
– Patients ≥ 65 years of age are more likely to experience
neutropenia and febrile neutropenia
 Avoid concurrent CYP-3A4 inhibitors or inducers
– Azole antifungals, rifampin, clarithromycin, phenytoin
IV = intravenous; po bid = by mouth, twice daily; GCSF = granulocyte colony stimulating factor.
Jevtana® prescribing information, 2011.

Abiraterone Acetate: CYP17 Inhibitor

Abiraterone

Attard et al, 2008.

CYP17 Inhibition:
Steroid Hormone Suppression
6

2
5 Testosterone Androstenedione
4
gd

Lower limit of
n/
l

3
sensitivity
1

m
2

o
n
/
l
1

0
0.07
10 20 60 70 At
Start of treatment
Days progression At progression
1 Start of treatment 28 Days 56

12.5
12.5

DHEA Estradiol
10.0 10.0

7.5 7.5
m
o
m

ρ/
l
o
n
/
l

5.0 5.0

2.5
2.5

0
0 10
Start of 20 30 40 50 60
28 Days 56 At progression
treatment Days post treatment

DHEA = dehydroepiandrosterone.
Attard et al, 2008.

COU-301 Phase III Trial (Post-Chemo)
Patients with mCRPC,
previously treated with Abiraterone 1000 mg QD
docetaxel, keto-naïve Prednisone 5 mg BID

n = 797
Randomization 2:1 Placebo-Controlled, Double-Blind

Placebo QD
Prednisone 5 mg BID
n = 398

Primary Objective: 25% overall survival improvement
Sample size: 1195


COU-301: Results

FDA Approved in April 2011

NA = not applicable.

COU-301: Updated Survival

Scher et al, 2011.

Abiraterone: Adverse Events
 Secondary mineralocorticoid excess – all grades
– Edema (26.7%)
– Hypokalemia (28%)
– HTN (9%)
 LFT elevations (10%)
 Cardiac abnormalities (13%)
– Tachycardia
– Atrial fibrillation

HTN = hypertension; LFT = liver function test.
De Bono et al, 2011; Zytiga® prescribing information, 2011.

Abiraterone:
Prescribing Information
 Dose = 1,000 mg po daily (250 mg tabs x 4)
 Combine with prednisone 5 mg po bid
 Take on an empty stomach
 Dose reduction in hepatic impairment: 250 mg
 Caution if EF < 50% or heart failure (NYHA
III/IV)
 Avoid co-administration with CYP 2D6
substrates
– SSRIs, beta-blockers, ondansetron, metoclopramide
EF = ejection fraction; NYHA = New York Heart Association; SSRIs = selective serotonin reuptake inhibitors.
Zytiga® prescribing information, 2011.

CRPC Progression (cont.)
 What options are available for prevention of
skeletal complications in men with mCRPC?

IV Bisphosphonates
(eg, Zoledronate)
 Treatment of osteoporosis (accelerated by ADT use)
 Treatment of hypercalcemia
 Prevention of fractures and SREs
 Pain relief from bone metastases
 Improved QOL
 Antitumor effects (?)

Doggrell, 2009; Winter et al, 2009.

Zoledronate: Prevention of SREs
Placebo
100
P = .001
 SREs
– Radiation to bone
– Pathologic fracture
50
Zoledronic acid – Spinal cord compression
– Surgery to bone
E
P
0
1
n
v
a
e
s
i
/
t

– Change in cancer therapy
0
0 12 24
Months

Saad et al, 2002.

Denosumab: RANKL MoAb

RANKL = receptor activator of nuclear factor kappa-B ligand; MoAb = monoclonal antibody.
Roodman, 2007.

Denosumab: SRE Prevention Trial
• Phase III trial of denosumab vs zoledronic acid for
prevention of SREs
R
A
• Patients with Denosumab 120 mg SQ q4w
N
bone-metastatic D
CRPC O N=1904
M
• No prior
I
bisphosphonates Zoledronic acid 4 mg IV q4w
Z
E

• Primary endpoint: prevention of 1st SRE (non-inferiority)
• Secondary endpoints: superiority analysis, safety

Fizazi, Carducci, et al, 2011.

Denosumab: Prevention of SREs
HR 0.82 (95% CI: 0.71, 0.95)
1.00 Risk
P=0.0002 (Noninferiority)
Reduction
P=0.008 (Superiority)

0.75 18%

0.50

Median (mo)
0.25 Denosumab 20.7
Zoledronic acid 17.1
W
M
R
E
S
P
u
h
e
n
p
o
r
f
t
i

0
0 3 6 9 12 15 18 21 24 27 (Mo)
Zoledronic acid 951 733 544 407 299 207 140 93 64 47
Denosumab 950 758 582 472 361 259 168 115 70 39

FDA-Approved in Nov 2010

Fizazi, Carducci, et al, 2011.

Denosumab: Adverse Events
 Hypocalcemia (13%)
– Occurs in first 6 months
– Grade 3 (5%)
 Acute phase reactions (8%)
 ONJ (2%)
 Fatigue, nausea, decreased appetite,
constipation, hypophosphatemia, anemia,
back pain, bone pain
ONJ = osteonecrosis of the jaw.
Xgeva® prescribing information, 2010; Fizazi, Carducci, et al, 2011.

Denosumab:
Prescribing Information
 Dose for SRE prophylaxis: 120 mg SQ q4wks
 Should correct hypocalcemia prior to initiation
 Consider using concurrent calcium/vitamin D
 No dose adjustments for renal impairment
– CrCl < 30 mL/min may increase risk of hypocalcemia
 Perform oral exam; no invasive dental
procedures

SQ = subcutaneous; CrCl = creatinine clearance.
Xgeva® prescribing information, 2010.

Key Takeaways
 Progression of CRPC may be defined by PSA criteria,
radiographic criteria, or clinical criteria
 Cabazitaxel is a novel taxane approved for mCRPC after
failure of a docetaxel-containing regimen
 Abiraterone is a novel androgen synthesis inhibitor
approved for mCRPC after receipt of prior docetaxel
 Denosumab is a novel osteoclast-inhibiting agent that is
superior to zoledronate in preventing SREs in men with
castration-resistant bone metastases

Section III:

Emerging Treatment Options
for mCRPC Patients

Emerging Therapies for CRPC

CTLA-4 = cytotoxic T-lymphocyte associated antigen-4; TKI = tyrosine kinase inhibitor; MET = MNNG HOS transforming gene;
VEGFR = vascular endothelial growth factor receptor..

Emerging Treatment Options for
mCRPC Patients
 What anti-androgens are being studied?

Abiraterone: COU-302 (Pre-Chemo)
Patients with mCRPC, Accrual Completed 4/2010
docetaxel-naïve,
ketoconazole-naïve, Abiraterone 1000 mg QD
asymptomatic or mildly
Prednisone 5 mg BID
symptomatic
n = 500
Randomization 1:1 Placebo-Controlled, Double-Blind

Placebo QD
Prednisone 5 mg BID
n = 500
Primary Objective: 20% OS improvement
Sample size: 1000 (fully accrued 4/2010 – data maturing)

US NIH, 2011a.

Abiraterone: Phase I/II Studies

RECIST = Response Evaluation Criteria in Solid Tumors.
Ryan et al, 2010; Attard et al, 2009; Reid et al, 2010; Danila et al, 2010.

Phase II Data: PSA Responses
PRE–DOCETAXEL PSA Response after 12 weeks

Attard G, et al. JCO 2009; 27: 3742-8.

POST–DOCETAXEL PSA Response after 12 weeks

Reid A, et al. JCO 2010; 28: 1489-95.

Attard et al, 2009; Reid et al, 2010.

MDV3100: Novel AR Antagonist
 Second generation AR antagonist
 Binds AR more potently than bicalutamide
 MDV3100 is not a partial agonist of AR
 Inhibits translocation of AR into nucleus and decreases
AR binding to DNA
 Oral agent: 160 mg daily (seizures at higher doses)
 Ongoing randomized phase III trials of MDV3100 vs.
placebo (post-chemo/pre-chemo)

DNA = deoxyribonucleic acid.
Tran et al, 2009.

MDV3100: PSA Declines (Phase I/II)

Pre-Chemotherapy (n=65) Post-Chemotherapy (n=75).

MDV-3100 induced >50% PSA declines in 56% of mCRPC patients

Scher et al, 2010.

MDV3100: Radiologic Responses

PR = partial response; SD = stable disease; FDG-PET = fludeoxyglucose-positron emission tomography.
Scher et al, 2010.

AFFIRM Phase III Trial (Post-Chemo)
N = 1170 Accrual complete
R
A MDV-3100 160 mg QD
Men with N 2
docetaxel- D
pretreated O Placebo-Controlled, Double-Blind
mCRPC M
(keto-naïve)
I 1 Placebo QD
Z
E

(median OS 12 mo → 15 mo)

US NIH, 2011b.

PREVAIL Phase III Trial (Pre-Chemo)

N = 1680 Ongoing
R
A MDV-3100 160 mg QD
N 1
Men with D
chemo-naïve
O Placebo-Controlled, Double-Blind
mCRPC
M
I 1 Placebo QD
Z
E

Co-Primary Endpoints: OS + PFS
Secondary Endpoints: SREs, time-to-chemo-initiation

US NIH, 2011c.

Other Novel Hormonal Agents
 TAK-700 (CYP17 lyase inhibitor) – Orteronel
– Pre-chemo/post-chemo phase III studies ongoing
 TOK-001 (CYP17 inhibitor and AR antagonist)
– Phase II study underway
 ARN-509 (AR antagonist, related to MDV3100)
– Phase I study underway

for mCRPC Patients
 What immunotherapies are being studied?

Sipuleucel-T:
Phase III Study in Hormone-Naïve mPCa

N = 1684 Pending Activation
R
A Androgen deprivation therapy (ADT)
N 1
Men with → Sipuleucel-T
hormone- D
naïve O Open Label study
metastatic M
prostate I 1
cancer Z Androgen deprivation therapy (ADT) alone
E

Primary Endpoint: Overall survival
Secondary Endpoints: Time to castration-resistance
Chemotherapy-free survival

Fizazi, Powles, et al, 2011.

Ipilimumab: Anti-CTLA4
 Human MoAb that binds to and blocks activity of
CTLA-4 on T cells, modulating immune
response
 Ipilimumab has shown significant activity against
metastatic melanoma (with or without vaccine),
with a survival benefit demonstrated in
pretreated patients and in the first-line setting

Hodi et al, 2010.

CTLA4 Blockade: Ipilimumab

Drake, 2010.

Ipilimumab in CRPC
 Phase I trials
– Ipilimumab combined with GM-CSF (N = 24)
– 1 patient had PR
– 3 patients had PSA declines > 50% at highest dose
 Phase II trials
– Ipilimumab combined with RT (N = 26)
– 6 patients had > 50% PSA declines
– 1 patient had PR

Fong et al, 2009; Beer et al, 2008.

Ipilimumab: Post-Chemo Phase III Trial

N = 800 Ongoing
R
A XRT to bone lesion →
Men with N 2
Ipilimumab IV (induction, maintenance)
docetaxel- D
pretreated O Placebo-Controlled, Double-Blind
CRPC with M
bone mets
I 1 XRT to bone lesion →
Z Placebo IV (induction, maintenance)
E

Primary Endpoint: Overall Survival

US NIH, 2011d.

Ipilimumab: Pre-Chemo Phase III Trial

N = 600 Ongoing
R
A
Men with N 1 Ipilimumab IV (induction, maintenance)
minimally/
D
asymptomatic
docetaxel- O Placebo-Controlled, Double-Blind
naïve M
mCRPC I 1
Z Placebo IV (induction, maintenance)
E

Primary Objective: Overall Survival

US NIH, 2011e.

ProstVac-VF
 Vaccinia and fowlpox-based vectors expressing PSA
antigen and 3 costimulatory molecules (TriCom)
designed to stimulate immune responses against
prostate cancer
 TriCom
– B7.1 (CD80)
– ICAM-1 (CD54)
– LFA-3 (CD58)
 Randomized phase II trial in mCRPC demonstrated no
significant difference in PFS with ProstVac-VF vs.
control, but significantly improved OS at 3 years
TriCom = triad of costimulatory molecules.
Drake, 2010; Kantoff, Schuetz, et al, 2010.

ProstVac-VF (cont.)

Drake, 2010.

ProstVac-VF: Phase II Trial

P
ProstVac-VF R Treated at
TriCom + O Physician’s
S
GM-CSF
G Discretion U
Asymptomatic (n = 84) R
or minimally R
E Cross-over V
symptomatic 2:1
mCRPC S I
(N=125) S V
Treated at
Empty Vector
I Physician’s
A
+ Placebo
O Discretion L
(n = 41)
N

Primary endpoint: PFS
Secondary endpoint: OS


Phase II Trial: Treatment Schema


Phase II Trial: Results

PFS OS

P = 0.6 P = 0.006


ProstVac-VF: ECOG 1809 Trial
N = 144 Ongoing
R
A ProstVac-VF sq Days 1, 15, 29, 43, 57
N 2
Men with → Docetaxel / Prednisone
docetaxel- D
naïve O
mCRPC M
I 1
Z Docetaxel / Prednisone (up-front)
E

(median OS 21 mo → 36 mo)

US NIH, 2011f.

ProstVac-VF: PROSPECT Trial
Pending Activation
N = 1200

R ProstVac-VF sq Wks 1, 3, 5, 9, 13, 17, 21

Men with A GM-CSF sq Wks 1, 3, 5, 9, 13, 17, 21
minimally/ N
asymptomatic D
docetaxel- O ProstVac-VF sq Wks 1, 3, 5, 9, 13, 17, 21
naïve M
mCRPC I
Z
Placebo sq Wks 1, 3, 5, 9, 13, 17, 21
E


US NIH, 2011g.

for mCRPC Patients
 What are the bone-targeted approaches?

Bone-Seeking
Radiopharmaceuticals
 Strontium-89
– Beta(b)-emitter, t½ = 51 days
– FDA approved (1993) for pain palliation of bone metastases
 Samarium-153
– Beta(b)-emitter, t½ = 46 hours
– FDA approved (1998) for pain palliation of bone metastases
 Radium-223 (investigational)
– Alpha(a)-emitter, t½ = 11 days
– Higher energy transfer with shorter range (< 100 mm)

Lewington et al, 1991; Serafini et al, 1998; Nilsson et al, 2007.

Radium-223: Phase III ALASYMPCA Trial

N = 900

R
A
2 Radium-223 IV q4wk (x6)
Men with N
symptomatic D
mCRPC and O Placebo-Controlled, Double-Blind
bone mets M
I 1 Placebo IV q4wk (x6)
Z
E


US NIH, 2011h.

Radium-223: Press Release (6/5/11)

 Pre-planned interim analysis conducted
 OS longer with Radium-223 than with placebo
– 14.0 months vs. 11.2 months (p = .002)
 IDMC closed the study early
 Men now may cross over from placebo to
Radium-223

Algeta Press Release, Oslo, Norway, 6/5/2011.

for mCRPC Patients
 What other novel agents are being studied?

Dasatinib in CRPC
 Phase II trial, 38 patients with metastatic CRPC
treated with one prior chem regimen
– Median duration of therapy – 55 days
– 46% had dose reduction or treatment delay
– One patient had stable disease for > 6 mos
– Tolerability was improved by reduction in starting
dose to 100 mg/d
 Ongoing phase III trial, dasatinib + docetaxel/
prednisone versus placebo +
docetaxel/prednisone

US NIH, 2011i; Twardowski et al, 2011.

Cabozantinib (XL184)
 Cabozantinib: TKI that blocks MET and VEGFR2
– MET and its ligand HGF drive invasion and metastasis
– MET and VEGFR2 synergize to promote angiogenesis
– Bone metastases have high levels of MET expression
• HGF and VEGF direct crosstalk between tumor cells, osteoblasts,
and osteoclasts
 In prostate cancer
– Preclinically, androgen ablation ↑ MET expression
– MET ↑ with progression and metastasis in bone and LNs

HGF = hepatocyte growth factor; LNs = lymph nodes.
Hussain et al, 2011.

SLD % Change in Prostate Cancer Subjects

Cabozantinib
% Change from Baseline

70

50
RESPONSES IN SOFT TISSUE LESIONS
30 74% of patients showed tumor regressions
10 *
*

*
-10 *
**
**
*
-30 Docetaxel-Naïve **

-50 Docetaxel-Pretreated *

-70 * Prior Abiraterone or MDV3100

100 100
80 SERUM BAP 80 PLASMA CTx
60
40
(Formation marker) 60
40
(Resorption marker)
20 20
0 0

-20 -20

-40 -40

-60 -60
-80
m
%

-80
Bisphosphonate-Treated
B
C
o
g
n
h
s
e
a
r
f
i
l

-100 -100
Bisphosphonate-Naïve

BAP = bone-specific alkaline phosphatase; CTX = carboxy-terminal cross-linking telopeptide of type I collagen.

Cabozantinib (cont.)
Baseline Week 12 Baseline Week 12

Docetaxel - naïve Docetaxel - pretreated
Bone Scan Improvements Seen in 76% of Patients (bone pain improvement in 67%)


Key Takeaways
 Several novel androgen synthesis inhibitors and
next generation AR antagonists are in
development
 Ipilimumab,ProstVac-VF, Zibotentan, dasatinib,
and lenalidomide have entered late stage clinical
trials
 Radium-223 is the fifth drug to show OS
improvement in men with mCRPC
 Cabozantinib (XL184) is a new TKI with marked
effects on castration-resistant bone metastases

Section IV:

Putting Evidence Into Practice:
Expert Perspective on Case
Examples

Case Study: Part 1
 57-yr-old man – T3a PCa, Gleason 4+4 = 8,
PSA = 8.2 ng/mL
 Undergoes radical prostatectomy
 Develops PSA recurrence with PSADT = 6 months
 Started on leuprolide + bicalutamide, and responds for
18 months
 Then develops rising PSA, despite bicalutamide
withdrawal
 PSAs: 4.2 → 5.6 → 7.2 ng/mL
 Testosterone: 28 ng/dL
 Bone scan and CT scan: Negative for metastatic disease
PSADT = prostate-specific antigen doubling time; CT = computed tomography.
NCCN, 2011.

Case Study: Part 1
Discussion Questions
 Does this patient meet criteria for CRPC?
 How would you manage this patient?

Case Study: Part 2
 Same patient – non-mCRPC
 Enrolls in phase II study or oral TAK-700 (orteronel)
 Has a PSA response lasting 6 months
 Then PSA begins to rise: 4.6 → 7.5 → 11.2 ng/mL
 Testosterone: 2 ng/dL
 CT scan repeated: Remains normal
 Bone scan: New lesions left 5th rib and L1 vertebral
body
 He remains asymptomatic – no bone pain – ECOG 0

Case Study: Part 2
Discussion Question
 How would you manage this patient now?

Case Study: Part 3
 Same patient – asymptomatic mCRPC
 Patient receives 3 infusions of sipuleucel-T
 PSA rises after 3 months, and again after 6 months
 CT scan: Para aortic lymphadenopathy (up to 3.8 cm)
 Bone scan: 2 rib, 2 vertebral, and 1 pelvic bone lesion
 Patient reports new rib and back pain (intensity 3/10)
 ECOG PS 0

Case Study: Part 3
Discussion Question

Case Study: Part 4
 Same patient – symptomatic mCRPC
 He receives docetaxel q3wks and denosumab q4wks
 Obtains PSA response and objective radiologic response
 After 8 cycles, stops docetaxel due to grade 3 neuropathy
 4 months later, he has further PSA progression
 CT: New liver lesions (up to 4 cm) and lung lesions (8 mm)
 Bone lesions: Stable
 Has persistent grade 2 peripheral neuropathy
 ECOG PS 1

Case Study: Part 4
Discussion Question

Key Takeaways
 Different treatment strategies may be appropriate for
patients with different disease states
– Non mCRPC
– Asymptomatic mCRPC
– Symptomatic mCRPC
– Docetaxel pretreated CRPC
 Bone-targeting therapies should be considered for men
with castration-resistant bone metastases, and can be
given concurrently with anticancer therapies
 Palliative approaches (eg, RT, radiopharmaceuticals)
should also be considered for patients with bone pain

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