DISCLAIMERDISCLAIMERThis slide deck in its original and unaltered format is for educational purposes and iscurrent as of November 2011. All materials contained herein reflect the views of the

faculty, and not those of IMER, the CME provider, or the commercial supporter. Thesematerials may discuss therapeutic products that have not been approved by the US

Food and Drug Administration and off-label uses of approved products. Readersshould not rely on this information as a substitute for professional medical advice,

diagnosis, or treatment. The use of any information provided is solely at your own risk,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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DISCLAIMERDISCLAIMERParticipants 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.

DISCLOSURE OF UNLABELED USEDISCLOSURE OF UNLABELED USEThis 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 use of any agent outside of the labeled indications.

The opinions and recommendations expressed by faculty and other experts whose input is included in this activity are their own. Use of Johns Hopkins

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 InterestDisclosure 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 ObjectivesLearning ObjectivesUpon completion of this activity, participants Upon completion of this activity, participants

should demonstrate the ability to: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 Expert Video Viewpoints on Castration-Resistant Prostate Cancer: Castration-Resistant Prostate Cancer:

Care Across the ContinuumCare Across the Continuum

Section I: Section I:

Identification and Initial Identification and Initial Treatment of CRPCTreatment of CRPC

CRPC = castration-resistant prostate cancer.

Testing and MonitoringTesting and Monitoring for CRPC for CRPC

How do you identify patients with CRPC?

Prostate Cancer Clinical StatesProstate Cancer Clinical States

ClinicallyLocalized

Prostate cancer

BiochemicallyRelapsed

Prostate cancer

Non-metastatic,Hormone-responsive

Prostate cancer

Metastatic,Hormone-responsive

Prostate cancer

Non-metastatic

CRPC

MetastaticCRPC

ProstatectomyRadiation ± ADTBrachytherapyPrimary ADTActive Surveillance

Chemo-refractoryCRPC

Salvage Radiation

10 - 15 years +

Death from co-morbidities

Prostate cancer-specific death

>200,000 60,000

>30,000

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

CRPCCRPC 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 ParadigmCRPC: 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 CRPCInitial 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 Drugs4 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: New Therapies: Where Do They Fit In?Where Do They Fit In?

ClinicallyLocalized

Prostate cancer

BiochemicallyRelapsed

Prostate cancer

Non-metastatic,Hormone-responsive

Prostate cancer

Metastatic,Hormone-responsive

Prostate cancer

Non-metastatic

CRPC

MetastaticCRPC

ProstatectomyRadiation ± ADTBrachytherapyPrimary ADTActive Surveillance

Observation Androgen Deprivation Therapy (ADT) Secondary hormonal therapies

Docetaxel

Zoledronic Acid or Denosumab

Chemo-refractoryCRPC

Sipuleucel-T

Abiraterone, Cabazitaxel, Mitoxantrone

Salvage Radiation

NCCN, 2011.

Sipuleucel-TSipuleucel-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.

Drake, 2010.

Sipuleucel-T: Phase III IMPACT TrialSipuleucel-T: Phase III IMPACT Trial

Asymptomatic or minimally symptomatic

mCRPC(N=512)

Sipuleucel-T Q 2 weeks x 3

PlaceboQ 2 weeks x 3

2:1

PROGRESSION

SURVIVAL

Treated at Physician’s Discretion

Treated at Physician’s Discretion

Primary endpoint: Overall survivalSecondary endpoint: Progression-free survival

Cross-over

Kantoff, Higano, et al, 2010.

IMPACT Trial: Overall SurvivalIMPACT Trial: Overall Survival

Kantoff, Schuetz, et al, 2010.

BUT, no difference in PFS (median 14.6 vs 14.4 wk compared to placebo; P = 0.648)

HR = 0.78 [95% CI 0.61 - 0.98]P = 0.03 (Cox model)Median Survival Benefit = 4.1 mo

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

Placebo (n = 171)Median survival: 21.7 mo

FDA-Approved in April 2010

0 6 12 18 24 30 36 42 48 54 60 660

25

50

75

100

Per

cent

Sur

viva

l

Survival (Months)

Sipuleucel-T: Adverse EventsSipuleucel-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 Treatments Post Sipuleucel-T ProgressionProgression

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

OS Following DP

Initial Treatment of CRPCInitial Treatment of CRPC

What treatment choices do patients with CRPC have?

– Symptomatic (docetaxel is not label-restricted to symptomatic patients)

Docetaxel for mCRPCDocetaxel 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.

Docetaxel for mCRPC (cont.)Docetaxel for mCRPC (cont.)

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

Ra

nd

om

ize

Mitoxantrone 12 mg/m2

Prednisone 10 mg q dayQ 21 days up to 10 cycles

Docetaxel 75 mg/m2

Prednisone 10 mg q dayQ 21 days up to 10 cycles

Docetaxel 30 mg/m2/wkPrednisone 10 mg q day5 on; 1 off x 6 cycles

N = 1006

TAX 327

SWOG 9916

Ra

nd

om

ize

Mitoxantrone 12 mg/m2

Prednisone 5 mg bidQ 21 days

Docetaxel 60 mg/m2 d 2Estramustine 280 mg d1-5Dexamethasone 20 mg, tid d 1 & 2

N = 770

Ra

nd

om

ize

Mitoxantrone 12 mg/m2

Prednisone 10 mg q dayQ 21 days up to 10 cycles

Docetaxel 75 mg/m2

Prednisone 10 mg q dayQ 21 days up to 10 cycles

Docetaxel 30 mg/m2/wkPrednisone 10 mg q day5 on; 1 off x 6 cycles

N = 1006

TAX 327

SWOG 9916

Ra

nd

om

ize

Mitoxantrone 12 mg/m2

Prednisone 5 mg bidQ 21 days

Docetaxel 60 mg/m2 d 2Estramustine 280 mg d1-5Dexamethasone 20 mg, tid d 1 & 2

N = 770

Docetaxel for mCRPC (cont.)Docetaxel for mCRPC (cont.)

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

HR: 0.83, P=0.03

SWOG 9916 TAX-327

Docetaxel: The Pivot PointDocetaxel: 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 StudiesDocetaxel 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.

Initial Treatment of CRPCInitial Treatment of CRPC

What are the consensus-based treatment guidelines for mCRPC?

NCCN Guidelines forNCCN Guidelines forSystemic TherapySystemic 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 forNCCN Guidelines forSystemic Therapy (cont.)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 forNCCN Guidelines forSystemic Therapy (cont.)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.

Initial Treatment of CRPCInitial Treatment of CRPC

Discussion: The optimal initiation of chemotherapy for patients with mCRPC

Key TakeawaysKey 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: Section II:

mCRPC ProgressionmCRPC Progression

Identifying and TreatingIdentifying and TreatingCRPC ProgressionCRPC Progression

What parameters define CRPC progression?

CRPC ProgressionCRPC 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.

Identifying and TreatingIdentifying and TreatingCRPC Progression(cont.)CRPC Progression(cont.)

What are the treatment options for patients with mCRPC who progress after docetaxel?

– Cabazitaxel

– Abiraterone

Cabazitaxel: Next Generation TaxaneCabazitaxel: 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 TrialTROPIC: Cabazitaxel Phase III Trial

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

Primary endpoint: OSSecondary endpoints: PFS, RR, safety

Cabazitaxel 25 mg/m² q 3 wk +prednisone 10mg QD for 10 cycles

(n=378)

Mitoxantrone 12 mg/m² q 3 wk +prednisone 10mg QD for 10 cycles

(n=377)

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

Patients with mCRPC and progression during/after treatment with a docetaxel-containing regimen

(N=755) – 146 sites in 26 countries

Pro

por

tion

Sur

vivi

ng (

%) 80

60

40

20

0

100

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

15.112.7Median OS (months)

0.59–0.8395% CI< .0001p Value

0.70HR

CBZPMP

Cabazitaxel

Mitoxantrone

FDA Approved in June 2010

TROPIC Primary End Point: SurvivalTROPIC Primary End Point: Survival

MP = mitoxantrone, prednisone; CBZP = carbazitxel;HR = hazard ratio; CI = confidence interval.De Bono et al, 2010.

TROPIC: Secondary End PointsTROPIC: Secondary End Points

TTP = time to progression; NR = no response.De Bono et al, 2010.

TROPIC: Adverse EventsTROPIC: Adverse Events

De Bono et al, 2010.

Cabazitaxel: Cabazitaxel: Prescribing InformationPrescribing 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: Abiraterone Acetate: CYP17 InhibitorCYP17 Inhibitor

Attard et al, 2008.

Abiraterone

CYP17 Inhibition: CYP17 Inhibition: Steroid Hormone Suppression Steroid Hormone Suppression

DHEA = dehydroepiandrosterone.Attard et al, 2008.

1

60

Testosterone

0

1

2

3

4

5

6

ng

/dl

10 20Start of treatment At

progression

70

Days

Lower limit of sensitivity

nm

ol/l

DHEA

Start of treatment

28 56 At progressionDays

0

2.5

5.0

7.5

10.0

12.5

2

1

0.07

28 56 At progressionDaysStart of treatment

Androstenedione

nm

ol/l

Estradiol

10 20 30 40 50 60Days post treatment

2.5

5.0

7.5

10.0

12.5

0

ρm

ol/l

COU-301 Phase III Trial (Post-Chemo)COU-301 Phase III Trial (Post-Chemo)

Primary Objective: 25% overall survival improvement

Sample size: 1195

Randomization 2:1

Abiraterone 1000 mg QDPrednisone 5 mg BID

Placebo QDPrednisone 5 mg BID

n = 797

n = 398

Patients with mCRPC, previously treated with docetaxel, keto-naïve

Placebo-Controlled, Double-Blind

De Bono et al, 2011.

COU-301: ResultsCOU-301: Results

NA = not applicable.De Bono et al, 2011.

FDA Approved in April 2011

COU-301: Updated SurvivalCOU-301: Updated Survival

Scher et al, 2011.

Abiraterone: Adverse EventsAbiraterone: 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:Abiraterone:Prescribing InformationPrescribing 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.

Identifying and TreatingIdentifying and TreatingCRPC Progression (cont.)CRPC Progression (cont.)

What options are available for prevention of skeletal complications in men with mCRPC?

IV BisphosphonatesIV Bisphosphonates(eg, Zoledronate)(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 SREsZoledronate: Prevention of SREs

SREs

– Radiation to bone

– Pathologic fracture

– Spinal cord compression

– Surgery to bone

– Change in cancer therapy

Saad et al, 2002.

Months

P = .001

0

100

50

0 12 24

Zoledronic acid

Placebo

Even

ts/1

00

Pat

ien

ts

Denosumab: Denosumab: RANKL MoAbRANKL MoAb

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

Denosumab: SRE Prevention TrialDenosumab: SRE Prevention Trial

Fizazi, Carducci, et al, 2011.

• Phase III trial of denosumab vs zoledronic acid for prevention of SREs

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

• Patients with bone-metastatic CRPC

• No prior bisphosphonates

Denosumab 120 mg SQ q4w

Zoledronic acid 4 mg IV q4w

RANDOMIZE

N=1904

Denosumab: Denosumab: Prevention of SREsPrevention of SREs

Fizazi, Carducci, et al, 2011.

Zoledronic acid 951 733 544 407 299 207 140 93 64 47

Denosumab 950 758 582 472 361 259 168 115 70 39

0

1.00

Pro

port

ion o

f M

en W

ithout

SR

E

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

Median (mo)

DenosumabZoledronic acid

20.717.1

HR 0.82 (95% CI: 0.71, 0.95)P=0.0002 (Noninferiority)P=0.008 (Superiority)

(Mo)

18%

Risk Reduction

FDA-Approved in Nov 2010

Denosumab: Adverse EventsDenosumab: 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:Denosumab:Prescribing InformationPrescribing 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 TakeawaysKey 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: Section III:

Emerging Treatment Options Emerging Treatment Options for mCRPC Patientsfor mCRPC Patients

Emerging Therapies for CRPCEmerging 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 Emerging Treatment Options for mCRPC PatientsmCRPC Patients

What anti-androgens are being studied?

Abiraterone: COU-302 (Pre-Chemo)Abiraterone: COU-302 (Pre-Chemo)

US NIH, 2011a.

Primary Objective: 20% OS improvement

Sample size: 1000 (fully accrued 4/2010 – data maturing)

Randomization 1:1

Abiraterone 1000 mg QDPrednisone 5 mg BID

Placebo QDPrednisone 5 mg BID

n = 500

n = 500

Patients with mCRPC, docetaxel-naïve, ketoconazole-naïve,asymptomatic or mildly symptomatic

Placebo-Controlled, Double-Blind

Accrual Completed 4/2010

Abiraterone: Phase I/II StudiesAbiraterone: 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 ResponsesPhase II Data: PSA Responses

PRE–DOCETAXEL PSA Response after 12 weeks

POST–DOCETAXEL PSA Response after 12 weeks

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

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

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

MDV3100: Novel AR AntagonistMDV3100: 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)MDV3100: PSA Declines (Phase I/II)

Scher et al, 2010.

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

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

MDV3100: Radiologic ResponsesMDV3100: Radiologic Responses

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

AFFIRM Phase III Trial (Post-Chemo)AFFIRM Phase III Trial (Post-Chemo)

US NIH, 2011b.

MDV-3100 160 mg QD

Placebo QD

RANDOMIZE

N = 1170

Men with docetaxel-pretreated mCRPC (keto-naïve)

Placebo-Controlled, Double-Blind

2

1

Accrual complete

Primary Objective: 25% overall survival improvement(median OS 12 mo → 15 mo)

US NIH, 2011c.

PREVAIL Phase III Trial (Pre-Chemo)PREVAIL Phase III Trial (Pre-Chemo)

MDV-3100 160 mg QD

Placebo QD

RANDOMIZE

N = 1680

Men with chemo-naïve mCRPC

Placebo-Controlled, Double-Blind

1

1

Ongoing

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

Other Novel Hormonal AgentsOther 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

Emerging Treatment Options Emerging Treatment Options for mCRPC Patientsfor mCRPC Patients

What immunotherapies are being studied?

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

Fizazi, Powles, et al, 2011.

Androgen deprivation therapy (ADT)

→ Sipuleucel-T

Androgen deprivation therapy (ADT) alone

RANDOMIZE

N = 1684

Men with hormone-

naïve metastatic prostate cancer

1

1

Pending Activation

Primary Endpoint: Overall survivalSecondary Endpoints: Time to castration-resistance

Chemotherapy-free survival

Open Label study

Ipilimumab: Anti-CTLA4Ipilimumab: 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: IpilimumabCTLA4 Blockade: Ipilimumab

Drake, 2010.

Ipilimumab in CRPCIpilimumab 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: Ipilimumab: Post-Chemo Phase III TrialPost-Chemo Phase III Trial

US NIH, 2011d.

Ongoing

Primary Endpoint: Overall Survival

XRT to bone lesion →Ipilimumab IV (induction, maintenance)

XRT to bone lesion →Placebo IV (induction, maintenance)

RANDOMIZE

N = 800

Men with docetaxel-pretreated CRPC with bone mets

Placebo-Controlled, Double-Blind

2

1

Ipilimumab: Ipilimumab: Pre-Chemo Phase III TrialPre-Chemo Phase III Trial

US NIH, 2011e.

Ongoing

Primary Objective: Overall Survival

Ipilimumab IV (induction, maintenance)

Placebo IV (induction, maintenance)

RANDOMIZE

N = 600

Placebo-Controlled, Double-Blind

Men withminimally/

asymptomatic docetaxel-

naïve mCRPC

1

1

ProstVac-VFProstVac-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.)ProstVac-VF (cont.)

Drake, 2010.

ProstVac-VF: Phase II TrialProstVac-VF: Phase II Trial

Kantoff, Schuetz, et al, 2010.

Asymptomatic or minimally symptomatic

mCRPC(N=125)

ProstVac-VF TriCom + GM-CSF (n = 84)

Empty Vector + Placebo

(n = 41)

PROGRESSION

SURVIVAL

Treated at Physician’s Discretion

Treated at Physician’s Discretion

Cross-over2:1

Primary endpoint: PFS

Secondary endpoint: OS

Phase II Trial: Phase II Trial: Treatment SchemaTreatment Schema

Kantoff, Schuetz, et al, 2010.

Phase II Trial: ResultsPhase II Trial: Results

P = 0.6 P = 0.006

PFS OS

Kantoff, Schuetz, et al, 2010.

ProstVac-VF: ECOG 1809 TrialProstVac-VF: ECOG 1809 Trial

US NIH, 2011f.

ProstVac-VF sq Days 1, 15, 29, 43, 57

→ Docetaxel / Prednisone

Docetaxel / Prednisone (up-front)

RANDOMIZE

N = 144

Men with docetaxel-

naïve mCRPC

2

1

Ongoing

Primary Objective: 70% overall survival improvement(median OS 21 mo → 36 mo)

ProstVac-VF: PROSPECT TrialProstVac-VF: PROSPECT Trial

US NIH, 2011g.

Pending Activation

Primary Endpoint: Overall Survival

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

GM-CSF sq Wks 1, 3, 5, 9, 13, 17, 21

Placebo sq Wks 1, 3, 5, 9, 13, 17, 21

RANDOMIZE

N = 1200

Men withminimally/

asymptomatic docetaxel-

naïve mCRPC

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

Emerging Treatment Options Emerging Treatment Options for mCRPC Patientsfor mCRPC Patients

What are the bone-targeted approaches?

Bone-Seeking Bone-Seeking RadiopharmaceuticalsRadiopharmaceuticals

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 TrialRadium-223: Phase III ALASYMPCA Trial

US NIH, 2011h.

Radium-223 IV q4wk (x6)

Placebo IV q4wk (x6)

RANDOMIZE

N = 900

Men with symptomatic mCRPC and bone mets

Placebo-Controlled, Double-Blind

2

1

Primary Endpoint: Overall Survival

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

Emerging Treatment Options Emerging Treatment Options for mCRPC Patientsfor mCRPC Patients

What other novel agents are being studied?

Dasatinib in CRPCDasatinib 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 (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.

CabozantinibCabozantinib

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

Hussain et al, 2011.

-100

-80

-60

-40

-20

0

20

40

60

80

100

-100

-80

-60

-40

-20

0

20

40

60

80

100

*

-70

-50

-30

-10

10

30

50

70

% C

ha

ng

e f

ro

m B

as

elin

e

*

*

** * * *

*

**

*

*

-70

-50

-30

-10

10

30

50

70

% C

ha

ng

e f

ro

m B

as

elin

e

*

*

** * * *

*

**

*

Docetaxel-NaïveDocetaxel-Pretreated

* Prior Abiraterone or MDV3100

74% of patients showed tumor regressions

RESPONSES IN SOFT TISSUE LESIONS

PLASMA CTx(Resorption marker)

SERUM BAP(Formation marker)

% C

hang

e fr

om B

asel

ine

Bisphosphonate-TreatedBisphosphonate-Naïve

Cabozantinib (cont.)Cabozantinib (cont.)

Hussain et al, 2011.

Docetaxel - pretreatedDocetaxel - naïve

Baseline Week 12Baseline Week 12

Bone Scan Improvements Seen in 76% of Patients (bone pain improvement in 67%)

Key TakeawaysKey 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: Section IV:

Putting Evidence Into Practice: Putting Evidence Into Practice: Expert Perspective on Case Expert Perspective on Case

ExamplesExamples

Case Study: Part 1Case 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 1Case Study: Part 1Discussion QuestionsDiscussion Questions

Does this patient meet criteria for CRPC?

How would you manage this patient?

Case Study: Part 2Case 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 2Case Study: Part 2Discussion QuestionDiscussion Question

How would you manage this patient now?

Case Study: Part 3Case 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 3Case Study: Part 3Discussion QuestionDiscussion Question

How would you manage this patient now?

Case Study: Part 4Case 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 4Case Study: Part 4Discussion QuestionDiscussion Question

How would you manage this patient now?

Key TakeawaysKey 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