Treatment of Advanced Prostate Cancer: Treatment of Advanced Prostate Cancer: The Changing LandscapeThe Changing Landscape

Wm. Kevin Kelly, DOProfessor, Medical Oncology and Urology

Director, Division of Solid Tumor OncologyThomas Jefferson University

Disclosures

Sanofi – Aventis: Research support

Outline 1. Evolving Biology of CRPC

2. Novel Agents for the treatment of CRPC• Androgen Biosynthesis Inhibitors (ABI’s)/novel anti-androgens

– Abiraterone, Enzalutamide (MDV-3100)

• Cytotoxics – Cabazitaxel

• Immunotherapies– Sipuleucel-T

• Bone\micro-environment directed therapies– Alpharadin

– “Picking the right treatment for the right patients at the right time”

Prostate Cancer: Growth Rate and Progression

Life Expectancy

Can

cer

Pro

gre

ssio

n

Onset ofCancer

EarlyDetection

LocalizedDisease

MetastaticDisease

Prostate Cancer Death

NaturalDeath

Castration resistant:deaths from disease

Diagnoses

Rising PSA

3Clinical

Metastases:Castrate1st Line

DocetaxelStandard

2Clinical

Metastases:Castrate

Pre-

ClinicallyLocalizedDisease

1Rising PSA:

Castrate

ClinicalMetastases:Non-Castrate

4Clinical

Metastases:Castrate2nd Line

No Standard

With detectable metastases:deaths from cancer exceed

that from other causes

28,660186,320

Non-CastrateAndrogen depletion /

blockade (bicalutamide)

Prostate Cancer Clinical States: A Framework for ClinicalPractice, Drug Development, and Biomarker Qualification

Mediansurvival Hazard

(mos) ratio P-value

Combined: 18.2 0.83 0.03D 3 wkly: 18.9 0.76 0.009D wkly: 17.3 0.91 0.3Mitoxantrone 16.4 – –

Months

Pro

bab

ilit

y o

f S

urv

ivin

g

0 6 12 18 24 300.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Docetaxel 3 wkly

Docetaxel wkly

Mitoxantrone

Eisenberger M, et al. ASCO Annual Meeting Proceedings. June 2004. Abstract 4.

Docetaxel – CRPCOverall Survival—TAX 327

What to do when first line What to do when first line Docetaxel treatment fails?Docetaxel treatment fails?

VS.

Three years ago the choices were limited

Palliative Chemotherapy Phase I study

Beach

Understanding the Biology of CRPCDriver Pathways of Dependency of PC

Tomlins, S. A. Eur Urol 2009Taylor, B et al, Cancer Cell 2010

Kong D. Cancer Sci 2008Jenkins, R. B. Cancer Res 1997

Khor, L. Y. Clin Cancer Res 2007

Androgen Receptor (AR) 55% 100%

PTEN loss 25%80%

PI3K/Akt, Ras/Raf, RB 42%100%

TMPRSS2-ETS fusion 50%33%

Genetic variants of androgen transporter genes

Primary Mets

Intratumoral Androgen Levels Are Increased Due ToOverexpression of The Androgen Synthetic Enzymes

Steroid content

Gerald et al, Amer J Pathol 164:217, 2004

LIVERPositive control

Non-castrate metastatic

Castrate metastatic

Montgomery et al. Cancer Res 68:4447, 2008

Squaline Monoxygenase

Prostate Cancer: “Adapting” to castrate environment

ALTERN.SPLICING

ABERRANTMODIFICATION•GF, cytokines

•Src

Sumo

AC

P

COFACTORPERTURBATION

•CoAct gain•CoR loss/dismissal

CoACT

INTRACRINEANDROGENSYNTHESIS

T

MUTATION•gain of function

AR

selectivepressure

Hormone Therapy

adaptation

RECURRENT TUMOR DEVELOPMENTCRPC

RESTORED AR ACTIVITY(rising PSA)

>30% CRPC

ARDEREGULATION•amplification

•overexpression

Penning & Knudsen2010

Targeting the Androgen Pathway

• Androgen Biosynthesis Inhibitors– *Abiraterone Acetate– TAK 700– VN/124-1 (TOK-001)

• Novel Anti-Androgens– *MDV3100– RD 162– EPI-001 (AR N-Terminal)

– SNARE-1 (selective nuclear receptor exporter-1)

* FDA approved

Hormonal Impact of Abiraterone

H O

H O

H O

H O

O H O H

O O O

O O O

O O

O O

O

O

O

O O

O H O H O H

H

H O

O H

O H

Pregnenolone Proges terone Corticos terone

17α-Hydroxypregnenolone 17αa-Hydroxyproges terone Cortis ol

Dehydroepiandroserone Andros tenedione Tes tos terone 5α-Dihydrotes tos terone

P45017a

(17α-hydroxylase)

P45017a

(C17,20-lyas e)

21-hydroxylase11bb-hydroxylase

tes tos terone5α-reductase

H O

P450SCC

Choles terol

Aldosterone

Abiraterone

Abiraterone

Low-dose steroid replacement minimizes mineralocorticoid-related toxicity

Confidential. For Internal Use Only. Do not distribute.

60

Testosterone (by LC-MS/MS)

01

1

2

3

4

5

6

ng

/dL

10 20Start of Treatment

At Progression

70

Days

Lower Limit of Sensitivity

DHEA

Start of Treatment

28 56 At ProgressionDays

0

2.5

5.0

7.5

10.0

12.5

Nm

ol/

L

0

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

Abiraterone Suppresses Steroids Downstream of C17,20-lyase: Proof-of-Concept Phase I Trial

Confidential. For Internal Use Only. Do not distribute.

Phase II Trials of Abiraterone Acetate in Castration Resistant Prostate Cancer

Phase II Trials of Abiraterone Acetate in Castration Resistant Prostate Cancer

1Ryan et al. J Clin Oncol 2009; 27(suppl):245s (abstract 5046)2Reid et al. J Clin Oncol 2009; 27(suppl):246s (abstract 5047)

3Danila et al. J Clin Oncol 2009; 27(suppl):246s (abstract 5048)

Patient population NPSA decline

≥ 50%

Tumor response

(RECIST)

ECOG PS Improvement(at least one

level)

CRPC: Chemotherapy naïve1 33 24 (73%)

PR: 9 (27%)SD: 19 (58%)

8 (61.5%)

CRPC: Prior docetaxel2

47 24 (51%)PR: 6 (13%)

SD: 25 (53%)11 (35%)

CRPC: Prior docetaxel3

No prior ketoconazolePrior ketoconazole

3127

16 (52%)8 (30%)

(n = 18)PR: 3 (17%)

SD: 11 (61%)16 (48%)

COU-AA-301 Study Design

• Phase III, multinational, multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada)

• Stratification according to – ECOG performance status (0-1 vs 2)

– Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs 4-10 [present])

– Prior chemotherapy (1 vs 2)

– Type of progression (PSA only vs radiographic progression with or without PSA progression)

Abiraterone 1000 mg dailyPrednisone 5 mg BID

n=797

Primary end point

• OS (25% improvement; HR 0.8)

Secondary endpoints (ITT)

• TTPP

• PFS

• PSA response

Efficacy endpoints (ITT)

Placebo dailyPrednisone 5 mg BID

n=398

RANDOMIZED

2:1

• 1195 patients with progressive mCRPC

• Failed 1 or 2 chemotherapy regimens, one of which contained docetaxel

Patients

Abbreviations: ; BPI=Brief Pain Inventory; TTPP=time to PSA progression; ITT=intent to treat; mCRPC=metastatic castrate-resistant prostate cancer.Source: Clinicaltrials.gov identifier: NCT00638690.

deBono N Engl J Med. 2011 May 26;364(21):1995-2005

COU-AA-301: Abiraterone Acetate Improves OS in mCRPC

HR=0.646 (0.54-0.77) P <0.0001

Placebo: 10.9 months (95% CI: 10.2, 12.0)

0 100 200 300 400 500 600 700

0

20

40

60

80

100

Ove

rall

Su

rviv

al,

%

Days from Randomization

Abiraterone: 14.8 months (95% CI: 14.1, 15.4)

1 Prior Chemo OS: 15.4 months abiraterone vs 11.5 months placebo

Abiraterone 797 728 631 475 204 25 0

Placebo 398 352 296 180 69 8 1

deBono N Engl J Med. 2011 May 26;364(21):1995-2005

Survival Benefit Consistently Observed Across Patient Subgroups

Variable Subgroup N HR 95% CI

All subjects All 1195 0.66 0.56-0.79

Baseline ECOG 0-1 1068 0.64 0.53-0.78

2 127 0.81 0.53-1.24

Baseline BPI <4 659 0.64 0.50-0.82

4 536 0.68 0.53-0.85

No. of prior chemo regimens 1 833 0.63 0.51-0.78

2 362 0.74 0.55-0.99

Type of progression PSA only 363 0.59 0.42-0.82

Radiographic 832 0.69 0.56-0.84

Baseline PSA above median YES 591 0.65 0.52-0.81

Visceral disease at entry YES 709 0.60 0.48-0.74

Baseline LDH above median YES 581 0.71 0.58-0.88

Baseline ALK-P above median YES 587 0.60 0.48-0.74

Region North America 652 0.64 0.51-0.80

Other 543 0.69 0.54-0.90

0.5 0.75 1 1.5Favors

AbirateroneFavors

PlaceboAbbreviations: HR=hazard ratio; ALK-P=alkaline phosphatase.

deBono N Engl J Med. 2011 May 26;364(21):1995-2005

COU-AA-301: Summary of AEs

Abiraterone(n=791)

Placebo (n=394)

All Grades Grades 3/4 All Grades Grades 3/4

All treatment-emergent AEs, % 98.9 54.5 99.0 58.4

Serious AEs, % 37.5 32.1 41.4 35.3

AEs leading to discontinuation, % 18.7 10.5 22.8 13.5

Deaths within 30 days of last dose, %

10.5 13.2

Underlying disease 7.5 9.9

Other specified cause 2.9 3.3

Drug-related deaths 0 0

deBono N Engl J Med. 2011 May 26;364(21):1995-2005

Overall Study Design of COU-AA-302

• Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada

• Stratification by ECOG performance status 0 vs 1

AA 1000 mg dailyPrednisone 5 mg BID

(Actual n = 546)

AA 1000 mg dailyPrednisone 5 mg BID

(Actual n = 546)

Co-Primary:

• rPFS by central review

• OS

Secondary:• Time to opiate use

(cancer-related pain)• Time to initiation of

chemotherapy• Time to ECOG-PS

deterioration• TTPP

Efficacy end points

Placebo dailyPrednisone 5 mg BID

(Actual n = 542)

Placebo dailyPrednisone 5 mg BID

(Actual n = 542)

RANDOMIZED

1:1

RANDOMIZED

1:1

• Progressive chemo-naïve mCRPC patients(Planned N = 1088)

• Asymptomatic or mildly symptomatic

Patients

Ryan et al. ASCO 2012

Statistically Significant Improvement in rPFS Primary End Point

NR, not reached; PL, placebo.Data cutoff 12/20/2010.

100

80

60

40

20

0

0

Pro

gre

ssio

n-F

ree

(%)

3 6 9 15 1812

546542

489400

340204

16490

123

00

AAPL

4630

Time to Progression or Death (Months)

AA + PPL + P

AA + P (median, mos): NR

PL + P (median, mos): 8.3

HR (95% CI): 0.43 (0.35-0.52)

P value: < 0.0001

Ryan et al. ASCO 2012

Strong Trend in OS Primary End Point

546542

538534

482465

452437

2725

00

524509

503493

02

120106

258237

412387

100

80

60

40

20

0

0

Su

rviv

al (

%)

3 12 15 27

Time to Death (Months)

33

AA + PPL + P

6 9 30242118

AAPL

AA + P (median, mos): NR

PL + P (median, mos): 27.2

HR (95% CI): 0.75 (0.61-0.93)

P value: 0.0097

Updated GU ASCO 2013: Rathkopf et al. Abstract # 5-r PFS 16.5 vs. 8.3 mo. HR 0.53 (0.45-0.62) p = <0.0001- OS 35.3 vs. 30.1 mo. HR 0.79 (0.66-0.96) p= 0.0151

No New Safety Concerns Identified with Longer AA Treatment than in 301 Study

AA + P(n = 542)

%

Placebo + P(n = 540)

%

All Grades Grades 3/4 All Grades Grades 3/4

Fatigue 39 2 34 2

Fluid retention 28 0.7 24 1.7

Hypokalemia 17 2 13 2

Hypertension 22 4 13 3

Cardiac disorders 19 6 16 3

Atrial fibrillation 4 1.3 5 0.9

ALT increased 12 5.4 5 0.8

AST increased 11 3.0 5 0.9

Most ALT and AST increases occurred during the first 3 months of treatment

Ryan et al. ASCO 2012

Subsequent Therapy Was Commonand Still a Survival Trend Observed

AA + P(n = 546)

n (%)

Placebo + P(n = 542)

n (%)

No. with selected subsequent therapy for mCRPC 242 (44.3) 327 (60.3)

Docetaxel 207 (37.9) 287 (53.0)

Cabazitaxel 45 (8.2) 52 (9.6)

Ketoconazole 39 (7.1) 63 (11.6)

Sipuleucel-T 27 (4.9) 24 (4.4)

Abiraterone acetate* 26 (4.8) 54 (10.0)

*Prior to unblinding (e.g. not per protocol)

Ryan et al. ASCO 2012

TAK-700 (Ortoronel) in mCRPC: PSA Response and Safety

• inhibit the enzyme 17,20-lyase • 53% with PSA decreases ≥ 50% at 12 wks• Serious AEs in 25 patients (26%): hypokalemia (n = 3), acute renal failure

(n = 3), pneumonia (n = 2), urinary tract infection (n = 2), hypotension (n = 2), neutropenia (n = 2), fatigue (n = 2)

• Efficacy and tolerability demonstrated with TAK-700 administered with or without prednisone, suggesting feasibility of a steroid-free regimen

X Previous ketoconazole therapy

Agus DB, et al. ASCO 2011. Abstract 4531.

275250225200175150125100

25

-25

-75

7550

0

-50

-100-125P

SA

Ch

an

ge

at

12

Wk

s (

%)

x x xx

X x x x xx

x xx x

X x xx x x x x x

300 mg BID (n = 23)600 mg BID + prednisone (n = 26)

400 mg BID + prednisone (n = 24)600 mg QDAM (n = 24)

Treatment

Enzalutamide (MDV3100)

Novel anti-androgens“Development of Enzalutamide”

• Built of the scaffolding of the non-steroidal agonist RU59063

• Screened ~ 200 derivatives • Derivatives were optimized –

RD162 and MDV3100

Tran et al. Science 324:787-790, 2009

MDV3100 (Enzalutamide) Was Designed to Overcome Deficiencies of Available Anti-Androgens and Has Several

Unique Mechanisms of Action and No Agonist Effects

Enzalutamide1

3

2

T

AR

T

Cell nucleus

Inhibits Binding of Androgens to AR

Inhibits Nuclear Translocation of AR

Inhibits AssociationOf AR with DNA

AR

1. MDV3100 is an oral investigational drug rationally designed as a new hormonal agent to target androgen receptor (AR) signaling, a key driver of prostate cancer growth.

2. MDV3100 is the first in a new class of Androgen Receptor Signaling Inhibitors that affects multiple steps in the androgen receptor signaling pathway.

Cell cytoplasm

Tran et al. Science 2009;324:787–90.

Bicalutamide vs. Enzalutamide

Enzalutamide has a 5-8 fold increased affinity to AR than bicalutamide

Enzalutamide does not have agonists effects in castrate resistant setting

Enzalutamide suppressed growth and

induced apoptosis in cells lines with AR gene

amplications

Tran et al. Science 324:787-790, 2009

Anti-tumor activity if MDV3100 in castration-resistant prostate cancer: a phase 1-2 study

Pre-chemotherapyN=65

Post-chemotherapyN=75

Grade 3-4 adverse events in >2 patients N (%)

Adverse eventAll doses(n = 140)

≤ 240mg/day (n = 87)

Fatigue 16 (11%) 5 (17%)

Anemia 4 (3%) 3 (3%)

Arthralgia 3(2%) 2(2%)

Seizure 3 (2%) 0Scher et al. Lancet 375:1437-1446, 2010

AFFIRM: Phase 3 Trial of Enzalutamide vs Placebo in Post-Chemotherapy Castration-

Resistant Prostate Cancer (CRPC)

RANDOMIZED

2:1

RANDOMIZED

2:1

Primary

Endpoint:Overall Survival

Enzalutamide 160 mg daily

n = 800

Enzalutamide 160 mg daily

n = 800

Placebon = 399Placebon = 399

Patient Population:

1199 patients with progressive CRPC

* Failed docetaxel chemotherapy

*Glucocorticoids were not required but allowed

ASCO June 2012Tran et al. Science 2009;324:787–90.

AFFIRM: Clinical Outcomes

Variable Enzalutamide(800 pts.)

Placebo(399 pts.)

Hazard Ratio P -value

OS(months)

18.4 13.6 0.631 <0.0001

PSA progression(months)

8.3 3.0 0.218 <0.0001

rPFS(months)

8.3 2.9 0.404 <0.0001

1st SRE(months)

16.7 13.3 0.621 <0.0001

CR + PR 28.9% 3.8% - <0.0001

FACT-P 43.3% 17.8% - <0.0001

De Bono et al. ASCO 2012

Favorable Adverse Risk Profile All Grades Grades >3*

Enzalutamide

(n = 800)

Placebo(n = 399)

Enzalutamide

(n = 800)

Placebo(n = 399)

AEs 98.1% 97.7% 45.3% 53.1%

Serious AEs 33.5% 38.6% 28.4% 33.6%

Discontinuations due to AEs

7.6% 9.8% 4.6% 7.0%

AEs leading to death

2.9% 3.5% 2.9% 3.5%

All Grades Grade ≥ 3 Events

Enzalutamide

(n = 800)

Placebo(n = 399)

Enzalutamide

(n = 800)

Placebo(n = 399)

Seizure 0.6% 0.0% 0.6% 0.0%

De Bono et al. ASCO 2012

rPFS

PSA

Association of PSA progression and rPFS

de Bono JS et al. N Engl J Med 2011;364:1995-2005De Bono et al. ASCO 2012

AFFIRM COU-AA-301

Agent Function PhaseAbiraterone Acetate CYP 17 α-hydroxylase\12,20-lyase

inhibitorFDA approved

TAK-700 CYP 17,20 lyase inhibitor -Phase III

Enzalutamide (MDV3100) Anti-androgen\androgen receptor signaling inhibitor

-Completed Phase III-Ongoing Phase III in non-castrate disease

ARN-509 Anti-androgen -Phase III

AZD3514 AR down-regulator\anti-androgen -Phase I

TOK-001 Anti-androgen\CYP 17 inhibitor -Phase I-II

EPI-001 Anti-androgen\N-terminal Domain

-pending clinical trials

Novel Agents Targeting the Androgen Pathway

Cabazitaxel

• Microtubule stabilizer

• Developed in docetaxel-resistant prostate cancer cell lines

• a favorable pharmacokinetic and safety profile

• decreased propensity for P-glycoprotein (Pgp)-mediated drug resistance.

• inhibited cell growth in a wide range of human cancer cell lines, including tumor models expressing Pgp.

TROPIC – Cabazitaxel vs Mitoxantrone

• CRPC• PD during or

after docetaxel

RA

ND

OM

IZE

Cabazitaxel 25 mg/m2 Q 21 dPrednisone 10 mg daily

N=755

MitoxantronePrednisone 10 mg daily

146 Sites / 26 Countries

Abbreviation: PD=progressive disease.Source: deBono et al. Lancet. 2010;376:1147-1154.

TROPIC Primary Endpoint – OS (ITT Analysis)

MP 377 300 188 67 11 1 CBZP 378 321 231 90 28 4

Numberat Risk

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

0.70Hazard Ratio

CBZPMP

Abbreviation: ITT=intent-to-treat.Source: deBono et al. Lancet. 2010;376:1147-1154.

Pro

po

rtio

n o

f O

S (

%)

Most Frequent Grade ≥3 Treatment-Emergent AEs*

MP (n=371) CBZP (n=371)

All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%)

Any AE 88.4 39.4 95.7 57.4

Febrile neutropenia 1.3 1.3 7.5 7.5

Diarrhea 10.5 0.3 46.6 6.2

Fatigue 27.5 3 36.7 4.9

Asthenia 12.4 2.4 20.5 4.6

Back pain 12.1 3 16.2 3.8

Nausea 22.9 0.3 34.2 1.9

Vomiting 10.2 0 22.6 1.9

Hematuria 3.8 0.5 16.7 1.9

Abdominal pain 3.5 0 11.6 1.9

*Sorted by decreasing frequency of events grade ≥3 in the CBZP arm.

deBono et al. Lancet. 2010;376:1147-1154

Immunotherapy Approaches in PC Active immunotherapy

tumor associated antigen is directly targeted by loading in that antigen in APC or into vaccine vector at protein or DNA level

Antigen specific immunotherapy Sipuleucel-T Poxvirus-based vectors DNA based vaccines

Passive immunotherapy Antibodies to specific receptors/antigens

Prostate Specific Membrane Antigen (PSMA)

Immune Checkpoint Inhibitors Strategies to maintain activated tumor specific T-cells by neutralizing co-inhibitory

receptors

Anti-cytotoxic T lymphocyte protein 4 (CTLA 4) Ipilumimab, tremelimumab

Anti- program death 1 (PD-1) MDX-1106

Patient’s white blood cells harvested

Short-term culture with protein “cassette”

Shipping

Cells infused back into patient (IV)

GM-CSFProstatic acid

phosphatase

Active Cellular Immunotherapy(Sipuleucel-T)

Overall Survival Study D9902B

Study D9902A

StudyD9901

Sip-T Placebo Sip-T Placebo Sip-T Placebo

Median, Months

(95% CI)

25.8

(22.8, 27.7)

21.7

17.7, 23.8)

19

(13.6, 31.9)

15.7

(12.8, 25.4)

25.9

(20.0, 32.4)

21.4

(12.3, 25.8)

Hazard Ratio

(95% CI)

0.775

(0614,0.979)

0.786

(0.484, 1.278)

0.568

(0.388, 0.884)

P 0.032 0.010 0.331

Sipuleucel-T in Prostate Cancer

Cheever and Higano., Clin Cancer Res 2011;17:3520-3526

CD54 is a surrogate marker of antigen presenting cell activation

Serum cytokines or humoral responses by ELISA have limited utility

Second Generation Anti-PSMA Abs: J591

2nd generation mAbs– Bind extracellular domain– Bind viable PSMA+ cells– Rapidly internalized– May be conjugated

Liu H et al. Cancer Res 1997; 57: 3629Liu H et al. Cancer Res 1998; 58: 4055

Capromab binding site

J591binding site

90% decline

177Lu-J591 Rx: Excellent Targeting & PSA Response

6 months

99mTc-MDP bone scan 177Lu-J591 mAb PSADT=3.9 mo

Ant Post Ant Post

Log scale

Arithmetic scale

30/32 (94%) with accurate targeting of known sites of disease

Tagawa et al, ASCO 2008

Defining the Future:Ongoing Immumotherapy Trials

Study Phase StudyPopulation

Treatment Outcome

PROTECTP-11

III Non-metastatic ADPC 3 mo. ADT + Sip-T vs. control

PSADT,Distant Failure,OS

NeoACTP07-1

II Localized PC Sip-T x 3 prior to RPPost-op Boost vs. no Boost

Immune response, Safety

ProACTP07-2

II Asymptomatic or minimally symptomatic CRPC

3 different dose levels of PA2024

CD54 upreg.,Immune response,QOL, CTC, OS

Cornell 177Lu-J591

II High risk non-metastatic CRPC

Ketoconazole + hydrocortisone ± active 177Lu-J591

PFS, OS, PSA, RECIST

BMS CA 184043Ipi\Prostate

III CRPC post docetaxel XRT + Ipi vs. XRT + placebo

OS, PFS, Pain, Safety

Radioisotopes Targets Bone Metastases

• Naturally targets new bone growth in and around bone metastases

• Most acts as a calcium mimic

• Strontium-89

• Samrarium-153

• Radium-223

Ra

Ca

Alpha Beta

Relative particle mass 7000 1

Initial energy (MeV) 3-8 0.01-2.5

Range in tissue (µm) 40-90 50-5000

LET (KeV/µm) 60-230 0.015-0.4

Charge +2 -1

Ion pairs/µm 2000-7000 5-20

DNA hits to kill cell 1-5 100-1000

Radium-223 (AlpharadinTM )

• Based on alpha emitter Radium-223• ideal half-life of 11.4 days• Excreted via small bowel• Safe and easy to produce, deliver and handle

Range of alpha-particleRange of alpha-particle

Radium-223Radium-223

Encouraging Phase II results

TREATMENT

6 injections at 4-week intervals

Radium-223 (50 kBq/kg) + Best standard of care

Radium-223 (50 kBq/kg) + Best standard of care

Placebo (saline) + Best standard of care

Placebo (saline) + Best standard of care

RANDOMISED

2:1

N = 922

PATIENTS

• Confirmed symptomatic

CRPC

• ≥ 2 bone metastases

• No known visceral

metastases

• Post-docetaxel or unfit for docetaxel

• Confirmed symptomatic

CRPC

• ≥ 2 bone metastases

• No known visceral

metastases

• Post-docetaxel or unfit for docetaxel

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design

Clinicaltrials.gov identifier: NCT00699751.

• Total ALP: < 220 U/L vs ≥ 220 U/L

• Bisphosphonate use: Yes vs No

• Prior docetaxel: Yes vs No

• Total ALP: < 220 U/L vs ≥ 220 U/L

• Bisphosphonate use: Yes vs No

• Prior docetaxel: Yes vs No

STRATIFICATION

Planned follow-up is 3 yearsPlanned follow-up is 3 years

Month 0 3 6 9 12 15 18 21 24 27

Radium- 223 541 450 330 213 120 72 30 15 3 0

Placebo 268 218 147 89 49 28 15 7 3 0

ALSYMPCA Overall Survival

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

% %Radium-223, n = 541

Median OS: 14.0 monthsRadium-223, n = 541

Median OS: 14.0 months

Placebo, n = 268Median OS: 11.2 months

Placebo, n = 268Median OS: 11.2 months

HR 0.695; 95% CI, 0.552-0.875

P = 0.00185HR 0.695; 95% CI, 0.552-0.875

P = 0.00185

EORTC 2011

Radium-223n (%)

Placebon (%)

P-value

Total ALP response(30% reduction)

165 (43) 4 (3) < 0.001

Total ALP normalisation* 83 (33) 1 (1) < 0.001

*In patients who had elevated total ALP at baseline.*In patients who had elevated total ALP at baseline.

Hazard ratio 95% CI

P-value

Time to Total ALP progression

0.163 (0.121 – 0.221)

< 0.00001

Time to PSA progression 0.671

(0.546 – 0.826) 0.00015

ALSYMPCA Secondary Endpoints: ALP and PSA

EORTC 2011

ALSYMPCA Adverse EventsAll Grades Grades 3 or 4

Radium-223(n = 509)

n (%)

Placebo(n = 253)

n (%)

Radium-223(n = 509)

n (%)

Placebo(n = 253)

n (%)

Haematologic

Anaemia 136 (27) 69 (27) 54 (11) 29 (12)

Neutropenia 20 (4) 2 (1) 9 (2) 2 (1)

Thrombocytopenia 42 (8) 14 (6) 22 (4) 4 (2)

Non-Haematologic

Bone pain 217 (43) 147 (58) 89 (18) 59 (23)

Diarrhoea 112 (22) 34 (13) 6 (1) 3 (1)

Nausea 174 (34) 80 (32) 8 (2) 4 (2)

Vomiting 88 (17) 32 (13) 10 (2) 6 (2)

Constipation 89 (18) 46 (18) 6 (1) 2 (1)

EORTC 2011

Targeting the micro-environment

• Bevacizumab (monoclonal VEGF)• Sunitinib (TKI VEGF 1,2,3)• Aflibercept (VEGF 1 and 2 domains fused to Fc

portion IgG1– VENICE Trial-completed

• Lenalidomide (Immunomodulatory derivative of thalidomide)– MAINSAIL Trial

• Tasquinimod (quinolone-3-carboxamide)• Cabozantinib (VEGFR2/MET inhibitor)• Dasatanib (SRC inhibitor)

Cabozantinib, Dual MET/VEGFR TKI, vs Placebo in mCRPC

*At progression, patients on placebo could cross-over to cabozantinib (n = 14).

Lead-in StageCabozantinib

100 mg/day PO(n = 171)

Patients with mCRPC and measurable

disease; rising PSA only, not eligible

SD(n = 31)

12 wks

Cabozantinib100 mg/day PO

(n = 14)

Placebo daily(n = 17)

Until PD*

Randomization

PR or CR

(n = 79)

Open-Label ExtensionCabozantinib

100 mg/day PO

PD(n = 61)

Discontinue cabozantinib

Hussain M, et al. ASCO 2011. Abstract 4516.

Cabozantinib vs Placebo in mCRPC: Efficacy and Safety

• Authors concluded that cabozantinib has substantial antitumor activity in progressive mCRPC– Disease control at Wk 12: 68%

– Measurable disease regression: 74%

– Evidence of improvement on bone scan: 76%

– Pain improvement: 67%

– Moderate but manageable toxicity profile; similar to other TKIs

Hussain M, et al. ASCO 2011. Abstract 4516.

-12 0 10 20 30 40 50 60

PFS per mRECIST, Postrandomization (Wks)

12-WkLead-in Stage

Pro

po

rtio

n

Pro

gre

ss

ion

Fre

e

1.00

0.75

0.50

0.25

Cabozantinib (n = 14)Placebo (n = 17)

(HR 0.13; log-rank P = .0007)

Median PFS, Wks21 6

Phase III Trials for CRPC (First line chemotherapy trials)

Sponsor Treatment

*Novacea Docetaxel ± DN101

*SWOG Docetaxel ± atrasentan

*CALGB Docetaxel ± bevacizumab

*Sanofi-Aventis Docetaxel ± aflibercept

NCI Docetaxel or KAVE

Doxorubicin ± Strontium-89

*Cell Genesys Docetaxel vs. GVAX

*Cell Genesys Docetaxel ± GVAX

*Zeneca Docetaxel ± zibotentan

*Bristol Docetaxel ± dasatinib

OncGeneX Docetaxel ± Custirsen*Closed to accrual*Closed to accrualNo improvement of Survival

OS Benefit in Recent CRPC TrialsTrial/

Agent/ Date

Approved

Mechanism ComparatorSurvival(months)

Hazard Ratio

P-value

AFFIRMEnzalutamid

e2012

Androgen Receptor Signaling Inhibitor

Placebo 18.4 vs. 13.6 0.631 <0.0001

COU-AA-301 Abiraterone

+ prednisone

2011

CYP17 Inhibitor

Placebo +prednisone

14.8 vs. 10.9 0.646 <0.0001

TROPIC Cabazitaxel

+ prednisone

2010

CytotoxicMitoxantrone +

prednisone15.1 vs. 12.7 0.70 <0.0001

Alpharadin*2012

Alpha-particle emitting

radionuclidePlacebo 14.9 vs. 11.3 0.69 0.0018

* Only 60% of these patients were post-docetaxel patients

Would suggest the post-chemotherapy population remains

heterogonous

Would suggest the post-chemotherapy population remains

heterogonous

De Bono et al. ASCO 2012

1. Who is the right patient for which novel therapy?

2. What is the optimal sequencing of these agents? Does it matter?

3. How long do I give these agents?

4. Why are patients still relapsing?

Multivariate Model: Higher Baseline Androgens Associate With Improved OS:

• Treatment effect: Robust• Laboratory parameters: All significant (LDH, Hgb, ALP, PSA)*Including 1 androgen at a time (dichotomized) and other lab parameters (dichotomized).

HR p Value

Testosterone 0.667 < 0.0001

HR p Value

Androstenedione 0.679 < 0.0001

HR p Value

DHEA 0.691 < 0.0001

Ryan et al Proc AACR 2012

Baseline Serum Adrenal Androgens Are Prognostic and Predictive of Overall Survival in Patients With mCRPC:

Results from the COU-AA-301 Phase 3 Randomized Trial

• androgen\enzyme tissue levels(A) Pretreatment intense nuclear

androgen receptor (AR) expression in combination with CYP17 expression in the bone marrow–infiltrating tumor of a patient with treatment duration more than 4 months.

Efstathiou E et al. JCO 2012;30:637-643

Effects of Abiraterone Acetate on Androgen Signaling in Castrate-Resistant Prostate Cancer in Bone

• Serum Androgen Levels

Molecular characterization of CTCs in CRPC(N= 89 patients treated with Abiraterone)

Attard, G. et al. Cancer Res 2009;69:2912-2918

1. CTC collected by Immunicon system

2. 57% had CTC ≥ 4 (40% chemo naïve; 82% Docetaxel treated)

3. ERG rearrangement was associated with magnitude of PSA decline on abiraterone

4. Concordance in ERG gene status of CRPC tumor biopsy and CTC’s

5. Heterogeneity in AR copy number and PTEN loss noted

The RB loss signature should be developed as a metric to direct therapeutic intervention for CRPC

Direct toward therapies that hyperactivate RB function

RB+ gene signature

e.g. CDK4 inhibitors

Capitalize on loss of cell cycle checkpoints

RB- gene signature

e.g. a subset of chemotherapeutics that induce DNA damage

•Feb 2011:Gene Chip to readout for RB

function & other key prostate-specific markers generated &

validated

Sharma et al, J. Clin Investigation

RB+/RB-tumors

Cabazitaxel + abiraterone acetateRegistration

A phase II multicenter trial combining Cabazitaxel and Abiraterone Acetate in treatment of metastatic

Castration Resistant Prostate Cancer (Knudsen\Kelly)

Lower quartile Interquartile range Upper quartile

RB

tar

get

gene

s

RB Prostate Signature

Androgen Profiles•Testosterone•Androstenedione•DHEA

Conducted in PCCTC

The Changing Landscape in Prostate Cancer

EnzalutamideAbirateroneCabazitaxelAlpharadinSipuleucel-T

AlpharadinSipuleucel-TZolendronic AcidDenosumabSamariumDocetaxelMitoxantrone

BicalutamideFlutamideNilutamide

LhRH agonistsLhRH antagonists

BicalutamideFlutamideNilutamide

LhRH agonistsLhRH antagonists

Therapies with a Clinical Benefit

Need for biomarker driven trials to direct patient treatment

17α hydrolase/17, 20 lyase inhibitor Abiraterone, TAK 700Anti-angiogenic/immunomodulatory CC-4047,Lenalidomide, ABR-215050, cediranib, AS1404Anti-CTLA4\PD-1 antibody Ipilimumab, MLN2704Anti-CCL2 CNTO 888Anti-FGFR3 TKI 258Anti-Il-6 antibody CNTO 95Anti-insulin-like GFR antibody IMC-A12Anti-integrin anti-body CNTO 95Anti-PSMA immunoconjugate MLN2704, 177 Lu-J591Anti-prostate stem cell antibody AGS-PSCAAnti-VEGF Bevacizumab, AlfiberceptCytotoxic agent ABT-751, abraxane, E7389, SB-715992, carbazitaxel

Irofulven, Paclitaxel poliglumex, TPI 287, E7389Clusterin inhibitor OGX-11EGFR antibodies\TKI Pertuzumab, Cetuximab, Erlotinib, Gefitnib, Faranesyl protein transferase inhibitor R115777GMP phospodiesterase inhibitor ExisulindHSP-90 inhibitor 17-AAG, IPI-504HDACi LBH589, Vorinostat, Belinostat, SB939HGF inhibitor AMG 102Hypoxia activated pro-drug TH 302IGF inhibotors Citutumumab, figitumumab, octreotide, pasireotideIntegrin receptor antagonist CilengitideIl-11 inhibitor BMTP-11JAK inhibitor INCB-18424M-TOR inhibitor Temsirolimus Multi-targeted TKI Sunitinib, Sorafenib, CEP 701, vatalinib, DMXAAMMP-9 inhibitor PCK 3145Pro-apoptotic agent AT-101Proteosome Inhibitor BortezomibRANKL inhibitor DenosumabSRC kinase inhibitor KX2-391Signal Transduction inhibitor PCK-3145Survivin suppressant YM155

Novel Agents in CRPC

Phase I Trial of Weekly Cabazitaxel with Concurrent Intensity Modulated Radiation Therapy and Androgen Deprivation Therapy for the Treatment of Locally Advanced High Risk Adenocarcinoma of the Prostate.- Lin

A Phase II Study of Cabazitaxel in Patients with Urothelial Carcinoma Who Have Disease Progression Following Platinum-Based Chemotherapy. -Hoffman

Phase I Trial of High Dose Rate Brachytherapy Combined with Stereotactic Body Radiation Therapy for Intermediate Risk Prostate Cancer Patients.-Den

A Pilot Phase II Study of Digoxin in Patients with Recurrent Prostate Cancer as Evident by a Rising PSA.-Lin

A Multi-Institutional Translational Clinical Trial of Disulfiram in Men with Recurrent Prostate Cancer as Evident by a Rising PSA.-Lin

A Phase I/II multicenter trial combining Cabazitaxel and Abiraterone Acetate in Treatment of Metastatic Castration Resistant Prostate Cancer. -Kelly

A Phase I/II Study of MLN8237 in combination with Abiraterone for patients with castration- resistant prostate cancer after progression on Abiraterone.-Lin

GU-Investigator Initiated Trails at KCC

Genitourinary Oncology TeamMedical Oncology•Jean Hoffman-Censits, MD•Jianqing Lin, MD•Gwen Slakind, RN•Diane Woodford, APRN

Radiation Oncology•Adam Dicker, PhD, MD•Robert Den, MD•Mark Hurwitz, MD

Urology•Lenny Gomella, MD•Edouard Trabulsi, MD•Costas Lallas, MD

Pathology•Peter McCue, MD•Ruth Birbie

Clinical Trials Office\Data Collection•Monica Byrnes•Christine Huberts•Brooke Kennedy•Deborah Kilpatrick, RN•Zachary Foerst

Basic Science•Allessandro Fatalis, MD•Karen Knudsen, PhD•Lucia Languino, PhD•Marja Nevalainen, PhD•Eric Wickstrom, PhD

Administrative Support•Teresa Bryant•Beth Schade

Thank You