systemic approaches for the treatment of …...2010/03/27 · 4 systemic approaches for the...

1

Systemic Approaches for the Treatment of Advanced Disease: Biology Dictates Therapy

Howard I. Scher, MD

D. Wayne Calloway Chair in Urologic OncologyChief, Genitourinary Oncology Service

Memorial Sloan Kettering Cancer Center

March 27, 2010


1. A framework and the systemic therapy standards.

2. Castration resistant prostate cancers are not “hormone refractory”.

3. Building on the “first lie” standard..3. u d g o e s e s d d..

4. The landscape is changing indeed.

2

A Framework for Management and The Development Of Systemic Therapies For Prostate Cancer

Castration resistant:Docetaxel

Deaths From Disease

Diagnoses Non-CastrateAndrogen depletion

/blockade (bicalutamide)

Rising PSA

3Clinical

Metastases:Castrate1st Line

DocetaxelStandard

2Clinical

Metastases:Castrate

Pre-

ClinicallyLocalizedDisease

1Rising PSA:

C t t

ClinicalMetastases:

Non-Castrate

4Clinical

Metastases:Castrate

Post-No Standard

28,660186, 320

Castrate

Hormone Therapy for Prostate Cancer: Reducing LigandLevels and/or Blocking Androgen Receptor Binding

DHT ligand LHRH agonists

ANDROGENRECEPTOR

P

g

BicalutamideFlutamide

Adrenal Androgens

CoR

ARAR

Pol II

ARE

NCoR/HDAC

AR responsive gene signatureAR protein

TMPRSS2-Erg fusion mRNA, etc

3

A Rising PSA Following Androgen Depletion Is A Transition to a Lethal Disease Phenotype

T < 50 ng/dl

At relapse

Incomplete suppression orearly resistance?

Median D t l 3 kl

For Castration Resistant Prostate Cancers Q3 Week DocetaxelCan Prolong Life And Is the First Line Standard of Care

MedianTrial Drugs No. Survival P=

99-16 D+E 386 18 mos. 0.02M+P 384 16

327 D 335 18.9 0.009 M+P 337 16.4

babi

lity

of S

urvi

ving

0 30.40.50.60.70.80.91.0 Docetaxel 3 wkly

Docetaxel wkly

Mitoxantrone

D = docetaxel, E = estramustine, M = mitoxantrone, P = prednisone

Petrylak et al., and Tannock et al., NEJM, 2004

–

Prob

0 6 12 18 24 300.00.10.20.3

Tax 327

Pivotal trials that have led to many hypotheses for testing.

4




3. Building on the “first line” standard..3. u d g o e s e s d d..


A Rising PSA Following Androgen Depletion Is A Surrogate for Restored AR Signaling and a Transition to a Lethal Disease Phenotype

T < 50 ng/dl

At relapse, AR signalingcontributes to progression.

Incomplete suppression orearly resistance?

Antagonist agonistconversion: anti-androgen

withdrawal responses

5

The Oncogenic Changes in the Androgen Receptor of Castration Resistant Prostate Cancers Are Targets for Therapy

UntreatedPrimary

Metastatic CastrationResistant

o

Post-AndrogenDepletion

Scher et al. Endocrine-RelatedCancer 11:2004;459

Increased AR proteinAR mRNA overexpressionIncreased AR DNA copy

numberOverexpressed androgen

synthetic enzymesElevated androgens in tumor

Abiraterone Acetate Inhibits Androgen Synthesis inThe Adrenal Gland and in The Tumor

ANDROGEN METABOLISM

Androgenprecursors Androgens

Adrenal synthesis

Tumor synthesis

Abiraterone Cell surface ligand/receptor

AR

HSP90AR degraded

Abiraterone

SRCDHT

AR AR

Akt

mutAR

LBD: PROMISCUITY:antiandrogens,

LIA: Truncated AR: LDB DeletionsSplice Variants

AR P

AR PARPTranscription of TMPRSS-ETS, etcfor growth and survival

ARPAR

ARARARAmp

AR

+

g ,progestins,glucocorticoids

Chen et al. Curr Opin Pharm, 2008

AROverexpression

6

Clinical Contexts for Use and Testing Androgen Receptor Signaling Directed Therapies

UNMET NEED:Effective therapies for castration resistant disease.

Rising PSAClinicallyLocalizedDisease

1

ClinicalMetastases:

Non-Castrate

3Clinical

Metastases:Castrate1st Line

DocetaxelS d d

2Clinical

Metastases:Castrate

Pre-

4Clinical

Metastases:Castrate2nd Line

No Standard

Delay the “need” for chemotherapy.

Rising PSA:Castrate

Standard No Standard

OBJECTIVE:Is there a role for AR directed therapies in CRPC?Development new biomarkers of prognosis,

efficacy, and for treatment selection.

The 17,20 Lyase Inhibitor Abiraterone Acetate LowersLigand Levels and Is Active in CRPC

Both Pre- and Post-Chemotherapy

N

RO

MW = 391.55 N

3β-Acetoxy-17-(3-pyridyl)androsta-5,16-diene

1. C17,20 lyase inhibitor : blocks selectively & irreversibly 17a-h d l / C17 20 lhydroxylase / C17,20 lyase

2. Inhibits androgen generation in the testis, adrenals and tumor. 3. Orally administered. 4. Effects on androgen synthesis shown in Proof-of-concept

phase 1 trials.

7

The 17,20 Lyase Inhibitor Abiraterone Acetate Is Active in CRPC Both Pre- and Post-Chemotherapy:These tumors are not hormone-refractory!

>50% PSA>50% PSA Trial No. Pts. Decline PR (RECIST)

Pre-Chemotherapy1 54 38 (70%) 15/29 (52%)#2 30 16 (53%) N.R.

Post ChemotherapyPost-Chemotherapy3 34 17 (46%) 5/19 (26%)#4 38 17 (45%) 26 >5 CTC*5 23 11 (48%) 1/4 (25%)*

Considering a tumor to be hormone refractory a priori, is not onlya misnomer, but can deprive a patient of potentially useful therapy.

Phase III Registration Trial of Phase III Registration Trial of AbirateroneAbiraterone Acetate in Acetate in PostPost--Chemotherapy Setting Chemotherapy Setting (NCT 00638690) (NCT 00638690) Is AccruedIs Accrued

Abiraterone 1000 mg daily2

RPrednisone 10 mg daily

Placebo dailyPrednisone 10 mg daily

2

1

DeBono, J (Europe) and Scher, H. (North America) Co-PI, Cougar Biotechnology

Primary Endpoint: 25% survival increase Sample size: 1158 (772 and 386)Statistics: 85% Power; (HR = 0.80), p=0.05, two sidedBiomarkers: CTC

8

The Phase III Registration Trial of Abiraterone Acetate in The Phase III Registration Trial of Abiraterone Acetate in PrePre--Chemotherapy Chemotherapy (Cougar 301): (Cougar 301): Start May, 2008:

Co-Primary Endpoints Are PFS and Overall Survival

Abiraterone 1000 mg dailyP d i 10 d il1 STATISTICS

RPrednisone 10 mg daily

Placebo dailyPrednisone 10 mg daily1

Primary: 25% survival increase

Statistics: Enrolled - 1200

1. Fully accrued ahead of schedule.

DeBono, J (Europe) and Scher, H. (North America) Co-PI, OrthoBiotech Oncology Research & Development (A Unit of Cougar Biotechnology)

2. Trial results available 2Q2009.

AbirateroneAbiraterone Acetate in CRPCAcetate in CRPC

1. The “decision” to offer chemotherapy does not mean a tumor is refractory to hormones.

2. PSA declines are an on-target effect: clinical benefits are yet to be “proven”.

3. A prospective randomized phase 3 registration trial was initiated in the 3rd quarter of 2008 in the post-q ptaxane setting (Cougar 301).

4. Accrual is near completion and pre-chemotherapy trialis under regulatory review (Cougar 302).

9

MDV3100: A Novel Anti-Androgen Engineered to AddressDeficiencies in the Currently Available Agents in The Class

Androgenprecursors Androgens

Adrenal synthesis

Tumor synthesis

Cell surface ligand/receptor

AR

HSP90AR degraded

MDV-3100

SRCDHT

AR AR

Akt

mut LBD: PROMISCUITY:antiandrogens

LIA: Truncated AR: LDB DeletionsSplice Variants

AR P

AR PARPTranscription of TMPRSS-ETS, etcfor growth and survival

ARPAR

ARARARAmp

AR

+

antiandrogens,progestins,glucocorticoids

MDV-3100

Chen et al. Curr Opin Pharm, 2008

NuclearLocalization

AROverexpression

Design tools:- Crystal structure NC

F C N

SRU 59063

RD-162 MDV3100 Identified in A Screen For Stronger Antagonism and No Agonism in Prostate CancerModel Systems with Overexpressed AR Blocks

- Homology modeling

- Binding affinity

F3C N N

O OHHigh AR binding affinitywith no agonistic activity

NF3C

NC

N

S R

H-bond interaction

Hydrophobic

Rigidity

Binding affinity to ARAntagonist Activity

NF3C N

O R1

R2inte raction

Hydrophobicinteractions with AR

Science (in press)

10

Waterfall Plot of PercentPSA Change from Baseline

62% 51%

MDV3100 Which is Active in Tumors With Overexpressed AR Blocks FDHT Uptake in Tumor and Produces Declines in PSA in Pre- and Post-Chemotherapy

CRPC (N=140)FDHT

Pre Treatment

62% (40/65)

51% (38/75)

Post Treatment

Pre-Chemotherapy

Scher et al. for the PCCTC, ASCO, June 2009

Post-Chemotherapy

EfficacyEfficacy--Response #2: Response #2: Phase III Registration Trial of Phase III Registration Trial of MDV3100 in CRPC PostMDV3100 in CRPC Post--Chemotherapy Chemotherapy (AFFIRM) Also (AFFIRM) Also Includes the Prospective Evaluation of CTC Number as a

Biomarker

Medivation 160 mg dailySTATISTICS

R

Medivation 160 mg daily

Placebo daily

2

1

Primary: 25% survival increaseSecondary: CTC numberSample size: Approximately 1200Biomarkers: CTC enumeration

Profiling

1 IRB approved

Scher H. (North America) and DeBono, J (Europe) Co-PI

1. IRB approved.2. Activation, October, 2009.3. CTC sampling mirrors Cougar 301.4. Associations with clinical outcomes: clinical and

biologic.

11




3. Building on the “first line” standard..3. u d g o e s e s d d..


Building on Docetaxel As the First-Line Standard of Care

3


1Rising PSA:

Castrate

ClinicalMetastases:

Non-Castrate

2Clinical

Metastases:Castrate

Pre-

3Clinical

MetastasesCastrate1st Line

DocetaxelStandard

4Clinical


No Standard

1. New agents: many classes:cytotoxics, biologics, signaling inhibitors, proapoptotic -microenvironment directed

2. Combinations:

12

A Partial List of Taxotere Combinations Under Evaluation As First-Line Therapy: A “Theme” of Targeting

the Tumor Microenvironment and Survival PathwaysPhase 3

1. + Avastin (anti-VEGF Ab) Genentech (CALGB)2 + Afib t (VEGF t ) S fi A ti2. + Afibercept (VEGF-trap) Sanofi-Aventis

3. + Atrasentan (endothelin) Abbott (SWOG)4. + ZD4054 Astra-Zeneca

5. + Dasatinib (src) Bristol-Myers-Squibb 6. + IGF1R antibody Pfizer

7 + clusterin antisense Oncogenex7 + clusterin antisense Oncogenex

Phase 21. + LBH-589 Novartis - Phase 1/22. + RAD-001 Novartis3. + Sunitinib Pfizer4. + quadramet Cytogen5. + alfaradin Bayer6. + AT-101 (bcl-2) Ascenta

CALGB 9040: Randomized Double Blinded Placebo controlled Phase III Trial Comparing Docetaxel + Prednisone

with or without Bevacizumab in men with HRPC

Docetaxel q 3 wks + Eligibility Stratification

RA

ND

OM

IZE

RA

ND

OM

IZE

qPrednisone + Placebo

Docetaxel q 3 wks +bevacizumab +

Metastatic PCT <50 ng/mlNo prior chemoAdequate hem, renal,

and liver function

Halabinomogram

N 1020 ti t prednisoneN = 1020 patientsCALGB, ECOG, NCIC

Endpoint: Overall survival; progression free survivalHazard Ratio = 1.26 (19 months to 24 months), 90% power

13

Docetaxel +/- Avastin

A negative trial.

Targeting the Bidirectional Tumor-Host Interaction in Bone

Tu and Lin, The Cancer Journal 14:35, 2008

14






Building on Docetaxel As the First-Line Standard of Care


1Rising PSA:

Castrate

ClinicalMetastases:

Non-Castrate

2Clinical

Metastases:Castrate

Pre-

3Clinical

MetastasesCastrate1st Line

DocetaxelStandard

4Clinical


No Standard

1. New agents: many classes:cytotoxics, biologics, signaling inhibitors, proapoptotic -microenvironment directed

2. Combinations:

17

Sipuleucel-T Immunotherapy for Advanced Prostate Cancer: A Randomized, Double-Blind, Placebo-

C ll d h 3 i lControlled Phase 3 Trial

IMPACT STUDY

Sipuleucel-T: Patient-Specific TherapyDay 1Leukapheresis

Day 2-3sipuleucel-T is manufactured

Day 3-4Patient is infused

Apheresis Center Dendreon Doctor’s OfficeApheresis Center Dendreon Doctor s Office

COMPLETE COURSE OF THERAPY:Weeks 0, 2, 4

18

Randomized Phase 3 IMPACT Trial

(IMmunotherapy Prostate AdenoCarcinoma Treatment)P

Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512)

Placebo Q 2 weeks x 3

Sipuleucel-T Q 2 weeks x 3

P R O G R E S SI

2:1

SURVIVA

Treated at Physician discretion

Treated at Physician discretion

Primary endpoint: Overall SurvivalSecondary endpoint: Time to Objective Disease Progression

(N 512) Q 2 weeks x 3 I O N

AL

discretion and/or Salvage Protocol

IMPACT Overall Survival: Primary EndpointIntent-to-Treat Population

100P = 0.032 (Cox model)HR = 0.775 [95% CI: 0.614, 0.979]

25

50

75

Perc

ent S

urvi

val Median Survival Benefit = 4.1 Mos.

Sipuleucel-T (n = 341)Median Survival: 25.8 Mos.

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

25P

Survival (Months)

Placebo (n = 171)Median Survival: 21.7 Mos.

19






AcknowledgementsDaniel DanilaDavid SolitDana RathkopfMichael MorrisS Sl i

Charles SawyersYu ChenAdriana Heguy

Neal Rosen

UCLA:Michael JungSamedi Ouk

OHSU

Royal Marsden:Johann De Bono

UCSF:Charles RyanSusan Slovin

Ethan Basch

James EasthamPeter Scardino

Glenn Heller

Neal RosenDavid Solit

Paul Marks

†William GeraldUma GopalanVictor Reuter

OHSU:Tom Beer

U Washington:Celestia Higano

MDACC:El i Ef t thi

Charles Ryan

VeridexRobert McCormack

Cougar BiotechnologyArturo MolinaChris Haqq

NIH SPORE; DOD; PCF

Martin FleisherMargaret LevershaHans LiljaAseem AnandJan Hendrix

Victor ReuterSamson Fine

Larry SchwartzSteven SolomonGeorge Getrajdman

Eleni Efstathiou

DFCI:Mary-Ellen Taplin

U Michigan:Maha Hussain

Chris Haqq

Medivation:Lynn SeelyMohammed Hirmand

systemic approaches for the treatment of …...2010/03/27 · 4 systemic approaches for the...

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