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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
Systemic Approaches for the Treatment of Advanced Disease: Biology Dictates Therapy
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.
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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
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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
Systemic Approaches for the Treatment of Advanced Disease: Biology Dictates Therapy
1. A framework and the systemic therapy standards.
2. Castration resistant prostate cancers are not “hormone refractory”.
3. Building on the “first line” standard..3. u d g o e s e s d d..
4. The landscape is changing indeed.
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
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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
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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.
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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
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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).
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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)
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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.
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Systemic Approaches for the Treatment of Advanced Disease: Biology Dictates Therapy
1. A framework and the systemic therapy standards.
2. Castration resistant prostate cancers are not “hormone refractory”.
3. Building on the “first line” standard..3. u d g o e s e s d d..
4. The landscape is changing indeed.
Building on Docetaxel As the First-Line Standard of Care
3
Rising PSAClinicallyLocalizedDisease
1Rising PSA:
Castrate
ClinicalMetastases:
Non-Castrate
2Clinical
Metastases:Castrate
Pre-
3Clinical
MetastasesCastrate1st Line
DocetaxelStandard
4Clinical
Metastases:Castrate2nd Line
No Standard
1. New agents: many classes:cytotoxics, biologics, signaling inhibitors, proapoptotic -microenvironment directed
2. Combinations:
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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
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Docetaxel +/- Avastin
A negative trial.
Targeting the Bidirectional Tumor-Host Interaction in Bone
Tu and Lin, The Cancer Journal 14:35, 2008
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Systemic Approaches for the Treatment of Advanced Disease: Biology Dictates Therapy
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.
Building on Docetaxel As the First-Line Standard of Care
Rising PSAClinicallyLocalizedDisease
1Rising PSA:
Castrate
ClinicalMetastases:
Non-Castrate
2Clinical
Metastases:Castrate
Pre-
3Clinical
MetastasesCastrate1st Line
DocetaxelStandard
4Clinical
Metastases:Castrate2nd Line
No Standard
1. New agents: many classes:cytotoxics, biologics, signaling inhibitors, proapoptotic -microenvironment directed
2. Combinations:
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16
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
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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.
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Systemic Approaches for the Treatment of Advanced Disease: Biology Dictates Therapy
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.
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