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Advanced Stage Disease:
Management of Disease Progression and
Emerging Drug Protocols
Howard I. Scher, MD
Chief, Genitourinary Oncology Service
Memorial Sloan Kettering Cancer Center
October 6, 2009
Advanced Stage Disease
1. Clinical States: A framework for drug development.
2. Dissecting the lethal phenotype.
3. Targeting AR signaling: MDV3100.
4. CTC as a biomarker.
Prostate Cancer Clinical States: A Framework For Clinical
Practice, Drug Development and Biomarker Qualification
Diagnoses
186, 320
Clinically
Localized
Disease
Non-Castrate
Androgen depletion
/blockade (bicalutamide)
Castration resistant:
Deaths From Disease
28,660
Rising PSA
Clinical
Metastases:
Non-Castrate
1
Rising PSA:
Castrate
2
Clinical
Metastases:
Castrate
Pre-
3
Clinical
Metastases:
Castrate
1st Line
Docetaxel
Standard
4
Clinical
Metastases:
Castrate
2nd Line
No Standard
For Castration Resistant Prostate Cancers Q3 Week Docetaxel
Can Prolong Life And Is the First Line Standard of Care
Drugs No.
99-16 D+E
M+P
327
D
M+P
386
384
335
337
18 mos. 0.02
16
18.9
16.4
0.009
D = docetaxel,
E = estramustine,
M = mitoxantrone, P = prednisone
Petrylak et al., and Tannock et al., NEJM, 2004
Probability of Surviving
Trial
Median
Survival P=
1.0
0.9
Docetaxel 3 wkly
0.8
Mitoxantrone
Docetaxel wkly
0.7
0.6
0.5
0.4
0.3
0.2
Tax 327
0.1
0.0
0
6
12
18
24
–
30
Clinical Trials Are Experiments Conducted
With Therapeutic Intent
1.
Objective:
Goals and therapeutic aim.
2.
Patient population:
Entry criteria: minimize heterogeneity,
or enrich for specific characteristics.
3.
Intervention:
Mechanism: cidal, static, targeted.
Dose and schedule: safety.
4.
Outcomes:
Endpoints: (aka response criteria).
Phase 2: ? Signal, if so, how strong?
Statistical design.
5. Conclusions:
Was the question answered?
Is continued development justified?
Outcome Measures Are Biomarkers To be
Validated Analytically and Qualified Clinically
1.
2.
3.
4.
Insure a drug is no longer working before stopping therapy.
Report PSA changes using waterfall plots.
Confirm bone scan findings with a second scan.
Eliminate overall response as an outcome: focus on time to event.
Building on Docetaxel As the First-Line
Standard of Care
Clinically
Localized
Disease
Rising PSA
Clinical
Metastases:
Non-Castrate
1
Rising PSA:
Castrate
2
Clinical
Metastases:
Castrate
Pre-
3
Clinical
Metastases
Castrate
1st Line
Docetaxel
Standard
1. New agents: many classes:
cytotoxics, biologics, signaling inhibitors, proapoptotic microenvironment directed
2. Combinations:
4
Clinical
Metastases:
Castrate
2nd Line
No Standard
Drug Development in Castration-Resistant Disease:
Clinical Contexts Around Docetaxel As A Standard
Clinically
Localized
Disease
Rising PSA
Clinical
Metastases:
Non-Castrate
1
Rising PSA:
Castrate
2
Clinical
Metastases:
Castrate
Pre-
3
Clinical
Metastases:
Castrate
1st Line
Docetaxel
4
Clinical
Metastases:
Castrate
2nd Line
No Standard
Chemotherapy
Drug Development Contexts:
1. Rising PSA castrate:
2 Pre-chemotherapy:
2nd line hormonal agents, biologics.
3. 1st line:
Docetaxel based combinations.
4. 2nd line:
Investigational: e.g. cytotoxics,
targeted / directed agents.
A Partial List of Taxotere Combinations Under Evaluation
As First-Line Therapy
Phase 3
1.
+ Avastin (anti-VEGF Ab)
Genentech (CALGB)
2.
+ Atrasentan
Abbott (SWOG)
3.
+ ZD4054
Astra-Zeneca (ENTHUSE)
4.
+ VEGF-trap
Sanofi-Aventis
5.
+ dasatinib
BMS
6.
+ Gossypol (BCL-2)
Ascenta
7.
+ clusterin antisense
Oncogenix
With caveat the PSA changes are misleading!
- accrued
Targeting the Bidirectional Tumor-Host Interaction
in Bone
Tu and Lin, The Cancer Journal 14:35, 2008
Eligibility
Stratification
Metastatic PC
T <50 ng/ml
No prior chemo
Adequate hem,
renal, hepatic
function
Halabi
nomogram
N = 1020 patients
CALGB, ECOG, NCIC
RANDOMIZE
CALGB 9040: Randomized Double Blinded Placebo controlled Phase
III Trial Comparing Docetaxel + Prednisone with or without
Bevacizumab in men with CRPC
Docetaxel q 3 wks +
Prednisone + Placebo
Docetaxel q 3 wks +
bevacizumab +
prednisone
Endpoint: Overall / progression free survival, PSA response rate;
Hazard Ratio = 1.26 (19 months to 24 months), 90% power
Advanced Stage Disease
1. Clinical States: A framework for drug development.
2. Dissecting the lethal phenotype.
3. Targeting AR signaling: MDV3100.
4. CTC as a biomarker.
Androgen Depletion Produces Declines in PSA and
Tumor Shrinkage, Followed by Regrowth as a
Castration-Resistant Lesion
Castrate “T” < 50 ng/dl
1.
As initial treatment: Androgen
depletion is not curative.
2.
A rising PSA shows the AR
is signaling and a transition to a
lethal phenotype.
Clinical Insights into Castration-Resistant Progression
Guiding Drug Development
1.
Rising PSA levels are consistent with continued AR signaling.
2.
Clinical significance of AR targeting is reinforced by the response to
secondary hormone therapies, as well as the “withdrawal”/
“discontinuation” of anti-androgens.
3.
This suggests antagonists later functions as an agonist as the disease
progresses.
4.
The AR ligand binding domain is clinically relevant and contributes to
progression.
Oncogenic Changes in the Androgen Receptor in Castration
Resistant Prostate Cancer Are Targets for Therapy
o
Untreated
Primary
Scher et al.
Endocrine-Related
Cancer 11:2004;459
Post-Androgen
Depletion
Metastatic Castration
Resistant
Mutations
Increased AR protein
AR mRNA overexpression
Increased AR DNA copy
number
Overexpressed androgen
synthetic enzymes
Advanced Stage Disease
1. Clinical States: A framework for drug development.
2. Dissecting the lethal phenotype.
3. Targeting AR signaling: MDV3100.
4. CTC as a biomarker.
MDV3100 and Abiraterone Acetate Target Specific Alterations in
Castration Resistant Prostate Cancer And Show Promising Activity
ANDROGEN METABOLISM
Adrenal synthesis
Abiraterone
Androgen
precursors
AR
AR degraded
mut
AR
AR
AR
AR
Amp
Cell surface
ligand/receptor
Androgens
Tumor synthesis
Abiraterone
DHT
HSP90
Receptor Promiscuity:
antiandrogens,
progestins,
AR
SRC
MDV-3100
AR
P
Nuclear
Localization
+
Akt
AR
AR
P
AR
Overexpression
AR
MDV-3100
Chen et al. Curr Opin Pharm, 2008
P
AR
AR
P
Transcription of
TMPRSS-ETS, etc
for growth and survival
17
MDV3100 For Castration-Resistant Disease: Phase I/II
Pre- And Post-Chemotherapy: PSA Based “Go-No Go”
Clinically
Localized
Disease
Rising PSA
Clinical
Metastases:
Non-Castrate
1
Rising PSA:
2
Clinical
Metastases:
Castrate
Pre-
3
Clinical
Metastases:
Castrate
1st Line
Docetaxel
Standard
4
Clinical
Metastases:
Castrate
2nd Line
No Standard
Castrate
Are castration resistant prostate
cancers sensitive to further
androgen depletion?
Does the decision to GIVE chemotherapy
render the tumor resistant to a
hormonal intervention?
MDV3100:
A Hormonal Therapy
Four Separate Phase 1 and Phase 2 Trials Demonstrated The
Activity of Abiraterone in Progressive CRPC
Pre- and Post-Chemotherapy
Trial
No.
Attard (Marsden)
Ryan (UCSF)
> 50% PSA Decline CTC Conversion
> 5 to 4 or less
Pre-Chemotherapy
42
27 (70%)
10/17 (59%)
30
16 (53%)
---
Reid (Marsden)
Danila (MSK)
Post-Chemotherapy
47
24 (51%)
56
25 (47%)
11/27 (41%)
9/25 (36%)
Royal Marsden, UCSF, Dana Farber, MSKCC, MDACC, JHU
Efficacy Response – 1: The Phase III Registration Trial of
Abiraterone Acetate in Post-Chemotherapy (Cougar 301)
Includes the Prospective Evaluation of CTC Number
STATISTICS
2
Abiraterone 1000 mg daily
Prednisone 10 mg daily
1
Placebo daily
Prednisone 10 mg daily
R
1.
2.
3.
4.
Primary:
Secondary:
Statistics:
Biomarkers:
25% survival increase
CTC number
Approximately 1200
CTC enumeration
Profiling
Fully accrued ahead of schedule: Analyses performed blinded and anonymously.
Screening and cycle 1 day 1 samples prior to therapy; monthly post-therapy.
Explore associations with clinical outcomes.
Exploratory molecular/biologic analyses.
Baseline and sequential samples on approximately 1000 patients.
DeBono, J (Europe) and Scher, H. (North America) Co-PI,
OrthoBiotech Oncology Research And Development (A Unit of Cougar Biotechnology)
Advanced Stage Disease
1. Clinical States: A framework for drug development.
2. Dissecting the lethal phenotype.
3. Targeting AR signaling: MDV3100.
4. CTC as a biomarker.
MDV3100 and Abiraterone Acetate Target Specific Alterations in
Castration Resistant Prostate Cancer And Show Promising Activity
ANDROGEN METABOLISM
Adrenal synthesis
Abiraterone
Androgen
precursors
AR
AR degraded
mut
AR
AR
AR
AR
Amp
Cell surface
ligand/receptor
Androgens
Tumor synthesis
Abiraterone
DHT
HSP90
Receptor Promiscuity:
antiandrogens,
progestins,
AR
SRC
MDV-3100
AR
P
Nuclear
Localization
+
Akt
AR
AR
P
AR
Overexpression
AR
MDV-3100
Chen et al. Curr Opin Pharm, 2008
P
AR
AR
P
Transcription of
TMPRSS-ETS, etc
for growth and survival
22
The AR Antagonist MDV3100 Is Active Against Bicalutamide
Resistant Xenografts with Overexpressed AR,
And Inhibits AR Nuclear Translocation
LNCaP
100
Intact males
75
+AR
50
Castrate males
25
Vector
0
0
50
100
150
Chen et al, Nature Medicine, 2004
Tran et al, Science, 324: 8 May 2009
Tran et al, Science, 324: 8 May 2009
The AR Antagonist MDV3100 is Active in Pre- and PostChemotherapy CRPC Based on PSA, Imaging and
CTC Conversion Rates
Waterfall Plot of Percent
PSA Change from Baseline
62%
(40/65)
Chemotherapy
-Naïve
Circulating Tumor Cells
51%
(38/75)
PostChemotherapy
Scher et al., ASCO, June 2009
No.
Pre-Therapy
Unfavorable
>5
Post-Therapy
Unfavorable
to Favorable
Total
128
51 (32%)
15 (49%)
Pre-
60
16 (23%)
12 (75%)
Post-
68
35 (54%)
13 (37%)
CTC successfully measured in 128 (92%)
of cases in a 5 Center PCCTC Trial
Efficacy-Response #2: Phase III Registration Trial of MDV3100
in CRPC Post-Chemotherapy (AFFIRM) Also Includes the
Prospective Evaluation of CTC Number as a Biomarker
STATISTICS
2
Medivation 160 mg daily
Prednisone 10 mg daily
1
Placebo daily
Prednisone 10 mg daily
R
1.
2.
3.
4.
Primary:
Secondary:
Sample size:
Biomarkers:
IRB approved.
Activation, October, 2009.
CTC sampling mirrors Cougar 301.
Associations with clinical outcomes:
25% survival increase
CTC number
Approximately 1200
CTC enumeration
Profiling
clinical and biologic.
Scher H. (North America) and DeBono, J (Europe) Co-PI
Therapy Development: A Multidisciplinary Team
Daniel Danila
David Solit
Dana Rathkopf
Michael Morris
Nicholas Mitsiades
Charles Sawyers
Yu Chen
Nicola Clegg
Royal Marsden:
Johann de Bono
Gerhart Attard
Neal Rosen
U. Miami: Richard Cote
Martin Fleisher
Hans Lilja
Rita EspinosaGonzalez
Aseem Anand
Adriana Heguy
Margaret Leversha
Jan Hendrix
Oscar Lin
OHSU:
Tom Beer
CSHL:
U Washington:
Celestia Higano
Bruce Montgomery
Glenn Heller
Larry Schwartz
Hedvig
Steven Solomon
Chris Sander
Nikki Schultz
†William Gerald
Anu Gopalan
Victor Reuter
Richard MacCombie
MGH SU2C: Dan Haber
FDA BQRT: Federico Goodsaid
MDACC: Chris Logothetis
Eleni Efstathiou
DFCI:
Steven Larson
Peter Smith Jones
Ortho Biotechnology (Cougar):
Arturo Molina
Chris Haqq
Medivation: Lynn Seely
Mohammed Hirmand
Veridex: Robert McCormack
Mary-Ellen Taplin
U Michigan:
Maha Hussain
NIH SPORE; DOD PCCTC
Prostate Cancer Foundation
STARR Foundation ,
FNIH
DeWitt Wallace