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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. Clinical States: A framework for drug development. - PowerPoint PPT Presentation
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Howard I. Scher, MDChief, Genitourinary Oncology Service
Memorial Sloan Kettering Cancer Center
October 6, 2009
Advanced Stage Disease:Management of Disease Progression and
Emerging Drug Protocols
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 ClinicalPractice, Drug Development and Biomarker Qualification
Rising PSA
3Clinical
Metastases:Castrate1st Line
DocetaxelStandard
2Clinical
Metastases:Castrate
Pre-
ClinicallyLocalizedDisease
1Rising PSA:
Castrate
ClinicalMetastases:
Non-Castrate
4Clinical
Metastases:Castrate2nd Line
No Standard
28,660
Castration resistant:Deaths From Disease
Diagnoses
186, 320
Non-CastrateAndrogen depletion
/blockade (bicalutamide)
MedianTrial Drugs No. Survival P=
99-16 D+E 386 18 mos. 0.02 M+P 384 16
327 D 335 18.9 0.009 M+P 337 16.4
D = docetaxel, E = estramustine, M = mitoxantrone, P = prednisone
Petrylak et al., and Tannock et al., NEJM, 2004
–
Pro
bab
ilit
y of
Su
rviv
ing
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
For Castration Resistant Prostate Cancers Q3 Week DocetaxelCan Prolong Life And Is the First Line Standard of Care
Tax 327
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.
1. Outcomes: Endpoints: (aka response criteria).Phase 2: ? Signal, if so, how strong?Statistical design.
5. Conclusions: Was the question answered? Is continued development justified?
1. Insure a drug is no longer working before stopping therapy.2. Report PSA changes using waterfall plots.3. Confirm bone scan findings with a second scan.4. Eliminate overall response as an outcome: focus on time to event.
Outcome Measures Are Biomarkers To be Validated Analytically and Qualified Clinically
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:
Rising PSA
3Clinical
Metastases:Castrate1st Line
Docetaxel
2Clinical
Metastases:Castrate
Pre-
ClinicallyLocalizedDisease
Drug Development in Castration-Resistant Disease:Clinical Contexts Around Docetaxel As A Standard
1Rising PSA:
Castrate
ClinicalMetastases:
Non-Castrate
4Clinical
Metastases:Castrate2nd Line
No Standard
ChemotherapyDrug 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
• + Avastin (anti-VEGF Ab) Genentech (CALGB) - accrued
• + Atrasentan Abbott (SWOG)
• + ZD4054 Astra-Zeneca (ENTHUSE)
• + VEGF-trap Sanofi-Aventis
• + dasatinib BMS
• + Gossypol (BCL-2) Ascenta
• + clusterin antisense Oncogenix
With caveat the PSA changes are misleading!
Targeting the Bidirectional Tumor-Host Interaction in Bone
Tu and Lin, The Cancer Journal 14:35, 2008
CALGB 9040: Randomized Double Blinded Placebo controlled Phase III Trial Comparing Docetaxel + Prednisone with or without
Bevacizumab in men with CRPC
RA
ND
OM
IZE
RA
ND
OM
IZE
Docetaxel q 3 wks + Prednisone + Placebo
Docetaxel q 3 wks +bevacizumab +prednisone
EligibilityMetastatic PCT <50 ng/mlNo prior chemoAdequate hem, renal, hepatic function
StratificationHalabinomogram
N = 1020 patientsCALGB, ECOG, NCIC
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.
UntreatedPrimary
Metastatic CastrationResistant
Scher et al. Endocrine-RelatedCancer 11:2004;459
Oncogenic Changes in the Androgen Receptor in Castration Resistant Prostate Cancer Are Targets for Therapy
MutationsIncreased AR proteinAR mRNA overexpressionIncreased AR DNA copy numberOverexpressed androgen synthetic enzymes
o
Post-AndrogenDepletion
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
AR
HSP90AR degraded
AR P
Abiraterone
AR PARP
MDV-3100
Transcription of TMPRSS-ETS, etcfor growth and survival
SRC
Androgenprecursors
AndrogensAdrenal synthesis
Tumor synthesis
Abiraterone
DHT
AR AR
Cell surface ligand/receptor
Akt
ARP
mutAR
ARARARAmpAR
+
Receptor Promiscuity: antiandrogens, progestins,
MDV-3100Chen et al. Curr Opin Pharm, 2008
NuclearLocalization
AROverexpression
17
Rising PSA
3Clinical
Metastases:Castrate1st Line
DocetaxelStandard
2Clinical
Metastases:Castrate
Pre-
ClinicallyLocalizedDisease
MDV3100 For Castration-Resistant Disease: Phase I/II Pre- And Post-Chemotherapy: PSA Based “Go-No Go”
1Rising PSA:
Castrate
ClinicalMetastases:
Non-Castrate
4Clinical
Metastases:Castrate2nd Line
No Standard
MDV3100:A Hormonal Therapy
Are castration resistant prostate cancers sensitive to further
androgen depletion?
Does the decision to GIVE chemotherapy render the tumor resistant to a hormonal intervention?
Four Separate Phase 1 and Phase 2 Trials Demonstrated The Activity of Abiraterone in Progressive CRPC
Pre- and Post-Chemotherapy
Trial No. > 50% PSA Decline CTC Conversion
> 5 to 4 or less
Pre-Chemotherapy
Attard (Marsden) 42 27 (70%) 10/17 (59%)
Ryan (UCSF) 30 16 (53%) ---
Post-Chemotherapy
Reid (Marsden) 47 24 (51%) 11/27 (41%)
Danila (MSK) 56 25 (47%) 9/25 (36%)
Royal Marsden, UCSF, Dana Farber, MSKCC, MDACC, JHU
Efficacy Response – 1: Efficacy Response – 1: The Phase III Registration Trial of The Phase III Registration Trial of Abiraterone Acetate in Post-Chemotherapy Abiraterone Acetate in Post-Chemotherapy (Cougar 301) (Cougar 301) Includes
the Prospective Evaluation of CTC Number
DeBono, J (Europe) and Scher, H. (North America) Co-PI, OrthoBiotech Oncology Research And Development (A Unit of Cougar Biotechnology)
R
Abiraterone 1000 mg dailyPrednisone 10 mg daily
Placebo dailyPrednisone 10 mg daily
2
1
STATISTICS
Primary: 25% survival increaseSecondary: CTC numberStatistics: Approximately 1200Biomarkers: CTC enumeration
Profiling
1. Fully accrued ahead of schedule: Analyses performed blinded and anonymously.2. Screening and cycle 1 day 1 samples prior to therapy; monthly post-therapy.3. Explore associations with clinical outcomes.4. Exploratory molecular/biologic analyses.
Baseline and sequential samples on approximately 1000 patients.
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
AR
HSP90AR degraded
AR P
Abiraterone
AR PARP
MDV-3100
Transcription of TMPRSS-ETS, etcfor growth and survival
SRC
Androgenprecursors
AndrogensAdrenal synthesis
Tumor synthesis
Abiraterone
DHT
AR AR
Cell surface ligand/receptor
Akt
ARP
mutAR
ARARARAmpAR
+
Receptor Promiscuity: antiandrogens, progestins,
MDV-3100Chen et al. Curr Opin Pharm, 2008
NuclearLocalization
AROverexpression
22
The AR Antagonist MDV3100 Is Active Against Bicalutamide Resistant Xenografts with Overexpressed AR,
And Inhibits AR Nuclear Translocation
0
25
50
75
100
0 50 100 150
+AR
Vector
LNCaP
Intact males
Castrate males
Chen et al, Nature Medicine, 2004
Tran et al, Science, 324: 8 May 2009
Tran et al, Science, 324: 8 May 2009
Waterfall Plot of PercentPSA Change from Baseline
Chemotherapy-Naïve
Post-Chemotherapy
62% (40/65)
51% (38/75)
Circulating Tumor Cells
Pre-Therapy Post-Therapy
UnfavorableUnfavorable
No. > 5 to Favorable
Total 128 51 (32%) 15 (49%)
Pre- 60 16 (23%) 12 (75%)
Post- 68 35 (54%) 13 (37%)Scher et al., ASCO, June 2009
The AR Antagonist MDV3100 is Active in Pre- and Post-Chemotherapy CRPC Based on PSA, Imaging and
CTC Conversion Rates
CTC successfully measured in 128 (92%)of cases in a 5 Center PCCTC Trial
Efficacy-Response #2: Efficacy-Response #2: Phase III Registration Trial of MDV3100 Phase III Registration Trial of MDV3100 in CRPC Post-Chemotherapy in CRPC Post-Chemotherapy (AFFIRM) Also (AFFIRM) Also Includes the
Prospective Evaluation of CTC Number as a Biomarker
Scher H. (North America) and DeBono, J (Europe) Co-PI
R
Medivation 160 mg dailyPrednisone 10 mg daily
Placebo dailyPrednisone 10 mg daily
2
1
STATISTICS
Primary: 25% survival increaseSecondary: CTC numberSample size: Approximately 1200Biomarkers: CTC enumeration
Profiling
1. IRB approved.2. Activation, October, 2009.3. CTC sampling mirrors Cougar 301.4. Associations with clinical outcomes: clinical and
biologic.
Therapy Development: A Multidisciplinary Team
Daniel Danila
David Solit
Dana Rathkopf
Michael Morris
Nicholas Mitsiades
Martin Fleisher
Hans Lilja
Rita Espinosa-
Gonzalez
Aseem Anand
Larry Schwartz
Hedvig
Steven Solomon
Steven Larson
Peter Smith Jones
Charles Sawyers
Yu Chen
Nicola Clegg
Neal Rosen
Adriana Heguy
Margaret Leversha
Jan Hendrix
Oscar Lin
Glenn Heller
Chris Sander
Nikki Schultz
†William Gerald
Anu Gopalan
Victor Reuter
Royal Marsden:
Johann de Bono
Gerhart Attard
U. Miami: Richard Cote
OHSU: Tom Beer
U Washington:
Celestia Higano
Bruce Montgomery
MDACC: Chris Logothetis
Eleni Efstathiou
DFCI: Mary-Ellen Taplin
U Michigan:
Maha Hussain
Ortho Biotechnology (Cougar):
Arturo Molina
Chris Haqq
Medivation: Lynn Seely
Mohammed Hirmand
Veridex: Robert McCormack
CSHL: Richard MacCombie
MGH SU2C: Dan Haber
FDA BQRT: Federico Goodsaid
NIH SPORE; DOD PCCTC
Prostate Cancer Foundation
STARR Foundation ,
FNIH
DeWitt Wallace