“Hormonal” Therapy in Advanced Prostate Cancer - … · “Hormonal” Therapy in Advanced...
Transcript of “Hormonal” Therapy in Advanced Prostate Cancer - … · “Hormonal” Therapy in Advanced...
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“Hormonal” Therapy in Advanced
Prostate Cancer - Beyond Simple
Castration
Martin Gleave MD, FRCSC, FACS
Distinguished Professor, UBC
B.C. Leadership Chair in Prostate Research
Director, The Prostate Centre at VGH
Chair, GU Tumour Group, BCCA
Chairman, NCIC GU Clinical Trials Group, & CUOG
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Hormonal therapy for CaP: Hormonal therapy for CaP: Beyond Simple CastrationBeyond Simple Castration
History of Androgen Therapy
� male sex hormones are collectively known as androgens, which is derived from the Greek andros, (man) and gennan (to produce)
� 1786: John Hunter described seasonal variations in the size of the testicles and prostate gland in animals. Later tested the effects of castration on secondary sex organs.
� 1893: William White measured changes in the prostate gland after castration using dogs. Proposed using castration to treat urinary obstruction disorders.
� 1935: Clyde Deming reported that castration decreased the size of the prostate in primates but had no effect on BPH.
Hormonal therapy for CaP: Hormonal therapy for CaP: Beyond Simple CastrationBeyond Simple Castration
� Charles Huggins
� Canadian-born; Urologic-scientist at U of Chicago
� Most men had incurable/metastatic disease
� Castration = surgical or estrogen
� Limited understanding of molecular basis of androgen
action or resistance
Nobel Laureate, 1966Nobel Laureate, 1966
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Hormonal Therapy for CaP: Hormonal Therapy for CaP: Approaches and IssuesApproaches and Issues
� Androgen Action
� Androgen Deprivation Therapy
� Maximal androgen blockade
� Timing
� Immediate vs deferred
� Intermittent vs continuous
� Androgen Resistance - CRPC
� Targeted therapies
Androgen Axis and Hormonal
Therapy
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Cell Survival and Proliferation
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Androgen Actiontestosterone
Androgen
Receptor
Bound AR-
DHT complex
5α-R
DHT
ARAR
AR
ARE
Androgen Receptor: Interactions
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http://www.androgendb.mcgill.ca/
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Androgen Action: Genomic and Non-genomic AR Activity
Modified from Gruber CJ, NEJM 2002, 346:340
Nuclear Androgen
Receptor
Androgen
Androgen
Receptor
Androgen
� AR is a ligand dependent nuclear transcription factor, part of the
steroid receptor super-family
Increased secretory activity
mitogenic + anti-apoptotic effects
Androgen Axis and Hormonal Therapy
testosterone
5αR ⇒ DHT
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Androgens rapidly phosphorylate Hsp27 in a dose and time dependent manner
0 1 2.5 5 7.5 10 (nM) R1881
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Total Hsp27
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0 5 15 30 60 Time (min)
0 5 15 30 60 Time (min)
A B
pHsp27 (S-82)
pHsp27 (S-78)
Total Hsp27
pHsp27 (S-82)
The rapid time frame of androgen action is consistent with non genomic effect of androgen
Hsp27 is phosphorylated predominantly on Ser 78, and 82
Can Res 67: 10455, 2007
Hsp 27 AR
CSS
DAPI Merge DAPI Merge
Hsp 27 AR
R1881 (15 min)
Androgen receptor interacts and co-localizes
with Hsp27 in LNCaP cells
WL IgG AR Hsp27
IP
AR
Hsp27
Can Res 67: 10455, 2007
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Effects of Hsp27 Expression Levels and AR Transactivation
Hsp27 antisense ↓↓↓↓↓↓↓↓ AR Induction of PSA-luciferase
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Hsp27 WT ↑↑↑↑↑↑↑↑ AR Induction of PSA-luciferase
Lu
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CasodexR1881
- - +- + +
pHsp27 (S-78)
pHsp27 (S-82)
Total Hsp27
Effect of hsp27 on AR Activity requires the AR since it is blocked by antiandrogen, CasodexHsp27 knockdown decreases AR and PSA levels
Hsp27
AR
30 50 70 30 50 70 (nM)
MM Hsp27 ASO
Vinculin
Can Res 67: 10455, 2007
Effects of Hsp27-AR interactions on genomic and
non-genomic activity of androgen/AR
OGX-427
Day 0 Day 4 Day 8
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Can Res 67: 10455, 2007
Androgens
AR
Hsp90
PSAARE ARE
AR
Survival
p38 P
Hsp27P
Hsp27AR
P
Hsp27AR
P
cytoplasm
nucleus
Hsp90
AR
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degradation
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AR
Hsp90
PSAARE ARE
Apoptosis
p38 P
Hsp27
cytoplasm
nucleus
Hsp90
AROGX-427
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MDM2
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Androgen Action: Androgen Action: ProPro--survival and Mitogenicsurvival and Mitogenic
010203040506070 S ub G 0 G0-G1 S G2-MPercentage of cell cycle population C SSR 1881
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+ paclitaxel + paclitaxel
HOW??HOW??
AndrogenAndrogen--Induced Changes in Induced Changes in Gene Expression Gene Expression
010203040506070 Sub G0 G0-G1 S G2-MPercentage of cell cycle population CSSR1881
miR 125b - AR regulated miRNA that negatively
regulates expression levels of Bak1, a proapoptotic
member of Bcl-2 family (Shi XB, PNAS, 2007)
- + - + - + R1881
AR-ChIP
sCLU mRNA
Total RNA
R1881
Clusterin is an AR-regulated Cytoprotective Gene
Cochrane et al, JBC, 2006
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Taxol (nM)
Miyake et al, Cancer Res, 2000
sCLU-2 - cytoprotective chaperone that interacts with
and inhibits Bax, a proapoptotic Bcl-2 family member
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Androgen Transcriptionally Regulate CLU Expression
Clusterin
mRNA
Total
RNA
clusterin
tubulin
60 kDa
40 kDa
1 nM R1881
1 µM Casodex
ClusterinmRNA
- + + - + + - + +
- - + - - + - - +
TotalRNA
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Androgen Action: Androgen Action: ProPro--survival and Mitogenicsurvival and Mitogenic
� T ⇒⇒⇒⇒ DHT regulates transcriptional activity of AR
� AR has both genomic and non-genomic effects
� Potentiates IGF-1 responsiveness through increased IGF-1R levels (Kruekl et al, Cancer Res, 2004)
� Increases expression levels and/or activation of cytoprotective
chaperones� eg - clusterin, phospho-Hsp27
� Increases expression miRNA that negatively regulates expression of
pro-apoptotic genes� eg - Bak
Apoptotic Rheostat
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Hormonal therapy for CaP: Hormonal therapy for CaP: Approaches and IssuesApproaches and Issues
� Androgen Action� Anti-apoptotic, effects on chemosensitivity
� ADT - (Dosing and Scheduling Issues)
� Maximal androgen blockade - Relevance today?
� Timing
� Immediate vs deferred
� Intermittent vs continuous
� Androgen Resistance - CRPC
Rationale for Combined Androgen Blockade
Adrenal androgens
Peripheral cells
Adipose muscle
Circulation
Adrenalglands
LH
ACTH
LHRH CRH
Leydigcells oftestes
Hypothalamus
Pituitary gland
Feedback
control
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10101010----Year Survival: Randomized Trials of MAB Year Survival: Randomized Trials of MAB Year Survival: Randomized Trials of MAB Year Survival: Randomized Trials of MAB vs AS Alonevs AS Alonevs AS Alonevs AS Alone
Prostate Cancer Trialist’s Collaborative Group. Maximum androgen blockade
in advanced prostate cancer: an overview of the randomized trials. Lancet
2000;355:1494.
� PCTCG meta analyses of MAB vs monotherapy
� 27 trials: 8,275 men
� 1.8% improvement in 5 year survival for MAB compared with monotherapy
� 25.4% vs 23.6%
� HR 0.96 (p=0.026)
10101010----Year Overall Survival: MetaYear Overall Survival: MetaYear Overall Survival: MetaYear Overall Survival: Meta----analyses analyses analyses analyses Randomized Trials of MAB vs AS AloneRandomized Trials of MAB vs AS AloneRandomized Trials of MAB vs AS AloneRandomized Trials of MAB vs AS Alone
Prostate Cancer Trialist’s Collaborative Group. Maximum androgen blockade
in advanced prostate cancer: an overview of the randomized trials. Lancet
2000;355:1494.
� PCTCG meta analyses of MAB vs monotherapy
� 27 trials: 8,275 men
� 1.8% improvement in 5 year survival for MAB compared with monotherapy
� 25.4% vs 23.6%
� HR 0.96 (p=0.026)
Meta-analyses:
4 month survival advantage with LHRH-A + NSAA (eg.
Bicalutamide, flutamide)
New RCT data - Overall survival improved in MAB arm- 0.78 HR:
Usami M, Akaza H, Arai Y et al. Bicalutamide 80 mg combined with a luteinizing
hormone-releasing hormone agonist (LHRH-A) versus LHRH-A monotherapy in
advanced prostate cancer: findings from a phase III randomized, double-blind,
multicenter trial in Japanese patients. Prostate Cancer Prostatic Diseases 2007;
10(2): 194–201.
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Hormonal therapy for CaP: Hormonal therapy for CaP: Approaches and IssuesApproaches and Issues
� Androgen Axis and Action
� Anti-apoptotic, chemo- and radio-sensitization
� Maximal androgen blockade
� Relevance today?
� implications for ↑↑↑↑↑↑↑↑ T suppression, AR blockade
� We are now recommending LHRH + bicalutamide at BCCA
� AR remains an important and relevant target
� Inhibition of intracrine T production (eg. abiraterone)
� Super AR antagonists
� AR disruptors (eg. Hsp27, Hsp90, HDAC inhibitors)
Hormonal therapy for CaP: Hormonal therapy for CaP: Approaches and IssuesApproaches and Issues
� Androgen Axis and Action� Anti-apoptotic, effects on chemosensitivity
� Maximal androgen blockade
� Relevance today? - implications for > T suppression, AR blockade
� Timing
� Immediate vs deferred
� Intermittent vs continuous
� Neoadjuvant, adjuvant, combination regimens
� Androgen Resistance - HRPC
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Effects of Timing of Androgen Ablation on Timeto AI Progression in Shionogi Tumour Model
So et al, BJU Int. 2004 Apr;93(6):845-50
•Time to androgen-independent recurrence is directly proportional to tumor burden at time of castration
Optimal Timing of ADT Optimal Timing of ADT --Immediate vs Delayed?
1. Xenografts: improved survival when castrated at low tumour volume
2. EORTC: improved survival with immediate HT post-RT (Bolla et al, NEJM
1995)
3. ECOG: 2% vs 30% PCa mortality with immediate vs delayed HT in N+
disease post-RP (Messing et al, NEJM 2000)
4. EPC Data (Casodex monotherapy trial)
-prolongs time to radiographic and biochemical progression (predictable)
-overall survival reduced in Casodex arm in low risk CaP! (HR 1.47)
-overall survival improved in Casodex arm in high risk CaP! (HR 0.68)
Evidence Supporting Immediate Therapy
�emphasizes need for careful selection (use life expectancy, risk factors, PSAdt as guide)
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Immediate vs Delayed Androgen Ablation?
1. Xenografts: improved survival when castrated at low tumour volume
2. EORTC: improved survival with adjuvant therapy post-radiotherapy
3. MRC: Delayed time to progression and improved survival M0 CaP
4. ECOG: 2% vs 30% PCa mortality with immediate vs delayed HT in
- N+ disease post-RP (NEJM 2000)
5. EPC Data (Casodex monotherapy trial)
-reduces radiographic and biochemical time to progression (predictable)
-OS adversely affected in Casodex arm in low risk CaP! (HR 1.47)
-OS improved in Casodex arm in high risk CaP! (HR 0.68)
Evidence Supporting Immediate Therapy
�No supporting evidence that delayed therapy equivalentto immediate in other tumours, but EPC emphasizes need for careful selection
Immediate vs Delayed Androgen Ablation + RT
RT alone 75% 44% 56%RT + HT 95% 85% 78%
Radiotherapy Plus Adjuvant HT
Bolla et al NEJM, 1998
LC cNED Survival
p<0.001 p<0.001 p<0.001
•Bolla et al, EORTC•Phase III; Tx, high grade or T3-T4, n=415•randomized to RT alone vs RT + adj Zoladex X 3 yrs.
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Survival Benefit of Earlier Hormone Therapy in Nonmetastatic Disease
Medical Research Council Prostate Cancer Working Party Investigators Group. Br J Urol. 1997 79:235-246.
-reduces radiographic and biochemical time to progression (predictable)
-OS adversely affected in Casodex arm in low risk CaP! (HR ~1.4)
-OS improved in Casodex arm in high risk CaP! (HR ~1.4)
EPC Survival — Trial 25Localized vs Locally Advanced PatientsEPC Survival — Trial 25Localized vs Locally Advanced Patients
HR=1.47 (1.06, 2.03)'Casodex' events = 90 (25.6%)placebo events = 64 (17.8%)
Time to death (years)
1.0
0.9
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Pro
po
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urv
ivin
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placebo'Casodex'
HR=0.68 (0.50, 0.92)'Casodex' events = 73 (28.6%)placebo events = 94 (37.6%)
Time to death (years)
1.0
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Pro
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placebo
'Casodex'
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Prostate cancer is not the only cause of death in men
• delayed progression
• decreased local complications
• improved survival
• psychological benefits
Balancing the Benefits of Early Hormone Therapy
• short-term side effects
• expense
• long-term metabolic effects» decreased muscle mass» osteoporosis» anemia» lipid profile» immune surveillance» cardiovascular risk» Cognition/mood
� IAS offers opportunity to improve quality of life
� balances benefits of immediate androgen ablation � reduces treatment-related side effects and expense
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Weeks Post-Castration0 2 4 6 8 10 12 14 16 18 20 22
0
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N5
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N1N3
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)
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Intact N1 P1 N3 P4 N5 P5 AIP
PSAmRNA
IAS
CAS
IAS Prolongs Time to Non-Androgen Regulated PSA Gene Expression in the LNCaP model
Sato et al, J Steroid Biochem Molec Biol 58:139, 1996
Time (months)
Se
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A (
µµ µµg
/L)
On Therapy
Off Therapy
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stero
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ol/L
)
Urology 45:839, 1995Mol Urol. 3:287, 1999
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Cycle 1 Cycle 2 Cycle 3 >Cycle 4(n=14) (n=32) (n=13) (n=11)
Clinical Experience with IAS
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Clinical Studies of IAS
1. Goldenberg et al (1995): 47 patients
• Mean time on 9 months; 50% off therapy; up to 5 cycles
2. Higano et al (1996): 22 patients
• median f/u 22 months, 2 completed cycles, 38% of time off therapy
3. Grossfield et al (1998): 47 patients, localized disease
• median f/u 24 months, 3 completed cycles, 50% of time off therapy
4. Crook et al (1999): 52 pateints localized CaP, post XRT
• up to 5 completed cycles, 8 months on; 50% of time off therapy
5. Bruchovsky et al: 100 pts, Multicentre Phase II, Post-XRT Failures
• median f/u 24 months, 1 completed cycle, 50% of time off therapy
• improved Q of L off treatment
Phase III Studies of Intermittent vs
Continuous ADT
1. SWOG/NCIC PR-8: 1300 accrued - closed aug 2008
• Hormone naïve M1 disease; 9 months on, restart PSA > 10-20
2. NCIC PR-7/SWOG 1300 accrued; closed 2007
• M0, post-RT failures; 9 months on, restart PSA 6-15
• Problem - low CaP death rate
German and Portugeuse IAS Trials
•Locally advanced, metastatic; 800 pts enrolled
•no difference in time to AI progression or survival (AUA, 2006, 2007)
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Hormonal therapy for CaP: Hormonal therapy for CaP: Approaches and IssuesApproaches and Issues
� Androgen Axis and Action
� Anti-apoptotic, effects on chemosensitivity
� Maximal androgen blockade
� Relevance today?
� Timing
� Immediate vs deferred
� Intermittent vs continuous
� Neoadjuvant, adjuvant, combination regimens
� Androgen Resistance - HRPC
Hormonal Therapy in Advanced Prostate cancer:
Neoadjuvant and Adjuvant Strategies
Cons
•Cell cycle arrest
•Increased Bcl-2 & clusterin
•Affects PSA as marker of RT response
Theoretical Pros & Cons of NHT Prior to RT
•Shionogi model data
•Lower tumor volume
•Androgens are anti-apoptotic
•Reduced hypoxia
Pros
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Theoretical Pros & Cons of NHT Prior to RT
Pros
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Yapp et al, Radiation Research, 2004,
•Shionogi model data
•Lower tumor volume
•Androgens are anti-apoptotic
•Reduced hypoxia
% hypoxic cells decreases after castration
•High recurrence rate with radiation monotherapy •RTOG 85-31•RTOG 86-10•RTOG 92-02•EORTC 22863 - Bolla et al
•Laverdiere et al
•Combined HT + XRT:•reduced local recurrence•decreased PSA recurrence•improved survival in high risk disease & longer term HT
Combined Hormone Therapy + RT for Localized Prostate Cancer
5 randomized studies
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Does RT Add anything above and beyond HT in High Risk Localized CaP?
NCIC CTG- PR.3
Continuousandrogen ablation
Continuousandrogen ablation
withradiation therapy
High Risk Loc CaPprostatecancer
PI: P. Warde; Intergroup participation (NCIC, MRC UK, SWOG)Primary Endpoint: Survival Sample Size: 1200 Accrual: 1200 (study now closedAnalysis: 2006
NHT Prior to Surgery:
Randomized Studies of 0 vs 3 Months NHT
•7 Phase 3 trials conducted during 1990’s compared 0 vs 3 months NHT prior to RP
•All powered for change in pos. margin rates as primary endpoint
•All studies show ~50% decrease in pos. margin rates
•No studies show improved bNED rates!
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CUOG P95A: Randomized 3 vs 8 Months
NHT Study
Gleave et al, J Urol. 166(2):500-6, 2001Gleave et al, J Urol. 166(2):500-6, 2001
• Mean pre-surgery PSA significantly lower in 8 month group �0.056 vs 0.12 µg/L (p<0.0001)
• Positive margin rates significantly lower in 8 month group �12% vs 23% (p=0.0106)
• Mean pre-surgery PSA significantly lower in 8 month group �0.056 vs 0.12 µg/L (p<0.0001)
• Positive margin rates significantly lower in 8 month group �12% vs 23% (p=0.0106)
N = 549
Surrogates of Treatment ResponseChanges in Serum PSA and Path Stage
N = 549
Surrogates of Treatment ResponseChanges in Serum PSA and Path Stage
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CUOG P95A 3 vs 8 Months NHT Study:
PSA-Free Survival
CUOG P95A 3 vs 8 Months NHT Study:
PSA-Free Survival
33%30%33%30%
7 Year Follow-upOverall Survival = 93%
Overall PSA Relapse Rate - 31%
7 Year Follow-upOverall Survival = 93%
Overall PSA Relapse Rate - 31%
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PSA Recurrence
by Risk Group
PSA Recurrence
by Risk Group
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High Risk (n=97)52% vs 59%
High Risk (n=97)52% vs 59%
Intermediate Risk (n=177)32% vs 25%
Intermediate Risk (n=177)32% vs 25%
Low Risk (n=229)25% vs 22%
Low Risk (n=229)25% vs 22%
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CUOG P95A 3 vs 8 Months NHT Study:
High vs Low Volume Centres
CUOG P95A 3 vs 8 Months NHT Study:
High vs Low Volume Centres
24%39%24%39%
K-M PSA Relapse Rate K-M PSA Relapse Rate
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CUOG P95A: 3 vs 8 Months NHT Study
Summary
• Overall Survival = 93% with Overall PSA relapse - 31%
• Despite improved biochemical and pathologic surrogates, no significant difference in PSA recurrence rates at 5 years post surgery
�Path response rates not predictive of improved bNED
• Subgroup analyses revealed significant site-to-site differences in PSA relapse rates that were independent of prognostic risk factors.
�Illustrate effects of surgical technique on study endpoints,
highlighting a need to stratify for site of surgery in future
randomized multimodal RP trials
� generates an interesting hypothesis that a benefit of prolonged
NHT may exist when employed by more experienced/higher-
volume surgeons.
• Overall Survival = 93% with Overall PSA relapse - 31%
• Despite improved biochemical and pathologic surrogates, no significant difference in PSA recurrence rates at 5 years post surgery
�Path response rates not predictive of improved bNED
• Subgroup analyses revealed significant site-to-site differences in PSA relapse rates that were independent of prognostic risk factors.
�Illustrate effects of surgical technique on study endpoints,
highlighting a need to stratify for site of surgery in future
randomized multimodal RP trials
� generates an interesting hypothesis that a benefit of prolonged
NHT may exist when employed by more experienced/higher-
volume surgeons.
Hormonal Therapy in Advanced Prostate Cancer:
Future Directions
� Taxotere-based hormone naïve disease
� M1 hormone naïve
� Adjuvant post RP in high risk pts
� Salvage in high risk PSA failures post RP
� Neoadjuvant in high risk pts pre RP
� Combined NHT + adj in high risk pts pre-RT
� Chemo-hormonal combination trials
� Which order, simultaneous or sequential?
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• Taxotere (docetaxel)
• Response rate - ~50%
• ~25% improvement OS, TTP, QoL
Chemoresistant disease:
• ~18 month median survival
The Problem: Hormone Refractory Prostate Cancer
Standard Therapy:
� Future = Combination Strategies with novel biologics
� Bio-Logical, based on relevant targets
Castration Resistance and Prostate Cancer
HormoneTherapy
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? ? Molecular mechanisms
Ser
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1. Androgen receptor (AR) related
• amplification (hypersensitive)
• Mutations (promiscuous)
• Intracrine T production
• cross-talk - TK, AKT, STAT3 (phosphorylation, co-regulators)
2. Adaptation
• Up-regulation of survival genes (Bcl-2, clusterin, Hsp27, YB-1)
• Increased alternative GF pathways (her2/neu; IGF-1/IGFBP2&5; IL-6/STAT3)
• underlying basis for most cancer deaths, and result from multiple, stepwise changes in DNA structure and gene expression arising from selective pressures of treatment.
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Mechanisms of Androgen ResistanceMechanisms of Androgen Resistance
Bcl-2, BclxLClusterinHsp27YB-1
IGF-1/IGF-1RHer-2/neuIL-6/stat-3
Hsp-chaperones
CaP Cell Survival and Proliferation
In Androgen-Depleted Environment
Hsp-chaperones
Intracrine T production
Androgen Action: Androgen Action: ProPro--survival and Mitogenicsurvival and Mitogenic
� TAB using non-steroidal anti-androgen like flutamide or bicalutamide
has small benefit in prolonging survival
BUT
� AR remains present, activated and biologically relevant in acquistion
castrate resistance
� What are the mechanisms of AR transactivation after castration?
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Residual Prostatic Androgens with ‘Castration’
Tissue androgen levels in benign prostate (gray) and castrate recurrent prostate cancer (white) previously treated with androgen deprivation.Mohler J et al, Clin Ca Res 10:440, 2004
Intraprostatic Effects of Castration: Intraprostatic Effects of Castration: Hormone MeasurementsHormone Measurements
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T, DHT, and Progesterone Levels Increase T, DHT, and Progesterone Levels Increase in Castrate Resistant LNCaP Tumorsin Castrate Resistant LNCaP Tumors
0
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#1
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-2 n
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Locke et al, Cancer Res; 2008
Hormone dependent, pre-castrate
Regressed, 7 days post castrate
Castrate Resistant
•LNCaP xenograft androgens, like PSA, increase during progression post castration
•Since mice synthesize scant adrenal androgens, we hypothesized that the tumors themselves are the source of increased androgens.
De Novo Androgen Synthesis in De Novo Androgen Synthesis in Prostate Cancer Cells: Backdoor Prostate Cancer Cells: Backdoor PathwayPathway
Pregnen-3,17-diol-20-
one
Cholesterol
Pregnenolone
Progesterone
17-OH progesterone(4-Pregnen-17-ol-3,20-dione)
Pregnan-3,20-dione
Androsterone
Androstenedione
Testosterone
Dihydrotestosterone Androstanediol
Cyp11A1Helper: STAR
HSD3B2
Cyp17A1
Cyp17A1
HSD17B3
HSD17B2,10
RDH5
AKR1C1AKR1C2 AKR1C3HSD17B
3
SRD5A1,2
SRD5A1,2
Pregnan-3α-ol-20-one
AKR1C2
Cyp17A1
Cyp17A1
AKR1C2SRD5A1 Classical
pathwayBackdoor pathway
OHA
C
B
D1
2
3 5 7
814 15
11
9
10
19
12
13 16
1718 20
4 6
STAR (30kDa)
CYP11A1 (52kDa)
CYB5A1 (17kDa)
CYP17A1 (57kDa)
HSD3B2 (40kDa)
HSD17B2 (55kDa)
HSD17B3 (32kDa)
AKR1C3 (37kDa)
SRD5A1 (29kDa)
RDH5 (29kDa)
PSA (34kDa)
Vinculin (110kDa)
AD N AI AD N AI AI AD N AI AD N AI AI AD N AIAD N AI AD N AI
Mouse 1 Mouse 2 Mouse 3 Mouse 4 Mouse 5 Mouse 6 Mouse 7
Locke et al, Cancer Res; 2008
29
Intraprostatic Sources of Androgen: Intraprostatic Sources of Androgen: Backdoor Pathway:Backdoor Pathway:
Locke et al, Cancer Res; 2008
[14C]-acetic acid is converted to DHT in AI LNCaP tumor cells
*
1 23 4
5
6
Identification
LC Radiometric RT
(min)14
C peak #
% of total 14
C
counts
LC MS Standard RT
(min)
Unknown 20.842 1 0.6
4-Pregnen-17-ol-3,20-dione 26.516 2 0.6 25.36
DHT 30.022 3 1.8 28.93
Unknown 33.037 4 2.0
Progesterone 37.319 5 0.4 36.35
Unknown 41.709 6 3.6
Cholesterol and lipids 45.0-70.0 * 91.0
30
Novel Agents In Clinical Trials for CRPC
� Atrasentan (ZD 4054)
� Bevacizumab
� Abiraterone
� Sutent
� OGX-011
� MDV3100
� OGX-427
� Sorafenib
� Trastuzumab
� CP-751,871 (IGF-1R Ab)
� Celecoxib
� Thalidomide
� Strontium
� Imantinib
� GTI-2040
� Erlotinib
� RAD001
� ABT-751
� Failed� Bortezomib (Velcade)
� GVAX
� G3139 (Bcl-2 ASO)
� DN101/calcitriol
Agents targeting critical pathways of progression such as AR,
angiogenesis, growth factors, and apoptosis with potential to
enhance docetaxel therapy
Applied Anatomist
Applied Pathophysiologist
Evolution of the Surgeon-Scientist
31
Applied Anatomist
Applied Pathophysiologist
Applied Molecular Biologist
Evolution of the Surgeon-Scientist
Courtesy of MSKCC
Applied Anatomist
Applied Pathophysiologist
???
Evolution of the Surgeon-Scientist
32
Cell Membrane
ExtracellularExtracellular
IntracellularIntracellular
SignalingmoleculesSignalingmolecules
K KpY pY
Substrate
ProliferationApoptosisAngiogenesisMetastases
ProliferationApoptosisAngiogenesisMetastases
Targeting AngiogenesisTargeting AngiogenesisTargeting AngiogenesisTargeting Angiogenesis
Substrate
pY
BEVACIZUMAB, VEGF-trap
VEGF
VEGF-R J. FolkmanSurgeon-Scientist
Sutent, sorafenab Sutent, sorafenab
Modified from Bagnato A, Catt KJ. Trends Endocr Met 1998;(9):378–83
Nucleus
Atrasentan (& AZ4054) and the
Endothelin Axis: Oncogenic Mechanisms
ET-1
DAGIns P3
Plasmamembrane
Raf
G-proteinPLC
PKC
Ras
MAPK
ETAR
� Cell growth
� Inhibition of apoptosis
� Angiogenesis
� Osteoblastic remodeling
ET-1 acting via ETAR Promotes:
Ca2+ release
Joel Nelson
Surgeon-Scientist
33
Overall survivalP
rop
ort
ion
o
f p
ati
en
ts a
live
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 50 100 150 200 250 300 350 500450400 550 600 650 700 750 800 850
ZD4054 15 mg vs placebo: HR=0.65 80%CI=(0.49, 0.86); P=0.052
ZD4054 10 mg vs placebo: HR=0.55 80%CI=(0.41, 0.73); P=0.008
Time to death (days)
ZD4054 10mg
ZD4054 15mg
Placebo
25 (23)28 (26)27 (28)Chemotherapy use*, n (%)
17.324.523.5Median OS, months513334Number of deaths, n
Placebon=107
10 mg n=107
15 mgn=98
ITT population
ZD4054
Endothelin in Prostate Cancer
Phase II Proof of Concept - ZD4054
Mechanisms of CRPC:Mechanisms of CRPC:Role of ARRole of AR
� AR remains a functionally active in CRPC (Chen et al, Nat Med. 2004: 10(1):33-9)
� Prostate cancer cells can make DHT from cholesterol precursors (Locke et al,
Cancer Res. 2008 1;68:6407-15)
� AR remains an important target in CRPC � Super AR antagonists (MDV3100, AZ, BMS)
� Inhibition of intracrine T production (eg. abiraterone)
� AR disruptors (eg. Hsp27, Hsp90, HDAC inhibitors)
34
Abiraterone Acetate (CB7630)(CB7630)(CB7630)(CB7630)
• irreversible inhibitor of CYP17 (P450c17)
• Reduces DHEA, Androstenedione and Testosterone by both the testis and adrenal glands
• Phase 1 and 2 studies: • Antitumor activity in CRPC
• ~40% PSA response, some with >90% PSA declines
• objective RECIST responses
• Phase 3 trial - Aberaterone vs Placebo in 2nd line CRPC now underway
JCO, 2008
� AR remains an important target in CRPC
� Super AR antagonists (MDV3100, AZ, BMS)
� Inhibition of intracrine T production (eg. abiraterone)
� AR disruptors (eg. Hsp27, Hsp90, HDAC inhibitors)
Abiraterone Acetate (CB7630)(CB7630)(CB7630)(CB7630)Abiraterone Abiraterone -- an Inhibitor of Androgen Synthesis:an Inhibitor of Androgen Synthesis:
Effects on PSA in Men with Metastatic HRPCEffects on PSA in Men with Metastatic HRPC
% c
han
ge P
SA
%
38/54: PSA↓ ≥50% (70%)
43/54: PSA↓ ≥30% (80%)
* * * * *
-100-80-60-40-20
020406080
100
Patient
CholesterolHO
CH3
CH3
O
CH3
CH3OH
TestosteroneO
CH3
CH3O
Androstenedione Dihydro-testosterone
(DHT)
O
CH3
CH3OH
HH
Testes, Adrenal, and Prostate Cancer:Secrete Testosterone
Adrenal Glands:Secrete Androstenedione
Target Organ:Testosterone to DHT
X
35
MDV3100 -
a 2nd generation anti-androgen testosterone
Androgen
Receptor
Bound AR-
DHT complex
5α-R
DHT
%
-100
-75
-50
-25
0
25
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
≥50% Decline: 23/42 (55%)
7 pt off study<12 wks
N=42 Chemo naïve
% c
ha
ng
e s
eru
m P
SA
Percent PSA Change from Baseline at 12
Weeks for Chemotherapy-Naïve Patients
X
Changes in Gene Expression After Castration Changes in Gene Expression After Castration and During AI Progression and During AI Progression Changes in Expression of StressChanges in Expression of Stress--Activated Activated Molecular Chaperones After Castration and in CRPCMolecular Chaperones After Castration and in CRPC
Androgen-
dependentTumour
regression
Androgen-
independent
Clonal selection
Adaptive responses
Hormone
withdraw
al
Progressio
nAI
ADAI
AI
clusterin
Hsp27
36
sCLU-2 and Hsp27: Stress-induced Cytoprotective Chaperones
1. Transcriptionally activated by HSF-1
a. Increased by diverse array of stress triggers (Heat shock, HT, CT, RT, velcade, herceptin)
b. Increased by cell survival factors like androgen, IGF-1
c. highly expressed in HRPC, other cancers, aggregapathies (eg Alzheimers, AMD, amyloid).
2. Over-expression confers broad spectrum treatment resistance
� Inhibits protein aggregation, facilitates UPP activity
� Interacts and inhibits activated Bax, prevents cytochrome C release
� Activates NF-kB by facilitating proteasomal degradation of Ik-B
3. ASO or siRNA knockdown (OGX-011, OGX-427)
� Enhances treatment-induced apoptosis in vitro and in vivo
� Pre-clinical anti-cancer activity in many models
Cancer Research 65(23):11083-93, 2005
Hsp27 Knockdown induces apoptosis and Delays
Progression in Human Prostate LNCaP Cancer
Proteasomal
degradation
Androgens
AR
Hsp90
PSAARE ARE
Apoptosis
p38 P
Hsp27
cytoplasm
nucleus
Hsp90
AROGX-427
X
X
XAR
MDM2
Can Res 67: 10455, 2007
treatment
0
100
200
300
400
500
600
700
800
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
OGX-427
Scr B (control)
Pe
rce
nta
ge
of
PS
A le
vel
Weeks post castration
Day of castration Week 2 Week 3 Week 4 Week 5 (After castration)
OGX-427
Week 1 Week 6
37
Phase 1 Study of OGX-427 in Solid Tumors:Investigational New Drug Application
� OncoGenex sponsored; PI - K. Chi (SPORE funded)
� Solid Tumors (Prostate, Breast, Ovary, Lung, Bladder)
� Cohorts 1-5 - single agent OGX-427 in dose escalation design
� 5 dose levels: 200mg up to 1000mg
� Cohort 6 & 7 evaluate OGX-427 in combination with docetaxel
� 3 pts with CaP had PSA declines of 43%, 58%, 62% and 3 pts with ovarian cancer had CA-125 declines of 27%, 28% and 41%.
� Declines in CTC and Hsp27+ CTC have been observed at all dose levels.
CK+/DAPI+/CD45- HSP27+
A B
Total CTC
0
10
20
30
40
50
60
70
80
90
W-L REB SL DJS A-K JRM MAB M-B
Pre-load dose 1
Cycle 1, day 1
Cycle 2, Day 1
Cycle 3, Day 1
Cycle 4, Day 1
Cycle 5, Day 1
OGX-011 Clinical Program Chart
Indication Treatment Status
HRPC OGX-011 with 2nd line chemotherapy (docetaxel or mitoxantrone)
67 patients; Fully enrolled
HRPC 1st line chemotherapy (docetaxel) with and without OGX-011
81 patients; Fully enrolled
Advanced NSCLC OGX-011 with 1st line chemotherapy (gemcitabine/cisplatin or carboplatin)
81 patients; Fully enrolled
Localized Prostate Cancer
OGX-011 with hormone ablation therapy 23 patients; Fully enrolled
Advanced Breast Cancer
OGX-011 with 2nd line chemotherapy (docetaxel) 15 patients; Fully enrolled
Over 300 patients enrolled in OGX-011 clinical trials
Phase 1 Clinical Trials - Completed :
Phase 2 Clinical Trials – Follow Up Ongoing:
Indication Treatment Status
Prostate Cancer OGX-011 with hormone ablation therapy 25 patients
Solid Tumors OGX-011 with chemotherapy (docetaxel) 40 patients
38
0
50
100
150
200
250
300
350
400
450
No treatment >2 m NHT OGX011-
40mg
OGX011-
80mg
OGX011-
160mg
OGX011-
320mg
OGX011-
480mg
OGX011-
640mg
Treatment Groups
Clinical Proof-of-Concept - Phase I Pre-surgery trial:Dose-dependent Decreases in Clusterin Levels in RP Specimens using LCM and Real-Time PCR
Chi et al, J Nat.Canc.Inst. 97:1287-96, 2005
NCIC IND.165: Taxotere +/- OGX-011 in 1st Line
Metastatic Castrate Resistant Prostate Cancer Time to Off Treatment & Progression Free Survival
Chi et al, ASCO, 2007* 79% of patients are still alive
OGX-011 + docetaxel Docetaxel
Median OS 27.53 mo. 16.89 mo.
Number of Treatment Cycles 9 cycles 7 cycles
Early Discontinuation of Chemo 2.5% 26.8%
Progressive Measurable Disease 4% 17%
Stable Measurable Disease 77% 50%
Primary PSA Progression 2.6% 12.5%
QuickTime™ and a decompressor
are needed to see this picture.Std Trt OS - 16.89 months
OGX-011 OS - 27.53 mo
39
Phase II Feasibility Trial of OGX-011 in 2nd Line Therapy
in CRPC: CUOG P-06 (PI F. Saad, E. Winquist)
R
A
N
D
O
M
I
ZE
Arm A
Docetaxel (75 mg/M2 IV) q 21 days and
OGX-011 (640 mg IV) weekly plus
Arm B
Mitoxantrone (12 mg/M2 IV) day 1 and
OGX-011 (640 mg IV) weekly plus
P
R
D O
I G
S R
E E
A S
S S
E I
ON
S F
U O
R L
V L
I O
V W
A
L U
P
n = 41
CRPC
Disease
Progression
During or
Within 6
Months of 1st
Line
Docetaxel
Treatment
n = 19
n = 22
� More treatment cycles administered to patients with OGX-011.• Median of 7.5 cycles vs. 3-4 cycles reported for most 2nd-line studies
� PSA responses higher than anticipated � >50% decrease in PSA - 40% (compared to 30% contemporary controls)
� >90% decrease in PSA - 20% (compared to 8% contemporary controls)
� Median survival > 13 months (compared to 9.6 months in historical controls)
CUOG 2nd Line Phase II Study of OGX-011 in CRPC Tumors:
Patient: 025-011
0
20
40
60
80
100
120
140
1/3/
07
1/17
/07
1/31
/07
2/14
/07
2/28
/07
3/14
/07
3/28
/07
4/11
/07
4/25
/07
5/9/
07
5/23
/07
6/6/
07
6/20
/07
7/4/
07
7/18
/07
8/1/
07
8/15
/07
8/29
/07
9/12
/07
9/26
/07
10/1
0/07
10/2
4/07
11/7
/07
11/2
1/07
12/5
/07
12/1
9/07
1/2/
08
1/16
/08
1/30
/08
2/13
/08
2/27
/08
3/12
/08
3/26
/08
4/9/
08
Date
Start 1st line therapy
End 1st line therapy
8 cycles
PSAProgression
OGX-011
2nd line therapyBaseline
In Treatment Cycle 14
40
Hormonal therapy for CaP: Hormonal therapy for CaP: SummarySummary
� Androgen/AR signaling are important pro-survival growth factors in CaP� Early HT yields optimal prolongation in survival
� BUT - Candidates require risk stratification
� IAS allows early therapy while reducing cost and side effects
� MAB (LHRH-A + NSAA) has yielded small clinically significant gains in survival
� Castrate Resistance remains critical hurdle� Understanding androgen action and mechanisms of CRPC yielding
promising new targets
� AR - super antagonists, AR disruptors, CYP17 inhibitors
� Anti-angiogenesis agents
� IGF-1, IL-6, ET-1a signaling inhibitors
� molecular chaperones like sCLU-2, Hsp27
Future of UroFuture of Uro--Oncology Oncology --Leaders or Dancing Bears? Leaders or Dancing Bears?
•Uro-oncologists must be trained tocover the spectrum of oncology
•Clinical aspects of early &
advanced disease
•Tumor and translational biology
•Clinical trials expertise
•Epidemiology
41
Bio-Logical Therapy: Multi-Targeted and Biologically Rational Combination Therapy
0
50
100
150
0 3 6 9 12 15 18 21 24 27 30
AndrogenWithdrawal
Apoptosis Enhancers
-docetaxel-inhibitors of cytoprotective
proteins eg. Bcl-2, AR,clusterin (OGX-011),
Hsp90 (geldanomycin), Hsp27 (OGX-427)
Growth Inhibitors
-signal transduction eg inhibitors of mTOR (CCI-
779), VEGF (Avastin), ET1a (AZ4054); IGF-1R;
IL-6
Castration alone
Castration +Multi-targeted
Combination therapies
Ser
um
PS
A
Tu
mor V
olu
me
Hormonal therapy for CaP: Hormonal therapy for CaP: SummarySummary
� Androgen/AR signaling are important pro-survival
growth factors in CaP
� Maximal androgen blockade has not yielded
clinically significant gains in survival
� Early HT at time of minimal tumor burden yields
optimal prolongation in survival
� Candidate require risk stratification
� Neoadjuvant/adjuvant combination strategies being evaluated
� Intermittent vs Continuous trials now completed
� Androgen Resistance remains critical hurdle
42
Post-docsAmina Zoubeidi
Eliana Beraldi
Hide Miyake
Moto MuramakiIsis PharmaceuticalsBrett Monia
PI’sColleen Nelson
Larry Goldenberg
Paul Rennie
Kim Chi
Alan So
Michael Cox
Chris Ong
Sue Ettinger
Dawn Cochrane
Richard Sowery
PathologyAntonio Hurtado
Ladan Fazli
David Huntsman
Torsten Neilsen
Ted Jones
Grant FundingNCICNIH SPOREDODPCF
CollaborationsUW - B. Vessella
P. Lange, P Nelson,
Tia Higano
OncoGenex Tech. Inc.Scott Cormack
CUOG
NCIC IND GroupElizabeth Eisenhauer
Hormonal therapy for CaP: Hormonal therapy for CaP: SummarySummary
� Androgen/AR signaling are important pro-survival growth
factors in CaP
� Understanding of androgen action and mechanisms of AI
progression yielding new targets
� AR disruption a relevant goal in delaying AI progression
� Cytoprotective chaperones like sCLU-2, Hsp27
� Guides rationale combination, multi-modal therapies