Christoper Logothetis, M.D., Dept. Chair, Dept. of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center: Current Landscapes in the Management of Prostate Cancer Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

1. Serial Microenvironment Targeted
Therapy Of Prostate Cancer
Christopher J. Logothetis, M.D.

2. • Chemotherapy
• The role of bone
• Accelerating progress
• Summary advances

3. Docetaxel in Castrate Resistant & Metastatic Prostate Cancer
Tannock et al

4. Solid Tumor Therapy
Paradigm
Optimize therapy in advanced setting:
Expect increased benefit when applied
in earlier disease state.
Control Primary
Systemic Therapy

5. Accepted Model of
Cancer Progression
Treatment Sensitive Treatment Resistant

6. Accepted Model of
Cancer Progression No effect on survival
(androgen dependent PCa)
A
1.0
Median (95% CI)
Androgen Ablation 65 (56, 93)
0.8 Chemohormonal 74 (61, 120+)
Overall Survival Probability
P = 0.41
0.6
0.4
0.2
Treatment Sensitive Treatment Resistant 0
0 20 40 60 80 100 120
Months from Initiation of Hormone Therapy
# At Risk, "AA": 135 92 55 27 12
# At Risk, "CH": 125 92 58 32 7

7. Solid Tumor Therapy
Paradigm
Therapeutic agents effective
in far advanced disease
states will be more effective
in earlier states

8. Proposed Progression Model
Chemotherapy resistance
Autocrine
Lethality
Paracrine
Epithelial
Physiology dysregulation
Time

9. • Chemotherapy
• The role of bone
• Accelerating progress
• Summary advances

10. Bone -Epithelial Central to
Prostate Cancer Progression
Epithelial
Bone development
program

11. Bone Consolidation Trial
1
Non-Randomized
Sr-89/Adriamycin
.8 Adriamycin Only
Overall Survival
.6
.4
.2
0
0 10 20 30 40 50 60 70 80
Time from Registration, mo
Tu et al Lancet 2003

13. MDA-BF-1 in Activated
Osteoblasts in Bone Metastasis
Vakar-Lopez et al. J. Pathol. 2004, 203: 688-695

14. MDA-BF-1 inhibits osteolytic
response of PC-3 cells in vivo
PC3 6 weeks
control Side
PC/MDA- 6 weeks
BF1
control Side

15. MDA- BF1 in Progressive
Prostate Cancer
Localized Lymph Androgen
Node independent
Bone
Epithelium
Stroma

16. osteoblast
PCa cells bone
MDA-BF-1
old
lamella
bone
new
MDA- woven
BF-1 bone

17. “Two Compartment Model”
Interaction of Autocrine &
Paracrine loops in Epithelial
and Host drives the organ
specific progression of
prostate cancer

18. Microenvironment in
Prostate Cancer
Epithelial
Bone
microenvironment

19. Prostate Cancer Progression Model
Bone Microenvironment
Dependence
Nora Navone et al

20. Endocrine-to-Paracrine Androgen Signaling
Transition
Normal Early Invasive Early-Stage Lethal
Physiologic Cancer Cancer Metastatic Cancer
State Cancer
Proposed Model of Prostate Cancer Progression
Role of endocrine-to-paracrine androgen signaling transition
Efstathiou et al. Clin Cancer Res. 2010.

21. Androgen-Mediated Progression
of Prostate Cancer
Endocrine
Testosterone
Gonadal
Adrenal
AR DHT

22. Androgen-Mediated Progression
of Prostate Cancer
Endocrine Microenvironment
Testosterone
Gonadal
Adrenal
AR DHT
CYP17

23. Where Androgen Signaling & Tumor
Microenvironment Transect
Endocrine Microenvironment
Testosterone
Gonadal
Adrenal
AR DHT
CYP17

24. Adaptive Response of Androgen Signaling in CRPC
Androgen rich
AR
AR AR
PSA
AR Genomic Signaling
Castration/ Disease Progression
SRC/
SH2
P
mAR P
AR
AR
mAR mAR
Cell survival/anti-apoptotic
CYP17 PSA
Increased intracrine AR overexpression Interface of AR signaling
steroid biosynthesis mutant/isoform AR with other pathways
(src, cMET, Hh and others)

25. Adaptive Response of Androgen Signaling in CRPC
Androgen rich
AR
AR AR
PSA
AR Genomic Signaling
Castration/ Disease Progression
AR
CYP17
Increased Intracrine
steroid biosynthesis

26. COU-AA-301: Abiraterone Acetate Improves
Overall Survival in Metastatic CRPC
100 HR = 0.646 (0.54-0.77) P < 0.0001 FDA Approved
Apr 28, 2011
80 Abiraterone acetate:
14.8 months (95% CI: 14.1-15.4)
Survival (%)
60
40 Placebo:
10.9 months (95% CI: 10.2-12.0)
20 AA
Placebo
0
0 3 6 9 12 15 18 21
Time to Death (Months)
CRPC, castrate resistant prostate cancer. De Bono et al. N Engl J Med. In press.

27. Bone Discovery Platform
Study Design
Bone Marrow Biopsy and Aspirate Intervals
Abiraterone Acetate
Baseline* Week 8* Maximum Progression*
Response*/**
*Tissue:
1) Serum and plasma blood and bone marrow aspirate
2) Transilial bone marrow biopsy
**Variable time point/optional

28. Maximizing Yield of “Blind” Transilial
Bone Marrow Biopsy
CT Directed

29. Cancer Acquisition Rates
(“Directed” Transilial Bone Marrow Biopsy)
Abiraterone Acetate Bone Marrow Trial 2007-0590
(56 pts)
Bone marrow involvement detected by transilial 30 (54%)
biopsy (all time points)
Baseline tumor infiltrated bone marrow 27 (48%)
Paired tumor infiltrated bone marrow (>5%) 17 (30%)
Baseline specimens evaluable for IHC (>5% tumor 25 (45%)
infiltration)
Baseline tumor infiltration ≥20% (FISH) 15 (27%)
Bone marrow aspirates 50 (89%)

30. Modulation of Serum PSA Following
Abiraterone Acetate Treatment
100
≥ 30% Reduction: 59% (34/56)
75
≥ 50% Reduction: 48% (28/56)
50
≥ 90% Reduction: 16% (9/56)
PSA Change (%)
25
0
-30
-50
-75
-90

31. Pretreatment Androgen Signaling
Pretreatment 0 1 2 3
Androgen Signaling No (<25%) (25%-75%) (>75%)
Components expression
Nuclear AR 0 0 8 17
CYP17 4 5 8 8
Mean
Range in ng/mL (n)
Bone marrow aspirate 0.056
testosterone (ng/mL) 0.0000-0.257 (50)
Bone marrow aspirate 0.001
dihydrotestosterone (0.000-0.04)
Blood testosterone 0.044
(ng/mL) 0.0000-0.214 (52)
Blood 0.01
dihydrotestosterone (0.00-0.0459)

32. Persistent Androgen Signaling in CRPC
With Bone Metastases
AR CYP17

33. Pretreatment CYP17 Expression in the
Tumor Correlates With Increased BMA
Testosterone Concentration
BMA-T.Plasma MS (ng/mL)
0.25
0.20
0.15
0.10
0.05
0.0
CYP17 ≥10% No CYP17 Expression
CYP17 Expression No CYP17 Expression P Value,
in Tumor ≥10% in Tumor Wilcoxon
BMA-T, ng/mL (mean ± SD) 0.074 ± 0.070 0.026 ± 0.019 0.045
BMA, bone marrow aspirate; BMA-T, bone marrow aspirate, testosterone.

34. Sustained Depletion of Testosterone
Following Abiraterone Acetate
Blood Testosterone
0.25
Concentration
0.20
(ng/mL)
0.15
0.10
0.05
0.00
Pretreatment Week 8 End of Study
Bone Marrow Testosterone
0.30
Concentration
0.25
(ng/mL)
0.20
0.15
0.10
0.05
0.00
Pretreatment Week 8 End of Study

35. Intense and Homogeneous Nuclear AR
Expression With CYP17 Co-expression
Correlate With Longer Treatment Duration
Primary Resistance* Stable Response
P Value
N (%) N (%)
>90% nuclear AR expression
and
≥10% CYP17 expression
in the tumor epithelium 1 (7) 13 (93)
<0.001
Lack of one or both 10 (91) 1 (9)
1.0
Progression Proportion
0.8
0.6
0.4
0.2
0.0
*Time to treatment
0 100 200 300 400 500 discontinuation
Time (Days) <4 months (122 days)

36. Persistent nuclear AR expression in patients
with benefit from ABI at end of treatment
Nuclear AR
Overexpression at
Progression Pretreatment End of Treatment
Benefit 9/11
Primary 2/6
Resistance
(P value :0.04)

37. Modulation of AR Copy Number
(Preliminary Observations)
Primary Resistance, 8 wks
0 wks
Primary Resistance 8 wks
0 wks
Responder, 8 wks
0 wks
Responder , 8 wks
0 wks
Responder , 8 wks
0 wks
Responder , 8 wks
0 wks
0 20 40 60 80 100 120 140 160 180
Copy Number
qPCR on ≥500 cells.

38. Adaptive Response of Androgen Signaling in CRPC
Androgen rich
AR
AR AR
PSA
AR Genomic Signaling
Castration/ Disease Progression
mAR
AR
mAR mAR
CYP17 PSA
Increase steroid AR Overexpression
biosynthesis mutant/isoform AR

39. Bone Marrow Biopsy Study
MDV 3100
Baseline Week 8 Progression

40. Modulation of Serum PSA Following
MDV3100 Treatment
100
≥ 30% Reduction: 56% (29/52)
75
≥ 50% Reduction: 46% (24/52)
50 ≥ 90% Reduction: 20% (10/52)
PSA Change (%)
25
0
-30
-50
-75
-90

41. Shift in AR subcellular localization
following MDV3100
in patients with PSA decline
Pretreatment Week 8
Nuclear Localization Cytoplasmic Localization

42. AR Inhibition (MDV 3100) Increased
Testosterone Concentration
100 100
80 80
T Change in Plasma (%)
60
60
40 40
T Change in BM (%)
20
20
-20 -20
-40 -40
-60 -60
-80 -80
-100
-100
Patients Patients
Pretreatment Week 8 P value
(mean) (mean) (wilcoxon)
Bone Marrow Τ 0.026 0.04 0.0001
Bone Marrow DHT 0.0 0.003 0.335
Blood Τ 0.041 0.066 <0.0001
Blood DHT 0.002 0.007 0.008

43. Persistent androgen signaling
driven by altered receptor or
adaptive steroid synthesis is a
hallmark of prostate cancer
progression and a central
component of the tumor
microenvironment

44. Increased pSrc expression correlates
with resistance to MDV3100
Non responders Responders P value
Wilcoxon’s rank test
Mean pSrc Expression (%) 70 10 0.002
(Range) (0-90) (0-30)

45. Adaptive Response of Androgen Signaling in CRPC
Androgen rich
AR
AR AR
PSA
AR Genomic Signaling
Castration/ Disease Progression
SRC/
SH2
P
mAR P
AR
AR
mAR mAR
Cell survival/anti-apoptotic
CYP17 PSA
Increase steroid Generation of mutant Non-genomic AR signaling
biosynthesis /isoform AR Activation of SRC kinase,
cMET,Hh

46. Increased Phospho-Src at Progression More Evident
in Patients With Primary Resistance to Abiraterone
Acetate
(Preliminary Observations)
Pretreatment End of Treatment
Phospho-Src
Increase at End of
Treatment
Benefit 4/8
P-Src
Primary 5/6
resistance
(P value: 0.05)
H&E
Patient with primary resistance to abiraterone acetate

47. Activation of Src kinase signaling in MDA-Pca-133 donor tumor and xenograft
AR Phospho-Src
Donor tumor
AR Phospho-Src
Xenograft
V. Tzelepi

48. Effect of dastinib, a Src kinase inhibitor, in tumor
growth of MDA-Pca-133 xenograft
2000
Control, n=5
Tumor growth (Mean sem) mm3
Castrated, n=4
1500
Dasatinib, n=5
Cast/Dasatinib, n=4
1000
500
0
Day 0 Day 12 Day 16 Day 20 Day 24 Day 28 Day 32
Days of Dasatinib treatment
J. Song and G. Gallick

49. Effect of dastinib, a Src kinase inhibitor, in tumor
growth of MDA-Pca-133 xenograft
2000
Control, n=5
Inhibition of Paracrine AR signaling &
interacting ”SE” will enhance efficacy of
Tumor growth (Mean sem) mm3
Castrated, n=4 therapy
1500
Dasatinib, n=5
Cast/Dasatinib, n=4
1000
500
0
Day 0 Day 12 Day 16 Day 20 Day 24 Day 28 Day 32
Days of Dasatinib treatment
J. Song and G. Gallick

50. Dasatinib Inhibits Growth of
Bone-selected MDA PCA 118b Cells Growing Intratibially
MRI
Control Treated
P=0.045
155.5 mm3 30.5 mm3
Park, Gallick, Navone

51. Osteoclast Function:
Dasatinib Inhibits Formation of
Multi-nucleated Osteoclasts
M-CSF MCSF + RL
Cont.
1500
1.25nM
Osteoclasts/well
1000
5nM
500
+TRAP
0 10nM
M-CSF + RL: + + + + + +
Dasat (nM): 0
. 1.3 2.5 5 10 20
20nM
Araujo and Darnay, unpublished

52. Phase 1/2 Dasatinib + Docetaxel
Trial on Metastatic Prostate
 Dasatinib was administered orally on a once-daily schedule
 Docetaxel was administered intravenously every 21 days
 At least three patients were enrolled at each dose level
Day 3
Continuous daily dasatinib
Day 21
Day 1 Day 14
Docetaxel
Docetaxel (Dasatinib Docetaxel Docetaxel
(Combination
(PK analysis) PK analysis)
PK analysis)
John Araujo, MD, PhD. PI

53. Maximum UNTx change from baseline
100
80 Bisphosphonate No bisphosphonate
60
40
20
Max % Change from Baseline
0
BENEFIT
-20
-40
-60
-80
-100

54. PSA response curve during and
post docetaxel (continued on
Dasatinib)
9/09 Last
Docetaxel
19 months on single agent dasatinib
with undetectable PSA

55. PSA response curve during and
post docetaxel (continued on
Dasatinib)
5/09 Last
Docetaxel
22 months on single agent dasatinib

56. Dasatinib In Castrate Resistant &
Metastatic Prostate Cancer
mCRPC Docetaxel 75 mg/m2
1st line R Dasatinib 100 mg po daily
Stratification A Prednisone 5 mg po BID
PS 0, 1 vs. 2 N
Urinary NTX D
O
M Docetaxel 75 mg/m2
I Prednisone 5 mg po daily
Z Placebo
E

57. • Chemotherapy
• The role of bone
• Accelerating progress
• Summary advances

58. Docetaxel in Castrate Resistant &
Metastatic Prostate Cancer
Tannock et al

59. Prostate Cancer

60. New Approach
No.
CVD 30
KAVE 30 1st
η = µ +αY + βZ
TE+E 30 2nd
TE+C 30
120

61. Current Practice
α + α Patient
Regimen + success
∆ to β β β
-
+ +
• Rapid selection of most effective regimen
• Arrives to patient success rapidly

62. Protocol Allocation
Prostate Cancer
TEE KAVE CVD TEC
First Regimen 61 57 48 66
Second Regimen 22 13 13 25
TOTAL 83 70 61 91

63. Most Efficacious
Sequence
CVD (1) TEC (2)

64. Beneficial Effect of a
“Reasoned” Treatment Approach
1.0
0.8
Serial CHT
0.6
0.4
0.2
Taxotere
0.0
0 20 40 60 80
Months from initiation of chemotherapy

65. Relative Impact of Serial
Therapy on Overall Survival
1.0
0.8
0.6
Serial CHT
0.4
0.2
Taxotere
0.0
0 20 40 60 80
Months from initiation of chemotherapy
Taxotere vs Mitanzantrone Taxotere vs. Serial chemotherapy*
*simulation

66. Chemotherapy & Castrate
Resistant Prostate Cancer
• Castrate Resistant Prostate Cancer is a
chemotherapy sensitive Combination(s)
may provide advantage
• Serial use of chemotherapy applied
based on “principles of cancer therapy”
can provide further benefit
• Integration into primary treatment

67. Serial Application of Therapy
Interaction Impact
Relative
Between Overall
Efficacy
Regimens Survival

68. Increased Phospho-Src at Progression More Evident
in Patients With Primary Resistance to Abiraterone
Acetate
(Preliminary Observations)
Pretreatment End of Treatment
Phospho-Src
Increase at End of
Treatment
Benefit 4/8
P-Src
Primary 5/6
resistance
(P value: 0.05)
H&E
Patient with primary resistance to abiraterone acetate

69. Synergy Between
Microenvironment Targeting
Therapies
R Sunitinib + Sunitinib +
A abiraterone abiraterone
O
N acetate acetate
F
D
F
O
Abiraterone M
acetate I
S
Z
T
A
Dasatinib + Dasatinib + U
T
abiraterone abiraterone D
I
acetate acetate Y
O
N
Circulating Microenvironment

70. Effect of Serial
Targeted Therapies
T1 T2 T3
A+S vs. A+D A+S → A+D Allocation
new Rx
A+D → A+S

71. Serial Application of Therapy
Interactio
n Impact
Relative Link To
Between Overall
Efficacy Biology
Regimen Survival
s

72. Microenvironment pathways
implicated in resistance to
maximal androgen ablation are
prioritized for individualized
therapy development

73. XL184 :Initial Clinical Observations
woven bone

74. • Chemotherapy
• The role of bone
• Accelerating progress
• Summary advances

75. Androgen Receptor Signaling in Prostate
Cancer Involves Multiple Pathways
Growth Factors and Their Receptors
T T
5-alpha Reductase MAPKKK
P13K
(I,II,III)
Caspase9
PTEN Bad MAPKK
P27
DHT AKT
MAPK
DHT
P P
AR
Li J. and Kim J., 2009

76. Genetic Networks
(anticipated outcome)
DHT
Dihydrotestosterone

77. Cancer Detection in REDUCE by
Time, Treatment and Gleason Score
Years 1-2 Years 3-4
Placebo Dutasteride Placebo Dutasteride
No. Subjects Biopsied 3345 3929 2342 2446
Gleason 5-6 401 290 216 147
Gleason 7 (3+4) 125 99 51 47
Gleason 7 (4+3) 32 28 6 17
Gleason 8-10 18 17 1 12
(0.5%) (0.5%) (0.04%) (0.5%)

78. Genetic Networks
(anticipated outcome)
DHT AR
Dihydrotestosterone Androgen
Signaling

79. “Earlier” Use of Androgen Biosynthesis Inhibitor
ABI

80. Genetic Networks
(anticipated outcome)
DHT AR Non
AR
Didydrotestosterone Androgen Microenvironment
Signaling Dependent

81. Chronic Myelogenous Leukemia
“Oncogene
Addiction”
“Blast Crisis”
BCR- ABL
Prostate Cancer
“Microenvironment
Dependence”
Androgen
S-E Signaling
Independent
Network Progression
Elucidating signaling
network will lead to
combinatorial
microenvironment
targeting

82. Proposed Progression Model
Chemotherapy resistance
Autocrine
Lethality
Paracrine
Epithelial
Physiology dysregulation
Time
Microenvironment
Dependence

83. Small Cell Carcinoma

84. The “Anaplastic” Prostate Carcinomas
Morphologically heterogeneous
Prostate Cancers with clinical features
common to small cell carcinomas
represent a significant subset of the
lethal disease.
APARICIO, A. 2009

85. “A Phase II Study of Carboplatin plus Docetaxel in Patients with Anaplastic
Prostate Carcinoma”
MDA 2006-0097 - PCCTC#c05-015
PSA at Registration
200
150
100
60
ng/dL
40
20
3.2
0
PSA
APARICIO, A. 2009

86. DNA Methylation Profiles of the
Anaplastic Prostate Carcinomas
SCC-1 (MDA 40) AR SCC-2 (MDA 46)
-1,000 +500
Ward Linkage and Absolute Correlation Coefficient Distance
SCC-3 (MDA 91b) SCC-4 (MDA 144-13)
39.08
59.38
Similarity
AC-1 (MDA 43) AC-2 (MDA 75) 79.69
100.00
SCC-4 SCC-2 SCC-1 SCC-3 AC-1 AC-4 AC-3 AC-2
Xenografts
AC-3 (MDA 80) AC-4 (MDA 137)
APARICIO, A. 2009

87. Androgen Signaling Networks
(Progression)
-
DHT AR Non Non
AR AR
Didydro- Androgen Micro- AR
testosterone Signaling Environment Interference
Dependent

88. Control Primary
Systemic Therapy
Control Primary Systemic
No Therapy Therapy
Microenvironment
Targeting

89. Acknowledgments
M. D. Anderson Cancer Center
Genitourinary Medical Oncology
W. Arap M. Karlou
J. Araujo Z. G. Li D Tsavachidou
A. Aparicio S. W. Lin T. Thompson
P. Corn S. Maity S.M. Tu
E. Efstathiou R. Millikan V. Tzelepi
G. Gallick N. Navone X. Wan
I. Gorlov R. Pasqualini J. Yang
P. Sharma A. Zurita
Pathology Urology Imaging
P. Troncoso C. Pettaway V. Kundra
J. Davis
L. Pisters Rice University
Texas A& M University C. Farach-Carson
W. L. McKeehan Institute for Molecular Medicine
F. Wang M .Kolonin
University of Athens Nijmegen
E Efstathiou P. Friedl

90. Adaptive Response of Androgen Receptor Signaling in CRPC
Androgen rich
AR
AR AR
PSA
AR Genomic Signaling
Castration/Abiraterone treatment
SRC/
SH2
P
mAR P
AR
AR
mAR mAR
Cell survival/anti-apoptotic
CYP17 PSA
Increase steroid Generation of mutant Non-genomic AR signaling
biosynthesis /isoform AR Activation of SRC kinase