This document discusses treatments for advanced prostate cancer. It begins by describing androgen deprivation therapy as the first line treatment. It then discusses newer FDA-approved treatments since 2010 like cabazitaxel, abiraterone, and immunotherapy drug Provenge. The rest of the document focuses on chemotherapy drug Taxotere/docetaxel, providing details on its efficacy compared to other drugs in clinical trials, side effects, and promising combinations with other treatments like Avastin, carboplatin, and thalidomide. It also discusses other emerging treatments like cabazitaxel, curcustersin, and immunotherapy drug Provenge.

1. XII. Advanced Disease
Richard Lam, MD
Research Director
Prostate Oncology Specialists
Marina del Rey, CA

2. Advanced Disease

3. Examples: Advanced Disease

4. Treatments for Advanced Disease
Androgen deprivation therapy--first line therapy.
Secondary hormone interventions—older drugs.
 Ketoconazole
 Estrogen
 Nilutamide
Immune approaches
Novel anti-testosterone agents
 Abiraterone
 MDV-3100
Chemotherapy (Taxotere, Jevtana)
Bone targeted therapy

5. FDA Approved Treatments for
Advanced Prostate Cancer since 2010
Cabazitaxel (Jevtana)
Provenge (1st immune treatment)
Abiraterone
MDV-3100 (very soon!)
Alpha-radin (very soon!)

6. Androgen Deprivation Therapy

7. Methods to Achieve Castration
Surgical
Medical
Lupron, Trelstar, Eligard, Viadur, Zoladex
Time

8. Androgen Deprivation Therapy for
Advanced Disease
Duration of effectiveness: average 18 months
(sometimes up to 10 years though)
Prognostic indicators
PSA
PSA doubling time
Gleason score
Small cell histology
Extent of disease
Addition of anti-androgens, such as bicalutamide
PSA nadir

9. Treatment Options for
Hormone Refractory Disease
Secondary Hormone Manipulations
Estrogens
Alternative anti-androgens, ie nilutamide, flutamide
Ketoconazole
Chemotherapy
Taxotere
Cytoxan, Mitoxantrone, Xeloda, Avastin, Carboplatin
Jevtana
Novel agents
Abiraterone
MDV-3100
Provenge

10. Secondary Hormone-based Therapies
For Hormone Refractory Disease
Nilutamide
Ketoconazole
Estrogens
Vivelle-Dot (Patch)
DES
Ethinyl estradiol

11. FDA-Approved Chemotherapy
Agents until 2010
1980s 1990s 2000s
Taxotere® (docetaxel)
Estramustine Mitoxantrone with injection concentrate
phosphate (EMP) corticosteroids with prednisone

12. TAXOTERE: Study Design
R Taxotere every 3 Primary endpoint
A weeks (n=335) • Overall survival
(OS)
N
D Secondary endpoints
O • Pain response
• 50% PSA decline
M • Response rates
I • Quality of life
Z Mitoxantrone
every 3 weeks
E (n=337)

13. Taxotere: Overall Survival Benefit
1.0
Overall Survival Probability (%)
0.8
0.6 Taxotere ®
Mitoxantrone 27.6% 2-year survival
advantage
0.4
0.2
P=0.009
0
0 3 6 9 12 15 18 21 24 27 30
Overall Survival Time (months )

14. PSA response does not matter to the FDA (even though it
predicts survival). However, for guiding individual treatment
decisions, PSA response is extremely useful.
1.00
PSA normalized (n=115)
Proportion surviving
PSA not normalized (n=743)
0.75
0.50
(%)
0.25
p<0.0001
0
0 5 10 15 20 25 30 35 40 45 50
Survival time
(months)

15. Taxotere: Side Effects
Effects on Blood
Red blood count can be lowered (Anemia).
 Fatigue
 Shortness of Breath
 Transfusions
White blood count.
 Fever
 Infection

16. Taxotere: Side Effects (Cont.)
Effects on Gastrointestinal Tract
Upper Tract
 Impaired taste
 Mild, if any, nausea
 Loss of appetite
Lower Tract
 Diarrhea
Liver
 Inflammation

17. Taxotere: Side Effects (Cont.)
Other systems
 Hair loss
 Numbness in fingers and toes
 Tear duct stenosis
 Finger nail discoloration, pain, discharge

18. Promising Taxotere Combinations
How Can We Improve on Taxotere?
Thalidomide
Avastin
Xeloda
Carboplatin
Samarium (Quadramet)
Custersin

19. Taxotere Combined with
Platinum Derivatives
Previous Response Reference
Chemo/ Combination Rate
# Pts.
2/34 Carboplatin 18% ASCO 2007
Abst. # 238
1/40 Carboplatin 95% Eur Urol
Emcyt 51:1252
1/40 Carboplatin 68% Cancer
Emcyt 98:2592
2/34 Oxaliplatin 64% GUCS 2008
Abst. # 155
Obtaining good results in men previously
treated with chemotherapy indicates a
more powerful and active regimen

20. Taxotere & Capecitabine (Xeloda)
# Pts. Response Reference
Rate
30 73% ASCO 2007
Abst. #5121
77 41% Clin. GU Cancer
5:155
50 68% Cancer
107:738

21. Inhibitors of Angiogenesis
Vascular Endothelial Growth Factor (VEGF)
1. Over expression of the COX-2 enzyme stimulates
production of VEGF. COX-2 inhibitors (Celebrex ®) reduce
VEGF (Fujita et al. The Prostate 2002).
2. Thalidomide blocks VEGF and basic fibroblastic growth
factor (D’Amato Proc Natl Acad Sci 1994).
3. Avastin® is a synthetic monoclonal antibody that blocks
VEGF directly (FDA approved for colon, lung, kidney and
brain cancer).

22. Taxotere & Thalidomide
Taxotere & Thalidomide
50 men
75 Men
Metastatic
Disease
Taxotere Alone
25 men
Journal of Clinical Oncology Vol. 22:2532

23. Taxotere & Thalidomide Results
> 50% PSA 18 Month
Decrease Survival
Taxotere 37% 43%
Taxotere & Thalidomide 53% 68%

24. Avastin is an Antibody that
Inactivates VEGF Receptor

25. Taxotere/Avastin/Thalidomide
Ning & Dahut NCI and FDA, ASCO 2008, #5000
60 men with metastatic disease
Medians for the group:
PSA was 99
Gleason was 8
PSA doubling time was 1.6 month

26. PSA Response Rate
50
40 Each Vertical Line Represents the Percentage
30
Drop in PSA in An Individual Patient
20
10
% of PSA at Enrollment
0
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39
-10
-20
-30
-40
50% Decline
-50
-60
-70
-80
-90
-100
Patients

27. Taxotere + Avastin Phase III
Trial
Taxotere, Prednisone & Avastin
(n = 524)
1050 Patients
Docetaxel & Prednisone
(n = 526)
Kelly WK, et al. ASCO 2010. Abstract LBA4511.

28. Taxotere + or (-) Avastin: Overall
Survival Data Median OS,
1.0 Mos (Range)
Bevacizumab + CT 22.6 (21.1-24.5)
0.8 Placebo + CT 21.5 (20.0-23.0)
HR: 0.91 (95% CI: 0.78-1.05)
Probability
0.6 Log rank P = .181
0.4
0.2
0
0 6 12 18 24 30 36 42
Mos
Patients at Risk, n
Placebo + CT 526 480 390 305 199 100 44 22
Bev + CT 524 484 417 327 217 117 52 23
Kelly WK, et al. ASCO 2010. Abstract LBA4511.

29. Rate of Cancer Progression
Median PFS,
1.0 Mos (Range)
Bevacizumab + CT 9.9 (9.1-10.6)
0.8 Placebo + CT 7.5 (6.7-8.0)
HR: 0.77 (95% CI: 0.68-0.88)
Probability
0.6 Log rank P < .0001
0.4
0.2
0
0 6 12 18 24 30 36 42
Mos
Patients at Risk, n
Placebo + CT 526 303 134 75 34 8 4 0
Bev + CT 524 381 194 97 44 15 5 1
Kelly WK, et al. ASCO 2010. Abstract LBA4511.

30. Avastin Significantly Improved
Other Clinical Endpoints
Outcome, % Bevacizumab Arm Placebo Arm P Value
(n = 524) (n = 526)
≥ 50% decline in PSA 69.5% 57.9% .0002
Scan response rate 53.2% 42.1% .0113
The Marginal Advantages Seen with Avastin & Taxotere in this
Study May Possibly Be Explained by the Failure to Incorporate
Thalidomide (or Revlimid) in the Regimen
Kelly WK, et al. ASCO 2010. Abstract LBA4511.

31. Taxotere and Curstersin
Curstersin blocks Clusterin, a cell protein secreted by
cancer cells that inhibits the killing effect of
chemotherapy
Curstersin is anti-sense oligonucleotide that reduces
Clusterin production
Chi, Kim. Proc. ASCO 2009, abs #5012.

32. The Cancer Cell Makes Clusterin From RNA
Clusterin
Protein
RNA

33. Curstersin No Translation,
this step fails
Clusterin
not
Created
RNA of Clusterin
RNA Exploded view:
Transcription

34. Taxotere/Curstersin
Taxotere alone Taxotere & Curstersin
(n=41) (n=41)
50% PSA 54% 58%
Drop
Any PSA 68% 87%
Drop
Overall 16.9 months 23.8 months
Survival
Chi, Kim. Proc. ASCO 2009, abs #5012.

35. Taxotere vs. Taxotere & Curstersin:
Overall Survival
Further Information
on a Clinical Trial
of Taxotere &
Curstersin
Is Available by
Calling Jennifer at
(310) 827-7707 Ext
#32

36. Taxotere Combined with ?
Effective Ineffective or Too Toxic
Cisplatin
Carboplatin with
Mitoxantrone
Emcyt
Adriamycin
Capecitabine
Vinorelbine (Velban)
Avastin and Revlimid
Vitamin D (Calcitriol)
Curstersin *
?Avastin/Revlimid?
*Available on trial and final results are still pending

37. Cabazitaxel (Jevtana)
Mitoxantrone &
755 patients Prednisone
whose cancer (n = 377)
is
Progressing
Cabazitaxel &
on Taxotere Prednisone 10
(n = 378)
Obtaining Results in Taxotere Resistant Patients
Would Constitute a Notable Accomplishment
De Bono JS, et al. ASCO 2010. Abstract 4508.

38. Cabazitaxel: Jevtana

39. Cabazitaxel: Side Effects
Toxicity manageable and similar between
treatment arms
Higher incidence of:
 grade 3 low blood counts (82% vs 58%)
 fevers from low blood counts (7.5% vs 1.3%)
diarrhea (46.6% vs. 10.5%)
De Bono JS, et al. ASCO 2010. Abstract 4508.

40. Immune Approaches to Combat
Advanced Prostate Cancer
Sipuleucel-T (Provenge)
Ipilimumab (Yervoy)

41. Immune System
Made of cells and
antibodies.
Underactive: allows cancer
to progress (post-
transplant, HIV)
Overactive: leads to
autoimmune illness.
Control cancer?

43. Immune System is
Very Complex!
Blood

44. T (Thymus) Cells: The Attack Cells
of the Immune System

45. Activated Immune Cells Attack and
Kill Cancer Cells Directly

46. Antigen Presenting Cell (APC)
T-Cell

47. Provenge: Sipuleucel-T
Small #4500 ASCO 2005
127 men with hormone resistance
Placebo vs. Provenge
Outcome
3x improvement in 3 year survival
Toxicity very mild

48. Provenge, Clinical Trials.
100 Round 1
Median Survival Benefit = 4.5 months
75
Percent Survival
Sipuleucel-T (n=82)
Median Survival: 25.9 months
50
Control (n=45) 34%
25 Median Survival: 21.4 months
11%
0
0 10 20 30 40
Survival (months)
Small EJ, Schellhammer PF, Higano CS, et. al. J Clin Oncol 24:3089-3094, 2006/Data on file,
Dendreon Corp.

49. Round #2: Larger Provenge Study
Sipuleucel-T Control
(N = 341) (N = 171)
Serum PSA median, ng/mL 51.7 47.2
Serum PAP median, U/L 2.7 3.2
Kantoff, IMPACT manuscript, submitted, 2010

50. Round #2: Overall Survival
HR = 0.759 (95% CI: 0.606, 0.951)
p = 0.017 (Cox model)
Median Survival Benefit = 4.1 months
Sipuleucel-T (n = 341)
Median Survival: 25.8 mo.
36 mo. survival: 32.1%
Control (n = 171)
Median Survival: 21.7 mo.
36 mo. survival: 23.0%
No. at Risk
Sipuleucel-T 341 274 142 56 18 3
Control 171 123 59 22 5 2
Kantoff, ASCO-GU March 2010

51. The Regulatory T-Cells (T-Regs): Suppress
Immune Activity, and can Enhance
Cancer Activity

52. “The T-Regs”
Treg cells are a subset of T cells that suppresses other T cells
“The Police”
Cancer patients have been demonstrated to have an increased
levels of Treg cells in the blood
Studies show that higher levels of Treg cells in the blood predict
shorter survival
CTLA is an important receptor on the surface.

53. Ipilimumab: Antibody against the CTLA-4
receptor on the T-Reg Cell Surface
CTLA-4
CTLA-4
Cell Surface

54. Antibody against CTLA-4
(ipilimumab)
Beer et al. ASCO Abstract # 5004, 2008
26 patients with hormone refractory, end stage,
metastatic prostate cancer treated with escalating
doses (phase I) with or without radiation to a
metastatic site.
6 men had greater than 50% decline in PSA.
2 men had PSA drop to zero.
Side effects were diarrhea, liver inflammation and
rash

55. PSA Control is Observed
100
Best PSA Change From Baseline (%)
50
100 a
Best PSA Change From Baseline (%)
50 0
0
a a
-50
-50 11/43 responses (26%)
25/43 PSA control (58%)
-100 -100
a
10 mg/kg +XRT Chemotherapy- +XRT Prior
a
Prior Chemotherapy Naïve Chemotherapy

56. Safety Summary
Grade 3/4 Side Effects
Prostate Cancer
10 mg/kg
Combo
(n = 31) XRTb
(n = 29)
Skin 4 (13%) –
GI 9 (29%) 4 (12%)
Liver 4 (13%) 2 (12%)
Endocrine 2 (6.4%) –

57. Pre-treatment: Post-treatment:
PSA 250 PSA <0.1

58. Randomized Phase III Trial
Ipilimumab
Ipilimumab
wks 1, 4, 7, 10 Ipilimumab
Radiation to every 12 wks
a bone
metastasis
Placebo
Placebo every 12 wks
wks 1, 4, 7, 10

59. Novel Anti-testosterone Agents
Abiraterone (Zytiga)
MDV-3100 (Enzalutamide)

60. Abiraterone: Brief Review
Evidence is accumulating that castration-resistant
prostate cancer frequently remains hormone-driven by
using adrenal hormones or through intracrine synthesis.
CYP17A1 (or 17-a-hydroxylase or 17,20-lyase) is a
cytochrome P450 enzyme responsible for androgen and
estrogen synthesis from adrenal hormones.
Abiraterone is a potent, selective, and irreversible
inhibitor of CYP17A1

61. .
Attard G et al. JCO 2008;26:4563-4571

62. Abiraterone suppresses steroids
6 2
Testosterone Androstenedione
5
4
nmol/l
ng/dl
Lower limit of
3 sensitivity 1
No rise at
2 progression No rise at
progression
1
0.07
0 0
1 Start of 10 20 60 70 At
Start of
28 56 At
treatment Days progression Days progression
treatment
12.5 12.5
DHEA Estradiol
10.0 10.0
ρmol/l
nmol/l
7.5 7.5
No rise at
5.0 progression 5.0
2.5 2.5
0 0
28 56 At 10 20 30 40 50 60
Start of
treatment Days progression Days post treatment

63. Abiraterone: Brief Review
Antitumor demonstrates activity pre-
docetaxel and post-docetaxel
•PSA, RECIST, bone scans
•
•Confirmed in Multiple phase II studies
•Pre-docetaxel: 60-80% PSA response rate
•Post-docetaxel: 40-50% PSA response rate
•Phase III studies
•Post-docetaxel: Completed accrual first quarter ’09
•Pre-docetaxel: Completed accrual first quarter ‘10

64. Abiraterone
Pre-Docetaxel Phase I/II:Maximal PSA Decrements

65. Abiraterone
Post-docetaxel Phase II (n=34)
17/34 (50%) pts ≥50% decline
22/34 (65%) pts ≥30%decline
24/34 (71%) pts had a PSA decline
3 pts did not reach 12-weeks but are included

67. Pre-Abiraterone Post-Abiraterone
Massively Enlarge Lymph Node Lymph Node Resolved

68. Abiraterone
Post-Chemotherapy Phase III Trial (CB-301)
Abiraterone 1000 mg daily (n=797)
Prednisone 10 mg daily
Or
Placebo daily (n=398)
Prednisone 10 mg daily

69. Abiraterone-CB-301 Results
(deBono, ASCO June 2011)
PSA Time to PSA Overall
response progression Survival
Abiraterone 38% 11 months 15.8 months
Placebo 10% 6.6 months 11.2 months

70. •Binds AR more potently than bicalutamide.
•Does not stimulate the AR
•Engineered for activity in prostate cancer cells with a
common and specific molecular defect: Overexpressed
AR
•Inhibits movement of the androgen receptor to the
nucleus where it binds to DNA and triggers a signalling
cascade leading to tumor growth

71. MDV3100 mechanism of action

72. MDV3100
MDV3100 attacks the androgen receptor at multiple
levels.
Appears effective
In chemo-naïve men (62% likelihood of 50% PSA
decline).
Post-chemotherapy disease (50% PSA response rate).
Scher, H. PASCO 2009, abs 5011.
Preliminary Phase III results 2012

73. Waterfall Plot of Percent PSA Change from Baseline at
12 Weeks for Chemotherapy-Naive Patients Treated at
60, 150, and 240 mg/day of MDV3100
7 pt off
N=42 Chemo-naïve study
<12 weeks
>50% Decline: 23/42 (55%)

74. MDV3100 Affirm Study Design

75. MDV3100 Affirm Study Results
(deBono, ASCO June 2012)
PSA Time to PSA Overall
Response Progression Survival
MDV- 54% 8.3mo 18.4
3100 months
Placebo 1.5% 2.9mo 13.6
months

76. Symptoms Commonly Seen in
Advanced Disease
Skeletal Complications
Bone pain
Spinal cord compression
Low blood counts
Fatigue
Infections

77. Quadramet
Samarium Sm 153 Lexidronam Injection
Indicated for relief of pain in patients with confirmed
osteoblastic metastatic bone lesions.
Controlled studies included patients with prostate
cancer, breast cancer, and others.
Administered intravenously, usually as an outpatient
procedure.
Repeat administrations are safe and effective.
1
Quadramet (samarium Sm 153 lexidronam injection) prescribing information. September 2003.
2
Resche I, et al. Eur J Cancer. 1997;33:1583–1591.
3
Serafini AN, et al. J Clin Oncol. 1998;16:1574–1581.

78. Pain Reduction
Change in AUPC-VAS in Prostate Cancer
Change from Baseline
2
Placebo
0 1.0 mCi/kg
-2
-4
-6 *
* *
-8
-10
0 1 2 3 4
AUPC: area under the pain curve.
VAS: visual analog scale; Week Number
PDS: pain descriptor scale.
*P≤0.05 vs placebo.
Sartor O, et al. Urology. 2004;63:940-945.

79. Radium 223 - Alpharadin

80. Radium 223 - Alpharadin

81. Radium 223 – Alpharadin
Updated data: June 2012

82. Hormone Refractory Disease:
Other Options

83. Successful Warfare:
Attack Multiple Fronts
Hormone Approaches: Lupron, Casodex
Monotherapy, Ketoconazole, Abiraterone,
MDV3100
Immune Mechanisms: Provenge, Ipilimumab
Anti-VEGF Targetting: Revlimid, Avastin
Chemotherapy: Taxotere, Jevtana
New Approaches: Alpha-radin, XL-184 (in
studies)