1
Charles J Ryan, MD
Associate Professor of Medicine and Urology
Helen Diller Family Comprehensive Cancer Center
University of California, San Francisco
UCSF

• Four new drugs approved for advanced prostate cancer by the US FDA
– Three based on improvements in survival (Cabazi,
Abiraterone, Sipuleucel T)
– (Initial phase I studies of abiraterone and Sip T done at
UCSF in GU Medical Oncology Program)
• Two Others- Alpharadin (Radium 223) and MDV-
3100 have shown OS Benefit in trials, FDA approval not yet granted.

1. How do we define Castration Resistant Prostate Cancer?
500 ng/mL
Testosterone
Progression of Disease despite a suppressed (castrate) testosterone level (<50ng/dL)
50 ng/ mL
PSA
Castration
Therapy
Castration Resistance
5
2. What makes prostate cancer lethal and how do we assess prognosis in patients?
500 ng/mL
Testosterone
+ =
Lethal Prostate cancer
50 ng/ mL
PSA
Castration
Therapy
Castration Resistance
5

Prostate Cancer
Standards and Novel Therapies:
AR Targeted
Therapy
Chemotherapy
Clinically
Localized
Rising PSA post RP/RT
ADT Resistant
Pre-Chemotherapy Chemotherapy
CRPC
Docetaxel
Resistant
Immunotherapy
Targeted Therapy
UCSF

Prostate Cancer
Standards and Novel Therapies: 2009
AR Targeted
Therapy
Chemotherapy
Clinically
Localized
Rising PSA post RP/RT
ADT Resistant
Pre-Chemotherapy Chemotherapy
CRPC
Docetaxel
Resistant
Docetaxel
(Standard)
Immunotherapy
Targeted Therapy
Therapies showing a survival benefit UCSF

New Treatments for Advanced Prostate Cancer
Targeting the T Cell
Androgen Synthesis Inhibitors
Second line chemotherapy
Alpha-emitting Radio-isotopes
UCSF

New Treatments for Advanced Prostate Cancer
Targeting the T Cell
UCSF


Cytotoxic chemotherapy quickly debulks tumors
– Resistance and tumor regrowth may occur

Immunotherapy activates the immune system
– Clinical effect may take time to develop
– Responses may be sustained due to immunologic memory
Time on treatment Chemotherapy
Progression
Immunotherapy
Time
Webster et al. J Clin Oncol. 2005;23:8262.

Precursor
APC
Antigen
Loading
Antigen-loaded precursor APC
APC8015
Sip-T
Antigen
Processing
Maturing antigenloaded APC
Infuse patient
20
15 s 10
5
0
-10 0 10
Week T cells attack
tumor cells
In vivo
T cell activation
20
Small EJ et al., J Clin Oncol 18: 3894, 2000
30

Sipuleucel-T : (second) Pivotal Trial Results
Phase 3 design allowed for crossover from placebo to vaccine
Adverse event
†
†
• Primary endpoint: Overall survival 1,2
•
Secondary endpoint: Objective disease progression 2
†
Control was nonactivated, autologous, peripheral blood mononuclear cells.
Kantoff PW et al. N Engl J Med . 2010;363:411-422.
Chills
Fever (pyrexia)
Headache
Influenza-like illness
Myalgia
Hypertension
Hyperhidrosis
Groin pain
Adverse Events
PROVENGE
(n=338)
All Grades
(%)
54.1
Grades 3–5
(%)
1.2
29.3
16.0
9.8
9.8
7.4
5.3
5.0
0.3
0.3
0
0.6
0.6
0
0
12.5
Control
(n=168)
All Grades
(%)
Grades 3–5
(%)
0
13.7
4.8
3.6
4.8
3.0
0.6
2.4
1.8
0
0
0
0
0
0
UCSF

Sipuleucel-T in CRPC: How do we use it?
• Sipuleucel-T prolongs life in patients with asymptomatic met CRPC
• Sipuleucel-T is extremely well tolerated
• For use only in asymptomatic CRPC with no visceral mets
•
Not remission inducing
• My bias – use it early before advancing to prednisone-containing regimens (abiraterone, docetaxel, cabazitaxel, mitoxantrone all require steroids)
UCSF

FDA Approves Sipuleucel-T on April 29, 2010
You +1‘d
UCSF

New Treatments for Advanced Prostate Cancer
CYP-17 Inhibitors
UCSF

Keeping our eyes on the AR target……
“Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.”
Charles Huggins MD
Nobel Lecture
Dec 13, 1966
Journal of Clinical Oncology 1997
Small and Vogelzang define
“secondary hormonal therapy”

Matching Biology to Therapy along the Path to AR signaling
Signaling Event
Androgen
Production
Aberration
Intracrine
Production
Intervention
SCC Inhibitors
CYP 17
Inihibitors
Drugs
Ketoconazole -
Abiraterone
Tak-700
Tok-001
Androgen
Transport/Ci rculation/Up take
Polymorphisms
Block Transport
None
Conversion to DHT
Amplified 5 Alpha
Reductase
5-Alpha
Reductase inhibitors
Dutasteride
AR
Binding
Amplified AR
Splice Variant AR
Novel AR
Inhibitors
MDV-3100
ARN-509
Tok-001

From Ryan and Tindall JCO 2011

AR expression in
Bone Marrow Mets
Stanbrough et al
Cancer Research
2006
CRPC samples have robust AR expression
Mohler et al
17
Holzberlein et al Am J
Pathology
At autopsy – 73% of 15 samples exhibit AR amplification.
Friedlander/Paris et al
UC
SF

-
-
-
-
-
-
-
-
-
10
15
20
25
10
15
20
-
5
0
0
5
10
15
-
-
10
-
-
-
-
-
-
-
-
-
-
10
15
-
0
5
5
0
BP CP METS BP CP METS
3BHSD1
P=0.0005
3BHSD2
5
-
-
-
15
20
-
5
10
-
0
5
BP
BP
BP CP METS
CYP17A
P=0.0026
P<0.0001
CP METS
AKR1C3
P=0.0050
CP METS
SRD5A1
P=0.0031
BP CP METS
17BHSD3
BP
P=0.0004
CP METS
SRD5A2
P=0.0013
-
-
-
-
-
25
20
BP CP METS BP CP METS
UGT2B15 UGT2B17
1.
Transcripts encoding steroidogenic enzymes are detected within tumor
Montgomery RB et alCancer Res.
2008 Jun 1;68(11):4447-54
2.
Tumor androgens in CRPC metastases from anorchid patients exceed levels in prostate cancer tissues from eugonadal subjects
3.
These may be particularly relevant for tumors with overexpressed AR

Abiraterone: Provides durable androgen suppression
0.2
0
1
0.8
0.6
0.4
1.2
Ketoconazole – Androgens
Rise at PD
Androgens during Rx with Ketoconazole (CALGB 9583)
DHEAS
Androstenedione
Baseline Month 1 Progresion
Abiraterone - no rise in
Androgens at PD.
Small et al JCO 2004
Ryan et al JCO 2010
DHEAS
TEST
UCSF

COU-AA-301: Abiraterone Acetate Improves
Overall Survival in post chemotherapy mCRPC
Abiraterone acetate: 14.8 months
100
80
HR = 0.646 (0.54-0.77)
P < 0.0001
60
40
Placebo: 10.9 months
20
0
0
AA
Placebo
797
398
AA
Placebo
100 200 300 400
Days From Randomization
728
352
631
296
475
180
204
69
500 600 700
25
8
0
1

Variable
All subjects
Baseline ECOG
Baseline BPI
No. of prior chemo regimens
Type of progression
Baseline PSA above median
Visceral disease at entry
Baseline LDH above median
Baseline ALK-P above median
Region
Subgroup N
All
0 –1
2
<4

4
1
2
PSA only
1195
1068
127
659
536
833
362
363
Radiographic 832
YES
YES
591
709
YES 581
YES 587
North America 652
Other 543
Favors
AA
ALK-P, alkaline phosphatase
0.68
0.63
0.74
0.59
0.69
0.65
0.60
HR
0.66
0.64
0.81
0.64
0.71
0.60
0.64
0.69
95% CI
0.56
–0.79
0.53
–0.78
0.53
–1.24
0.50
–0.82
0.53
–0.85
0.51
–0.78
0.55
–0.99
0.42
–0.82
0.56
–0.84
0.52
–0.81
0.48
–0.74
0.58
–0.88
0.48
–0.74
0.51
–0.80
0.54
–0.90
0.5 0.75
1 1.5
Favors placebo de Bono et al. N Engl J Med. 2011;364:21.

UCSF Study: Abiraterone Provides Durable and Complete
Responses in the chemotherapy naïve setting
Baseline
Post Cycle 6
Response
PSA Decline ≥30%
PSA Decline ≥50%
PSA Decline ≥90%
Undetectable PSA (≤0.1) n (%)
27/31 (87.1)
26/31 (83.9)
13/31 (41.9)
2/31 (6.0%)
Ryan et al CCR 2011 UCSF

COU-AA-302: Does Abiraterone Improve Survival in its physiologic space (pre-chemotherapy mCRPC)?
Arm A
•Abiraterone plus
Prednisone
•
Progressive Prostate Cancer
WITHOUT prior Docetaxel based chemotherapy
Arm B
Placebo plus Prednisone
Endpoints – PFS, Overall Survival
UCSF

Abiraterone in CRPC: How do we use it?
• Abiraterone prolongs life in patients with met CRPC post chemotherapy
• Does benefit translate into the pre-chemotherapy setting?
• Can it be combined with other therapies? Should it be continued after disease progression?
• What are the mechanisms of resistance?
– Pharmaco-kinetic?
– Pharmaco-genomic?
– Alternate signaling paths?
– AR mediated progression?
UCSF

MDV3100
• Second-generation AR antagonist
• Binds AR more potently than does bicalutamide
• Not a partial agonist of AR
• Inhibits translocation of AR into nucleus and decreases
AR binding to DNA
• Oral agent; 160 mg daily (seizures at higher doses)
• Compared with placebo in ongoing randomized phase
3 trial (post-chemotherapy, ketoconazolenaïve )
Tran et al . Science. 2009;324(5928):787-790. Clinicaltrials.gov. NCT00974311. Accessed December
28, 2010. Scher et al. Lancet . 2010;375(9724):1437-1446.

Soft tissue
Partial response
Stable disease
Bone scan (week 12)
Stable disease
FDG-PET (week 12)
≥25% ↓ from baseline
<25% ↓ from baseline
Total
59
13 (22%; 13%-35%)
29 (49%; 36%-62%)
109
61 (56%; 46%-65%)
22
10 (45%; 25%-67%)
12 (55%; 33%-75%)
No prior chemotherapy
25
9 (36%; 19%-57%)
11 (44%; 25%-65%)
41
26 (63%; 47%-77%)
12
4 (33%; 11%-65%)
8 (67%; 35%-89%)
MDV3100 induced >50% PSA declines in 56% of mCRPC patients, including those were prechemotherapy (n = 65) and postchemotherapy (n = 75).
.
FDG-PET, 2¹⁸F-fl uoro-2-deoxy-D-glucose positron emission tomography.
Scher et al. Lancet . 2010;375(9724):1437-1446.
Prior chemotherapy
34
4 (12%; 4%-28%)
18 (53%; 30%-70%)
68
35 (51%; 39%-64%)
10
6 (60%; 27%-86%)
4 (40%;14%-73%)

Scher HI et al. Lancet. 2010;375:1437.

Men with docetaxelpretreated mCRPC (ketonaïve)
N = 1170
O
M
I
Z
E
R
A
N
D
2
1
Primary objective: OS
MDV3100 160 mg once daily + prednisone 5 mg twice daily
Placebo once daily + prednisone 5 mg twice daily
Clinicaltrials.gov. NCT00974311. Accessed December 28, 2010.

Placebo
Overall
Survival
13.6 mo
Rx Duration 3.0 mo
8.3% Soft Tissue resp
Subsequent therapy
-Abiraterone
-Cabazitaxel
*Seizures
24.3%
12%
MDV-3100
18.4 mo
8.3 mo
2.9%
21%
14%
0.6% (5cases) 0
Scher-Proc ASCO GU 2012 San Francisco 2/2/2012
P value
<0.001
<0.001
<0.001

New Treatments for Advanced Prostate Cancer
Second Line Chemotherapy
UCSF

• CRPC patients inevitably progress following Docetaxel treatment 1-5
• Despite Many studies (6,7,8):
– There has been no data showing that we can improve survival with second line chemotherapy
– UCSF led early studies of second line chemotherapy (Rosenberg, Harzstark) and helped establish this the estimates for survival and response in this setting.
1. Petrylak DP, et al. N Engl J Med. 2004;351(15):1513-1520.
2. Tannock IF, et al. N Engl J Med. 2004;351(15):1502-1512.
3. Oudard S, et al. J Clin Oncol. 2005;23(15):3343-3351.
4. Nelius T, et al. BJU Int. 2006;98(3):580-585.
5. Nelius T, et al. Onkologie. 2005;28(11):573-578.
6. Garmey EG, et al. Clin Adv Hematol Oncol. 2008;6(2):118-132.
7. Rosenberg JE, et al. Cancer. 2007;110(3):556-563.
8. Sternberg CN, et al. J Clin Oncol. 2009;27(32):5431-5438.

Docetaxel
Cabazitaxel (XRP6258)
( C
43
H
53
NO
14
)
Docetaxel is an esterified product of 10-deacetyl baccatin III
(C
45
H
57
NO
14
)
Cabazitaxel is a 7,10 dimethoxy analogue of docetaxel
Mita AC, et al. Clin Cancer Res 2009;15:723-730; Ojima I, et al. J Med Chem 1996;39:3889-3896; Greenberger LM,
Sampath D. Resistance to taxanes. In: Teicher BA, ed. Cancer Drug Discovery and Development: Cancer Drug
Resistance . Totowa, New Jersey: Humana Press; 2006:329-358; Raub TJ. Mol Pharm 2005;3:3-25; www.Taxotere.com
.

The TROPIC study: cabazitaxel or mitoxantrone with prednisone in patients with metastatic CRPC previously treated with docetaxel (De Bono et al)
Men with metastatic CRPC progressing during and after docetaxel
(N=755)
O
M
I
Z
E
R
A
N
D
Cabazitaxel 25 mg/m² q 3 wk
+ prednisone for 10 courses (CBZP, n=378)
Mitoxantrone 12 mg/m² q 3 wk
+ prednisone for 10 courses (MP, n=377)
Primary objective: Overall survival
Secondary objectives: PFS (tumor progression, pain progression, PSA progression, or death from any cause), response rate, safety
UCSF

Primary Endpoint (Overall Survival) Met
60
40
20
100
80
0
0
Median OS (months)
Hazard ratio
95% CI
P-value
MP
12.7
0.72
CBZP
15.1
0.61
–0.84
<.0001
6 12 18 24
Censored
MP
CBZP
Combined median follow-up: 13.7 months
30 Time (months )
UCSF

Hematologic AEs a
JEVTANA® 25 mg/m² q 3 wk
+ prednisone 10 mg qd (n=371) mitoxantrone 12 mg/m² q 3 wk
+ prednisone 10 mg qd (n=371)
Neutropenia b
Febrile neutropenia
Anemia b
Leukopenia b
Thrombocytopenia b
Grade 1–4, n (%) Grade 3–4, n (%) Grade 1–4, n (%) Grade 3–4, n (%)
347 (94%) 303 (82%) 325 (87%) 215 (58%)
27 (7%)
361 (98%)
355 (96%)
176 (48%)
27 (7%)
39 (11%)
253 (69%)
15 (4%)
5 (1%)
302 (82%)
343 (93%)
160 (43%)
5 (1%)
18 (5%)
157 (42%)
6 (2%)
3
7 a b
In ≥5% of patients.
Based on laboratory values: JEVTANA® (n=369), mitoxantrone (n=370).
• Protocol did not permit primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) at cycle 1
JEVTANA® Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010.
Data on file. Clinical study report/EFC6193 (TROPIC).

1. Cabazitaxel significantly improved survival when compared to mitoxantrone, in patients with metastatic
CRPC who had received prior docetaxel.
2. It may prolong sensitivity to taxane chemotherapy in patients with acquired docetaxel resistance
3. Its use in the overtly taxane refractory patient may be limited
UCSF

1. As an incremental step forward, it merits testing as front line chemotherapy
2. Combination studies are also warranted.
3. As before, a study of the mechanisms of resistance to this therapy are warranted. (Friedlander/Paris project)
4. FDA mandated 25mg/m2 vs 20 mg/m2 study.
UCSF

Oral Multi-targeted TKI
RET
MET
3.8 nM
1.8 nM
VEGFR2 0.035 nM
KIT 4.6 nM
How do we use it?
Where do we go?
Stay tuned….

New Treatments for Advanced Prostate Cancer
Radium 223
UCSF

• Radium-223 acts as a calcium mimic
• Naturally targets new bone growth in and around bone metastases
• Radium-223 is excreted by the small intestine
Ca
Ra

Range of alpha-particle
Radium-223
Bone surface
• Alpha-particles induce double-strand DNA breaks in adjacent tumour cells 1
– Short penetration of alpha emitters (2-10 cell diameters) = highly localised tumour cell killing and minimal damage to surrounding normal tissue
1. Perez et al . Principles and Practice of Radiation Oncology.
5th ed. Lippincott Williams &
Wilkins; 2007:103.

TREATMENT
PATIENTS
6 injections at
4-week intervals
• Confirmed symptomatic
CRPC
• ≥ 2 bone metastases
• No known visceral metastases
• Post-docetaxel or unfit for docetaxel
STRATIFICATION
• Total ALP:
< 220 U/L vs ≥ 220 U/L
• Bisphosphonate use:
Yes vs No
• Prior docetaxel:
Yes vs No
O
M
I
S
R
A
N
D
E
D
2:1
Radium-223 (50 kBq/kg)
+ Best standard of care
Placebo (saline)
+ Best standard of care
N = 922
Planned follow-up is 3 years
Clinicaltrials.gov identifier: NCT00699751.

Radium-223
(n = 541)
Placebo
(n = 268)
Parameter
Age, y
Mean
Race, n (%)
Caucasian
Baseline ECOG score, n (%)
≤ 1
2
Extent of disease, n (%)
< 6 metastases
6-20 metastases
> 20 metastases/superscan
WHO ladder, cancer pain index ≥ 2, n (%)
70.2
507 (94)
467 (86)
71 (13)
88 (16)
235 (44)
217 (40)
294 (54)
70.7
252 (94)
229 (85)
37 (14)
33 (12)
129 (48)
106 (40)
142 (53)

Parameter
Median (min, max)
Haemoglobin, g/dL
Albumin, g/L
Total ALP, µg/L
LDH, U/L
PSA, µg/L
Radium-223
(n = 541)
12.2
(8.5-15.7)
40
(24-53)
213
(32-4661)
317
(76-2171)
159
(3.78-6026)
Placebo
(n = 268)
12.1
(8.4-16.4)
40
(23-50)
224
(29-3225)
328
(132-3856)
195
(1.5-14500)

100
%
90
80
70
60
50
40
30
20
10
0
Month 0
Radium- 223 541
Placebo 268
3
450
218
6
330
147
9
213
89
HR 0.695; 95% CI, 0.552-0.875
P = 0.00185
12
120
49
15
72
28
Radium-223, n = 541
Median OS: 14.0 months
Placebo, n = 268
Median OS: 11.2 months
18
30
15
21
15
7
24
3
3
27
0
0

1. Oral, Well tolerated therapies will extend the option of treatment for m
CRPC to more patients than previous….(only about 50% of CRPC pts get docetaxel)
2. Prostate cancer will become a model for ( or a victim of ?) cost effectiveness research.
3. Management of CRPC will be done by those most capable of understanding biology and the integration of therapies – no matter what their prior training.
4. Combined oral therapies will push therapy and survival further – e.g
with better survival more patients will be available for therapy (“If you build it, they will come”)_
5. New targeted therapies will need to be developed in conjunction with biomarkers that predict response (e.g. Her 2  trastuzumab in breast cancer)
UCSF

Thank You
UCSF