1. Castrate resistance prostate cancer: Integrating novel agents 
into a therapeutic algorithm
Charles J Ryan, MD
Associate Professor of Medicine and Urology
Helen Diller Family Comprehensive Cancer Center
University of California, San Francisco U C S F

2. Since 2010…
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.

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

4. Prostate Cancer Standards and Novel Therapies:
Clinically
Localized
Rising PSA
post RP/RT
ADT Resistant
Pre-Chemotherapy Chemotherapy
CRPC
Docetaxel
Resistant
AR Targeted
Therapy
Chemotherapy
Immunotherapy
Targeted Therapy U C S F

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

6. New Treatments for Advanced Prostate Cancer
Targeting the T Cell
Androgen Synthesis Inhibitors
Second line chemotherapy
Alpha-emitting Radio-isotopes U C S F

7. New Treatments for Advanced Prostate Cancer
Targeting the T Cell U C S F

8. Theoretical Kinetics of Treatment Response: Cytotoxic Therapy vs Immunotherapy
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
Tumor size
Progression
Immunotherapy
Time
Webster et al. J Clin Oncol. 2005;23:8262.

9. Sipuleucel-T: Background
Small EJ et al., J Clin Oncol 18: 3894, 2000

10. Sipuleucel-T : (second) Pivotal Trial Results
Phase 3 design allowed for crossover from placebo to vaccine
Adverse Events
The pivotal trial was a randomized, multicenter, double-blind, controlled Phase 3 trial that enrolled 512 men with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer1,2,3
Men were randomized 2:1 to the treatment groups with 341 men randomized to receive PROVENGE and 171 men randomized to receive control1,2,3
Control was nonactivated, autologous, peripheral blood mononuclear cells 1,3
The primary endpoint was overall survival1,2,3
Following independent confirmation of objective disease progression (as determined by bone scan and CT imaging2,3), subjects were treated at the physician’s discretion1,2,3
Patients randomized to the control group had the option to enter a Phase 2, open-label protocol to receive an autologous immunotherapy made from cells that were cryopreserved at the time of control generation2
63.7% of patients in the control group entered the Phase 2, open-label protocol3
References
PROVENGE [package insert]. Dendreon Corporation; April 2010.
Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration–resistant prostate cancer. N Engl J Med. 2010;363:
D9902B Clinical Study Report; Biologics License Application: PROVENGE® (sipuleucel-T). October Seattle, WA: Dendreon Corporation.
†Control was nonactivated, autologous, peripheral blood mononuclear cells. U C S F
Kantoff PW et al. N Engl J Med. 2010;363:

11. 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) U C S F

12. FDA Approves Sipuleucel-T on April 29, 2010
You +1‘d U C S F

13. New Treatments for Advanced Prostate Cancer
CYP-17 Inhibitors U C S F

14. 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”

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

16. From Ryan and Tindall JCO 2011

17. Higher AR levels in CRPC tumors
CRPC samples have robust AR expression Mohler et al
Holzberlein et al Am J Pathology
AR expression in Bone Marrow Mets
Stanbrough et al Cancer Research 2006
At autopsy – 73% of 15 samples exhibit AR amplification.
Friedlander/Paris et al U C S F
Friedlander et al

18. Prostate Cancer can make its own androgens
Montgomery RB et alCancer Res Jun 1;68(11):

19. Abiraterone: Provides durable androgen suppression
Abiraterone - no rise in Androgens at PD.
Ketoconazole – Androgens Rise at PD
DHEAS
TEST
Small et al JCO 2004
Ryan et al JCO 2010 U C S F

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

21. Survival Benefit Consistently Observed Across Patient Subgroups
Curatio PowerPoint Template
Survival Benefit Consistently Observed Across Patient Subgroups
4/19/2017 6:18 PM
Variable
Subgroup N HR
95% CI
All subjects
All
1195
0.66
0.56–0.79
Baseline ECOG
0–1
1068
0.64
0.53–0.78 2
127
0.81
0.53–1.24
Baseline BPI
<4
659
0.50–0.82
 4
536
0.68
0.53–0.85
No. of prior chemo regimens 1
833
0.63
0.51–0.78
362
0.74
0.55–0.99
Type of progression
PSA only
363
0.59
0.42–0.82
Radiographic
832
0.69
0.56–0.84
Baseline PSA above median
YES
591
0.65
0.52–0.81
Visceral disease at entry
709
0.60
0.48–0.74
Baseline LDH above median
581
0.71
0.58–0.88
Baseline ALK-P above median
587
Region
North America
652
0.51–0.80
Other
543
0.54–0.90
Fact check:
Similar to but not identical with fig 2 p2001
0.5
0.75 1
1.5
Favors AA
Favors placebo
ALK-P, alkaline phosphatase
de Bono et al. N Engl J Med. 2011;364:21.

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

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

25. 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? U C S F

27. 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, ketoconazole-naïve)
Tran et al. Science. 2009;324(5928): Clinicaltrials.gov. NCT Accessed December 28, Scher et al. Lancet. 2010;375(9724): 27

28. MDV3100: Phase 1/2 Study Radiographic Responses
Total
No prior chemotherapy
Prior chemotherapy
Soft tissue
Partial response
Stable disease 59
13 (22%; 13%-35%)
29 (49%; 36%-62%) 25
9 (36%; 19%-57%)
11 (44%; 25%-65%) 34
4 (12%; 4%-28%)
18 (53%; 30%-70%)
Bone scan (week 12)
109
61 (56%; 46%-65%) 41
26 (63%; 47%-77%) 68
35 (51%; 39%-64%)
FDG-PET (week 12)
≥25% ↓ from baseline
<25% ↓ from baseline 22
10 (45%; 25%-67%)
12 (55%; 33%-75%) 12
4 (33%; 11%-65%)
8 (67%; 35%-89%) 10
6 (60%; 27%-86%)
4 (40%;14%-73%)
MDV3100 induced >50% PSA declines in 56% of mCRPC patients, including those were prechemotherapy (n = 65) and postchemotherapy (n = 75). .
FDG-PET, 2-¹⁸F-fl uoro-2-deoxy-D-glucose positron emission tomography.
Scher et al. Lancet. 2010;375(9724): 28

29. MDV-3100 Time to PSA Progression
Curatio created slide
Scher HI et al. Lancet. 2010;375:1437.

30. MDV3100: Phase 3 Trial (AFFIRM)
POSITIVE
MDV mg once daily +
prednisone 5 mg twice daily
Placebo once daily + R A N D O M I Z E
N = 1170
Men with docetaxel-pretreated mCRPC (keto-naïve) 2 1
Primary objective: OS
Clinicaltrials.gov. NCT Accessed December 28, 2010.

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

32. New Treatments for Advanced Prostate Cancer
Second Line Chemotherapy U C S F

33. SeSecond Line Chemotherapy
CRPC patients inevitably progress following Docetaxel treatment1-5
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): Tannock IF, et al. N Engl J Med. 2004;351(15): Oudard S, et al. J Clin Oncol. 2005;23(15): Nelius T, et al. BJU Int. 2006;98(3): Nelius T, et al. Onkologie. 2005;28(11): Garmey EG, et al. Clin Adv Hematol Oncol. 2008;6(2): Rosenberg JE, et al. Cancer. 2007;110(3): Sternberg CN, et al. J Clin Oncol. 2009;27(32):

34. Two Different Chemical Entities
Docetaxel
Cabazitaxel (XRP6258)
Cabazitaxel chemical structure differs from docetaxel chemical structure: R2 and R7 positions: cabazitaxel OCH3; docetaxel OH.
According to Raub, replacing electronegative atoms such as O with CH2 is one structural change/step to likely decrease the affinity of binding to Pgp.
Ojima et al described a series of taxoids with 19 C-10 modifications where acetyl analogues are more active in resistant cell lines; and, adding aliphatic or aromatic H-bonding groups and more hydrophobicity decreases the effect, or presumably increases Pgp recognition. Additional studies showed that a C-10 substitution results in a 7-10 fold increase in BBB permeability in rat brain and improved efficacy in vivo versus paclitaxel.
(C43H53NO14)
Docetaxel is an esterified product of 10-deacetyl baccatin III
(C45H57NO14)
Cabazitaxel is a 7,10 dimethoxy
analogue of docetaxel
Mita AC, et al. Clin Cancer Res 2009;15: ; Ojima I, et al. J Med Chem 1996;39: ; 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: ; Raub TJ. Mol Pharm 2005;3:3-25; 34

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

36. Primary Endpoint (Overall Survival) Met
TROPIC slide deck. Slide5
100 80 60 40 20 MP
CBZP
Median OS (months)
12.7
15.1
Hazard ratio
0.72
95% CI
0.61–0.84
P-value
<.0001
Proportion of OS (%)
Censored MP
CBZP
Combined median follow-up: 13.7 months 6 12 18 24 30
Time (months) U C S F

37. Summary of Hematologic AEs
Hematologic AEsa
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)
Grade 1–4, n (%)
Grade 3–4, n (%)
Neutropeniab
347 (94%)
303 (82%)
325 (87%)
215 (58%)
Febrile neutropenia
27 (7%)
5 (1%)
Anemiab
361 (98%)
39 (11%)
302 (82%)
18 (5%)
Leukopeniab
355 (96%)
253 (69%)
343 (93%)
157 (42%)
Thrombocytopeniab
176 (48%)
15 (4%)
160 (43%)
6 (2%)
JEVTANA.USPI.Jun p10-11/T2
DOF.CSR.TROPIC p9/L12-13
a In ≥5% of patients. b 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 Data on file. Clinical study report/EFC6193 (TROPIC).

39. Cabazetaxel: How do we use it?
Cabazitaxel significantly improved survival when compared to mitoxantrone, in patients with metastatic CRPC who had received prior docetaxel.
It may prolong sensitivity to taxane chemotherapy in patients with acquired docetaxel resistance
Its use in the overtly taxane refractory patient may be limited U C S F

40. Cabazitaxel: Where do we go?
As an incremental step forward, it merits testing as front line chemotherapy
Combination studies are also warranted.
As before, a study of the mechanisms of resistance to this therapy are warranted. (Friedlander/Paris project)
FDA mandated 25mg/m2 vs 20 mg/m2 study. U C S F

41. XL184: Cabozantanib XL- Oral Multi-targeted TKI RET 3.8 nM MET 1.8 nM
VEGFR nM
KIT 4.6 nM
How do we use it?
Where do we go?
Stay tuned….

42. New Treatments for Advanced Prostate Cancer
Radium 223 U C S F

43. Radium-223 Targets Bone Metastases
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

44. Radium-223 Targets Bone Metastases
Range of alpha-particle
Radium-223
Bone surface
Alpha-particles induce double-strand DNA breaks in adjacent tumour cells1
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.

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

46. ALSYMPCA Patient Demographics and Baseline Characteristics (ITT; N = 809)
Parameter
Radium-223
(n = 541)
Placebo
(n = 268)
Age, y
Mean
70.2
70.7
Race, n (%)
Caucasian
507 (94)
252 (94)
Baseline ECOG score, n (%)
≤ 1 2
467 (86)
71 (13)
229 (85)
37 (14)
Extent of disease, n (%)
< 6 metastases
6-20 metastases
> 20 metastases/superscan
88 (16)
235 (44)
217 (40)
33 (12)
129 (48)
106 (40)
WHO ladder, cancer pain index ≥ 2, n (%)
294 (54)
142 (53)

47. ALSYMPCA Patient Baseline Characteristics, cont (ITT; N = 809)
Parameter Median (min, max)
Radium-223 (n = 541)
Placebo (n = 268)
Haemoglobin, g/dL
12.2 ( )
12.1 ( )
Albumin, g/L
40 (24-53)
40 (23-50)
Total ALP, µg/L
213 ( )
224 ( )
LDH, U/L
317 ( )
328 ( )
PSA, µg/L
159 ( )
195 ( )

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

49. The Future – My predictions
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)
Prostate cancer will become a model for ( or a victim of ?) cost effectiveness research.
Management of CRPC will be done by those most capable of understanding biology and the integration of therapies – no matter what their prior training.
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”)_
New targeted therapies will need to be developed in conjunction with biomarkers that predict response (e.g. Her 2  trastuzumab in breast cancer) U C S F

50. Thank You U C S F