This document summarizes a presentation on tackling prostate cancer and improving treatment outcomes. It discusses that prostate cancer incidence is increasing due to aging and screening. Prostate cancer is the second most common cancer in men and is an androgenic disease related to testosterone and the androgen receptor. The presentation reviews prostate cancer risk stratification and how docetaxel added to androgen deprivation therapy can improve outcomes for metastatic hormone-sensitive prostate cancer based on clinical trial results. It also discusses therapies such as abiraterone that have shown survival benefits for castrate-resistant prostate cancer based on additional clinical trials.

1. Tackling Prostate Cancer:
Can we go better?
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Kasr Al-Aini School of Medicine
Cairo University
NEMROCK – Sanofi Symposium
Wednesday 7th, 2015
Sofitel Tower & Hotel

2. Basic Facts & Figures:
• Increasing Incidence: Aging and Screening
Programs.
• 2nd Most Common Cancer in Men.
• 1/6 Men.
• Black Races.
• Rare Before Age of 40 and then Readily Rises.
• Prostate Cancer is an Androgenic Disease.
MJA 2008; 189: 315–318

3. Prostate Cancer: Best Identity:
Natural History
Androgen
Biosynthesis
Androgen Receptor
Activity
Aggressiveness

4. Hypothalamus
LHRH
Pituitary
Testes Supra-renal
Testosterone
LH ACTH
Prostate Cancer is an Androgenic
Disease: “Androgen Synthesis”
LHRH
Analogue
Bilateral
Orchiectomy

5. Steroidogenesis & Prostate
Cancer :
Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone

6. NTD DBD Hinge LBD
Nuclear
& Steroid
Superfamily
Androgen
Estrogen
Glucocorticoid
Mineralocorticoid
Progesterone
Constitutively Active DNA
Promoter
Gene
AndrogensN/C
HSP
Prostate Cancer is an Androgenic Disease:
“Androgen Receptor Structure”

7. Prostate Cancer is an Androgenic Disease:
“Androgen Receptor Activity”
5@ Reductase
Genomic Activity
PSA, IGF, …

8. Testosterone 5 α Reductase DHT + AR (LBD)
PI3K
Caveolae
RTK
GPCR
AR Activation &
Dimerization
HSP
AKT
Src
MAPK
ERK1/2
Nuclear Transcription
Factors
• Proliferation, Angiogenesis, …
• No AR Degradation.
Prostate Cancer is an Androgenic Disease:
“Androgen Receptor Activity”
Non Genomic Activity

9. Androgen Receptor in Prostate Cancer:

10. Natural History of Prostate Cancer:
Time
TumorVolume&Mortality

11. Pre-Treatment Assessment:
Basics Factors:
Management of Newly
Diagnosed Prostate Cancer
Risk of
Local
Recurrence
Risk of
Disseminated
Disease
PSA Staging
Gleason
Score

12. Prostate Cancer:
Risk Stratification:

13. Long versus Short Term ADT:
Lancet Oncol 2015; 16: 320–27

14. Long versus Short Term ADT:
Lancet Oncol 2015; 16: 320–27
Long Term ADT > Short Term ADT
Biochemical Failure
Free Survival
OAS
Metastasis Free
Survival

15. Long versus Short Term ADT:
Lancet Oncol 2015; 16: 320–27

16. Long versus Short Term ADT:
NCCN GUIDELINES

17. androgen-dependent cell
CRPC
Intrinsic Resistance to ADT

18. The Hypothesis
• Docetaxel added at the time of starting ADT in
hormone-sensitive metastatic prostate cancer
(mHSPC) will prolong overall survival (OS)

19. Metastatic HSPC:
GETUG 15 Trial Design
n = 385 pts
2 ADT:
- LHRH agonist
- or maximum androgen blockade
- or orchiectomy
3 75 mg/m2 q3 up to 9 cycles
Gravis G, et al. Lancet Oncol. 2013;14(2):149-158.
1 Glass TR, et al. J Urol.
2003;169(1):164-169.

20. Median PFS:
ADT + D: 23 mo [19.6-28.4]
ADT: 13 mo [11.9-17.7]
HR [95%CI]: 0.72 [0.57-0.91] P = .0052
ADT+ docetaxel
ADT
ADT
ADT+ docetaxel
Gravis G, et al. Lancet Oncol. 2013;14(2):149-158.
Biochemical Progression-Free
Survival:

21. Median cPFS:
ADT + D: 23 mo [20.5-32]
ADT: 15 mo [12.5-20]
HR [95%CI]: 0.75 [0.59-0.94] P = .0147
ADT+ docetaxel
ADT
Clinical Progression-Free
Survival:
ADT
ADT+ docetaxel
Gravis G, et al. Lancet Oncol. 2013;14(2):149-158.

22. Median OS:
ADT + D: 59 mo [51-69]
ADT: 54 mo [42-NR]
HR [95%CI]: 1.01 [0.75-1.36] P = .95
ADT + docetaxel
ADT
ADT
ADT + docetaxel
Median follow-up: 50 months [49 - 54]
Overall Survival
Gravis G, et al. Lancet Oncol. 2013;14(2):149-158.

23. E3805 – CHAARTED
STRATIFICATION
Extent of Mets
-High vs Low
Age
≥70 vs < 70yo
ECOG PS
- 0-1 vs 2
CAB> 30 days
-Yes vs No
SRE Prevention
-Yes vs No
Prior Adjuvant ADT
≤12 vs > 12 months
R
A
N
D
O
M
I
Z
E
ARM A:
ADT + Docetaxel
75mg/m2 every 21
days for maximum
6 cycles
ARM B:
ADT (androgen
deprivation therapy
alone)
Evaluate
every 3 weeks
while
receiving
docetaxel and
at week 24
then every 12
weeks
Evaluate
every 12
weeks
Follow for time
to progression
and overall
survival
Chemotherapy
at investigator’s
discretion at
progression
Presented by: Christopher J. Sweeney, MBBS ASCO Plenary 2014
Sweeney C, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA2.

24. Primary Endpoint: Overall Survival
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
36 48
OS(Months)
0 12 24 60 72 84
Probability
Sweeney C, et al. J Clin Oncol. 2014;3A2(Suppl): Abstract7A2.
HR = 0.61 (0.47-0.80) P = .0006
Median OS:
ADT + D: 57.6 months
ADT: 44.0 months
ADT + D
ADT

25. Causes of Death
Sweeney C, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA2.
ADT + D
(N=397)
N
ADT
(N=393)
N
Due to prostate
cancer
83 112
Due to protocol
treatment
1 0
Other cause 8 11
Unknown 8 9
Missing 1 4
Total 101 136

26. 0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
36 48
OS(Months)
0 12 24 60 72 84
Arm ALIV
E
115
116
DEA
D19
26
MEDIAN
.
.
TOTAL
A 134
High-voB
lume dise25
a1
se:110
17 m141
onth32.2
improvement inB
median OS142
Probability
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
36 48
OS(Months)
0 12 24 60 72 84
Probability
49.2 versus 32.2 months
OS by Extent of Metastatic Disease at
Start of ADT
High Volume Low Volume
p=0.0006
HR=0.60 (0.45-0.81)
Median OS:
ADT + D: 49.2 months
ADT : 32.2 months
p=0.1398
HR=0.63 (0.34-1.17)
Median OS:
ADT + D: Not reached
ADT : Not reached
ADT + D
ADT
ADT + D
ADT
Sweeney C, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA2.

27. Upfront Docetaxel + ADT in Castrate
Sensitive Disease: NCCN Guidelines:

28. Prostate Cancer: Clinical Scenarios:
Loco-
Regional
Metastati
c
HRPC
Risk Stratification Risk Stratification
• Active
Surveillance.
• L-R Treatment.
• L-R Treatment +
HM
• HM
• Chemotherapy
• L-R Treatment

29. 1984-1989
...but this rapid change has left many unanswered
questions, including the optimal selection and
sequence of therapy
Mitoxantrone3 Docetaxel5,6*
Sipuleucel-T8*
LHRH agonists1*
1. The Leuprolide Study Group. N Engl J Med. 1984;311(20):1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321(7):419-424. 3. Tannock I et
al. J Clin Oncol. 1996;14(6):1756-1764. 4. Saad F, et al. J Natl Cancer Inst. 2002;94(19):1458-1468. 5. Petrylak DP, et al. N Engl J Med.
2004;351(15):1513-1520. 6. Tannock I, et al. N Engl J Med. 2004;351(15):1502-1512. 7. de Bono JS, et al. Lancet. 2010;376(9747):1147-1154. 8.
Kantoff P, et al. N Engl J Med. 2010;363(5):411-422. 9. Fizazi K, et al. J Clin Oncol. 2009;27(10)1564-1571. 10. de Bono JS, et al. N Engl J Med.
2011;364(21):1995-2005. 11. Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197.
1996 2002 2004 .... 2010
Abiraterone10*
Reversible AR
blockers2
Cabazitaxel7*
2011
Denosumab9
Radium 223?
Zoledronic Acid4
2012
Enzalutamide11*

30. Management of CRPC:
1. ADT should be continued.
2. Inhibition of bone resorption
3. Risk Stratification.
4. Choose between therapies associated with
survival benefit.

31. Castrate Resistant Prostate Cancer:
Prognostic Factors:
Halabi et al. J Clin Oncol 32:671-677. © 2014

32. Castrate Resistant Prostate Cancer:
Prognostic Factors:
1. Site of Metastases: 5 RCTs:
0 5 10 15 20 25 30
Liver
Lungs
Bone
LNs
Months
OAS
Halabi et al. Journal of Clinical Oncology, 2014 ASCO Annual Meeting Abstracts. Vol
32, No 15_suppl (May 20 Supplement), 2014: 5002

33. 2. Circulating Tumor Cells:
– < 5/7.5 mL: med. OAS 22.1 months.
– > 5/7.5 mL: med. OAS 10.9 months.
3. Markers of Bone Metabolism:
– 2 markers of bone resorption (N-Telopeptide &
Pyridinoline) and 2 markers of bone formation (C-
Terminal Collagen Peptide & Bone Alkaline Phosphatase).
– Higher levels are correlated with poor med. OAS  5
versus 13 months.
4. Gene Expression Profiles: 6 &9 Gene Assays.
Castrate Resistant Prostate Cancer:
Prognostic Factors:
Scher et al. J Clin Oncol. 2011;29:293s.
Lara et al. J Natl Cancer Inst. 2014.
Olmos et al. Lancet Oncol. 2012;13(11):1114

34. Therapies Associated with Survival
Benefit:

35. COU-AA-301 Study Design
Phase III Post-Docetaxel
Abiraterone 1000 mg QD
Prednisone 5 mg BID
n = 797
Primary endpoint:
• OS
Secondary endpoints:
• PSA response
• Time to PSA progression
• rPFS
Placebo QD
Prednisone 5 mg BID
n = 398
R
A
N
D
O
M
I
Z
E
D
2:1
Phase 3, double-blind placebo-controlled trial of abiraterone +
prednisone versus placebo + prednisone in mCRPC post-
chemotherapy
de Bono JS, et al. N Engl J Med. 2011;346(21):1995-2005.
• 1195 patients
with progressive
mCRPC
• Failed 1 or 2
chemotherapy
regimens, 1 of
which contained
docetaxel

36. OverallSurvival,%
0
20
40
60
80
100
12 18
Time to Death, months
0 6 24 30
AA + P 797 657 473
Placebo + P 398 306 183
273 15 0
100 6 0
AA + P:
AA, abiraterone acetate; CI, confidence interval; P, prednisone
Placebo + P:
HR = 0.74 (95% CI,0.638-0.859) P<.0001
26% reduction in risk of death
Median follow-up: 20.2 months
Fizazi K, et al. Lancet Oncol. 2012;13(10):983-992.

37. 0.5 0.75 1 1.5
Favors abiraterone Favors placebo
de Bono JS, et al. N Engl J Med. 2011;364(21):1995-2005.
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 0.64 0.50-0.82
≥ 4 536 0.68 0.53-0.85
No of prior
chemotherapy regimens
1 833 0.63 0.51-0.78
2 362 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
Age, years < 65 0.66 0.48-0.91
≥ 65 0.67 0.55-0.82
Visceral disease at entry Yes 353 0.70 0.52-0.94
Baseline PSA above
median
Yes 591 0.65 0.52-0.81
Baseline LDH above
median
Yes 581 0.71 0.58-0.88
Baseline ALK-P above
median
Yes 587 0.60 0.48-0.74
Region N America 652 0.64 0.51-0.80
Other 543 0.69 0.54-0.90

38. Abiraterone 1000 mg QD
+ Prednisone 5 mg BID
n = 546
Co-Primary endpoints:
• OS
• rPFS
Placebo BID
+ Prednisone 5 mg BID
n = 542
R
A
N
D
O
M
I
Z
E
D
1:1
COU-AA-302 Study Design
Phase III Pre-Docetaxel
Phase 3, double-blind placebo-controlled trial of abiraterone +
prednisone versus placebo + prednisone in mCRPC pre-
chemotherapy
Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148.
• 1088 progressive
chemonaïve
patients with
mCRPC
• Asymptomatic
or mildly
symptomatic

39. Abiraterone Doubled Time to rPFS1
1. Rathkopf DE et al. Eur Urol 2014; [Epub ]
Ryan C et al. ESMO 2014; Abstract 7530 (oral presentation)

40. COU-AA-302: Updated OS
Placebo +
prednisone,
30.1 months
Months From Randomization
Second interim analysis: 43% death1
Third interim analysis: 56% death2
SubjectsWithoutDeath,%
HR = 0.79 (95% CI, 0.66–0.95) P = .0151
Prespecified P for significance: .0035100
80
60
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Abiraterone + prednisone,
35.3 months
1. Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148. 2. Rathkopf DE, et al. J Clin Oncol. 2013;31(Suppl 6): Abstract 5.

41. Significant Improvement in Time to
Opiate Use for Cancer-Related Pain
in the Final Analysis
• At the time of IA3, the median time to opiate use had not been reached for abiraterone
• All secondary end points showed significant improvement with abiraterone
Ryan C et al. ESMO 2014; Abstract 7530 (oral presentation)

42. Enzalutamide, an AR Signaling
Inhibitor: Targets Multiple Steps in the (AR)
Signaling Pathway
A
1. Competitively
inhibits androgen
binding to AR
2. Impairs AR
nuclear
translocation
3. Inhibits AR
interaction with DNA
A
AR
Cell nucleus AR
Cell cytoplasm
Tran C, et al. Science. 2009;324(5928):787-790.

43. Enzalutamide 160 mg QD
n = 800
Efficacy end points (ITT)
Primary endpoint:
• OS
Secondary endpoints:
• PSA response
• Time to PSA progression
• rPFS
• Time to first SRE
Placebo QD
n = 399
R
A
N
D
O
M
I
Z
E
D
2:1
AFFIRM Study Design:
Phase III Post-Docetaxel
Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197
Phase 3, double-blind placebo-controlled trial of enzalutamide
versus placebo in mCRPC post-chemotherapy
No corticosteroids required
• 1199 patients
with progressive
mCRPC
• Failed 1 or 2
chemotherapy
regimens, 1 of
which contained
docetaxel

44. %OAS
0 3 6 9 12 15 18 21 24
AFFIRM Overall Survival:
Median of 4.8 Months
Enzalutamide: 18.4 months
(95% CI: 17.3, NYR)
Placebo: 13.6 months
(95% CI: 11.3, 15.8)
100
90
80
70
60
50
40
30
20
10
0
Duration of Overall Survival, months
HR = 0.631 (95% CI: 0.529, 0.752) P < .0001
37% reduction in risk of death
Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197.
Enzalutamide 800 775 701 627 400 211 72 7 0
Placebo 399 376 317 263 167 81 33 3 0

45. PREVAIL Phase III Trial:
Enzalutamide Pre-Docetaxel CRPC:
1717
Patients
with CRPC
Enzalutamide
160 mg/d
Placebo
• Radiographic PFS
• OAS
NEJM, 01 JUNE 2014

46. PREVAIL Trial:
Effect on Radiographic PFS:
Rate PFS at 12 months
65% vs 14%
NEJM, 01 JUNE 2014

47. • Reduction of Risk of
death by 29%.
• mOAS: 32.4 vs 30.2
months.
• CTH Delay by 17
months.
PREVAIL Trial:
Effect on OAS:
NEJM, 01 JUNE 2014

48. ALLIANCE TRIAL: Co-Targeting
Androgen Receptor & Biosynthesis:
• 1224 pts.
• Progressive
Metastatic CRPC.
• No Prior Taxanes
Enzalutamide 160 mg
QD
Enzalutamide 160 mg
QD
Aberaterone 1000 mg
QD
Prednisone 5 mg bid
2
1
OAS
Clinicaltrials.gov:/01949337

49. Tannock IF, et al. N Engl J Med. 2004;35(15):1502-1512.
Docetaxel + Prednisone or Mitoxantrone +
Prednisone for CRPC:
Overall Survival
Petrylak DP, et al. N Engl J Med. 2004;351(15):1513-1520.
100
80
60
40
20
0
ProbabilityOverallSurvival,%
0 3 6 9 12 15 18 21
Months
217 104
24 27 30 33
Docetaxel
q3w
Weekly
docetaxel
Mitoxantrone
100
80
60
40
20
0
P = .02
Docetaxel + estramustine
(217 deaths; median: 17.5 months)
24
Months
480 12 36
Mitoxantrone
+ prednisone
(235 deaths; median: 15.6
months)
No at Risk
Docetaxel
every 3 wk
Wkly docetaxel 334
Mitoxantrone 337
335 296 37 5
297
297
200
192
105
95
29
29
4
3

51. Post Docetaxel: Cabazitaxel/Prednisone
vs Mitoxantrone/Prednisone
Overall Survival MP CBZP
30 Time, Months
ProportionofOS,%
377
CBZP 378
299
321
195
241
94
137
31
60
9
19
0 6 12 18 24
Median OS (mos)
Hazard ratio
95% CI
P value
12.7 15.1
0.70
0.59-0.83
<.0001
Number MP
at Risk
Censored
MP
CBZP
Combined median
follow-up: 13.7 months
CBZP
MP
de Bono, et al. Lancet. 2010; 376: 1147

52. Sequence of Therapies in CRPC

53. • Pain
• Bone vs visceral metastases
• Performance status
• Neuropathy
• Comorbidity
• “Early or late” CRPC
• Prior therapy exposure and response
• Response biomarkers
• Tumor characteristics
CRPC, castration-resistant prostate cancer

54. AR-Targeted Agents1
• Retrospective analysis in
173 patients with metastatic PCa
• Poor response to subsequent
hormone therapies (including
abiraterone, enzalutamide) if time
to CRPC with first ADT ≤1 year
2. Huillard O, et al. J Clin Oncol. 2013;31(Suppl); Abstract 5075.
↓PSA ≥ 50%
Median TTP (months)
16% 41%
3.2 6.6
• 188 patients with mCRPC in 2
prospective databases
• High Gleason score and visceral
mets more common if early CRPC
(≤1 year)
• Good response to docetaxel
irrespective of time to CRPC
↓PSA ≥ 50%
Median TTP (months)
67% 81%
6.1 7.1
Docetaxel2
1. Loriot Y, et al. J Clin Oncol. 2012;30(Suppl5): Abstract 213.
Duration of ≤1 >1 Duration of ≤1 >1
response yr. yr. response yr. yr.
Duration of Response According to Response to
Primary ADT:

55. Docetaxel1
• Post hoc analysis of TAX327
randomized trial (n = 1006 mCRPC)
• Marked survival benefit with
docetaxel q3w in patients
with high Gleason score
All
Median OS months
Gleason
7-10
Months
OS benefit vs
mitoxantrone
2.9 mo 4.4 mo
Abiraterone2
• Post hoc analysis of COU-AA-302
randomized trial (n = 1088)
Gleason <8
Significant
OS benefitHR [95% CI]
0.72 [0.54-0.97]
p=0.0295
Gleason 8-10
No OS benefit
with ABI vs P
HR [95% CI]
0.84 [0.64-1.09]
P = .1789
1. van Soest R, et al. Eur Urol. 2013 Aug 11. [Epub ahead of print].
2. Fizazi K, et al. J Clin Oncol. 2014;32(Suppl 4): Abstract 20.
HR [95% CI]
0.72 [0.54-0.97]
P = .0295
P, prednisone
Docetaxel + P 19.2 mo 18.9 mo
Mitoxantrone + P 16.3 mo 14.5 mo
Initial Gleason Score Might Help to Choose
Therapy in Chemonaive Patients:

56. Poor response to Abiraterone in patients
progressing on Enzalutamide?
Loriot1
(n=38)
Noonan2
(n=30)
COU-AA-3013
(n=797)
Prior Enzalutamide Yes Yes No
Median PFS, mths 2.7 3.6 5.6
Median OS, mths 7.2 11.8 14.8
↓PSA ≥ 50%* 8% 3% 29%
1. Loriot Y et al. Ann Oncol 2013; 24: 1907-12; 2. Noonan Kl et al. Ann Oncol 2013; 24: 1802-04;
3. Fizazi K et al. Lancet Oncol 2012; 13: 983-92
OS: Overall survival; PFS: progression-free survival
[1-2] trials are retrospective studies conducted in 38 and 30 patients, respectively
*PSA response confirmed by a second value

57. Poor response to Enzalutamide in
patients progressing on Abiraterone?
Schrader
1
(n=35)
Bianchini
2
(n=39)
Thomsen
3
(n=24)
Badrising
4
(n=61)
AFFIRM
5
(n=800)
Prior ABI Yes Yes Yes Yes No
Partial response 2.9% 4.3% - - 29%
Median PFS, mths - 2.8 - 3.0 8.3
Median OS, mths 7.1** - 4.8 7.9 18.4
↓PSA ≥50% 28.6% 12.8%* 16.7% 21% 54%*
57
1. Schrader A et al. Eur Urol 2014; 65: 30-36; 2. Bianchini D et al. Eur J Cancer 2014; 50: 78-84; 3. Thomsen FB et al. Scand J Urol
Nephro 2014; 48: 268-75; 4. Badrising S et al. Cancer. 2014; 120: 968-75; 5. Scher HI et al. Lancet Oncol 2012; 13: 983-92
ABI: Abiraterone actetate, PFS: Progression-free survival; OS: overall survival
*PSA response confirmed by a second value; [1-4] trials are retrospective studies

58. Antonarakis E, et al. Presented at: American Association for Cancer ResearchAnnual Meeting; April 5-9, 2014;
San Diego, California. Abstr 2910.
• 31 mCRPC patients treated with enzalutamide
• Detectable AR-V7 mRNA from CTCs in 12/31 (38.7%)
• Presence of AR-V7 associated with:
– Worse PSA response (0% vs 52.6%, P = .004)
– Shorter PSA-PFS (median 1.4 vs 5.9 months, HR 7.4 [2.7-20.6], P0.001)
– Shorter PFS (median: 2.1 vs 6.1 months, HR 8.5 [2.8-25.4], P<.001)
– Multivariable analysis: presence of AR-V7 (HR 3.5 [1.2-10.5], P = .027),
baseline PSA (HR 1.01 [1.00-1.01], P = .042) and prior abiraterone
(HR 5.4 [1.1-26.5], P = .039) were all independently predictive of PSA-PFS
• Conclusions: If confirmed by prospective studies, AR-V7 could
be used as a biomarker to predict enzalutamide resistance
AR-V6 As a Predictor to
Enzalutamide Effect

59. Take Home Message:
• Unequivocal evidence of continued involvement
of AR signaling axis.
• We need to better understand prostate cancer
heterogeneity.
• Broad array of therapeutic options.
• Non – Cytotoxic therapies are now of interest
before chemotherapy administration; however
upfront cyto-toxic agents might be of help in
certain subset of patients.
• Evaluate for the best sequence  Biomarker
Studies.