Suggested roadmap to treat castrate resistant prostate cancer

1. Sequencing Therapy for CRPC:
A Practical Approach.
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Kasr Al-Aini School of Medicine
Cairo University
SUN – Genitourinary Cancer Meeting
Radisson Blue Hotel – Alexandria
07/11/2014

2. Basic Facts & Figures:
• Increasing Incidence: Aging and Screening
Programs.
• 2nd Most Common Cancer in Men.
• 1/6 Men.
• African Americans – Black Races,
• Rare Before Age of 40 and then Readily Rises.
• Prostate Cancer is an Androgenic Disease
Circulating Androgens & Androgen Receptors.
Uptodate.com 06/02/2014

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

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

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

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

7. Androgen
Androgen
Receptors
Perfect Disease Control
• Surgical Castration.
• Medical Castration.
• Blocking Receptors.

9. Androgen Receptor in Prostate
Cancer:

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

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

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

13. Cabazitaxel7*
Zoledronic Acid4
Mitoxantrone3 Docetaxel5,6*
1984-1989
Sipuleucel-T8*
1996 2002 2004 .... 2010
Denosumab9
Abiraterone10*
Enzalutamide11*
2011
Radium 223?
2012
...but this rapid change has left many unanswered
questions, including the optimal selection and
sequence of therapy
LHRH agonists1*
Reversible AR
blockers2
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.

14. • 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

15. Management of CRPC:
1. ADT should be continued.
2. Choose between therapies associated with
survival benefit.

16. COU-AA-301 Study Design
Phase III Post-Docetaxel
Phase 3, double-blind placebo-controlled trial of abiraterone +
prednisone versus placebo + prednisone in mCRPC post-chemotherapy
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
• 1195 patients
with progressive
mCRPC
• Failed 1 or 2
chemotherapy
regimens, 1 of
which contained
docetaxel
de Bono JS, et al. N Engl J Med. 2011;346(21):1995-2005.

17. Overall Survival, %
100
80
60
40
20
0
AA + P:
Placebo + P:
0 6 24 30
12 18
Time to Death, months
AA + P 797 657 473
Placebo + P 398 306 183
273 15 0
100 6 0
AA, abiraterone acetate; CI, confidence interval; P, prednisone
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.

18. 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
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
Yes 591 0.65 0.52-0.81
median
Yes 581 0.71 0.58-0.88
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
0.5 0.75 1 1.5
Favors abiraterone Favors placebo
No of prior
chemotherapy regimens
Baseline LDH above
median
Baseline ALK-P above
median
de Bono JS, et al. N Engl J Med. 2011;364(21):1995-2005.

19. 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
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
• 1088 progressive
chemonaïve
patients with
mCRPC
• Asymptomatic
or mildly
symptomatic
Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148.

20. COU-AA-302: rPFS
HR = 0.53 (95% CI, 0.45-0.62) P<.001
47% reduction in risk of progression
Abiraterone + prednisone, 16.5 months
Prednisone alone,
8.3 months
Progression-Free Survival, %
110 –
80 –
60 –
40 –
20 –
0 –
0 3 6 9 12 15 18 21 24 27 30
Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148.

21. COU-AA-302: Updated OS
Abiraterone + prednisone,
Placebo +
prednisone,
30.1 months
Months From Randomization
35.3 months
Second interim analysis: 43% death1
Third interim analysis: 56% death2
Subjects Without Death, %
HR = 0.79 (95% CI, 0.66–0.95) P = .0151
Prespecified P for significance: .0035 100
80
60
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36
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.

22. 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 cytoplasm
Cell nucleus AR
Tran C, et al. Science. 2009;324(5928):787-790.

23. AFFIRM Study Design:
Phase III Post-Docetaxel
Phase 3, double-blind placebo-controlled trial of enzalutamide
versus placebo in mCRPC post-chemotherapy
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
No corticosteroids required
• 1199 patients
with progressive
mCRPC
• Failed 1 or 2
chemotherapy
regimens, 1 of
which contained
docetaxel
Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197

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

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

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

27. • 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

28. 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

29. Subsequent Hormonal Therapies
Following ADT: Data From Last ASCO:
• Gleason Score: No
• Duration of Response to Previous ADT:
Better Response to Subsequent Hormonal Therapy if:
 PSA Control > 12 months.
 Longer PFS.
• Aberaterone or Enzalutamide First?
Enz  Abt Abt  Enz
PSA ↓ 50% 3% 29%
PSA ↓30% 11% 37%

30. Metastatic
Castration Resistant
Symptomatic
First Line
Category 1
• Docetaxel
• Radium-223‡
Nonmetastatic
Local
Therapy
Castration
Hormone
Therapy Asymptomatic or
Minimally Symptomatic
Category 1
• Sipuleucel-T*
• Abiraterone acetate
Symptomatic
Second Line
Category 1:
Post-Docetaxel
• Abiraterone acetate
• Enzalutamide
• Cabazitaxel
• Radium-223‡
Category 2A
• Sipuleucel-T*
• Salvage chemotherapy
• Docetaxel rechallenge
• Mitoxantrone
• Secondary hormonal
therapy
• Clinical trial
• Best supportive care
Category 2A
• Secondary
hormonal therapy
• Docetaxel†
• Clinical trial
Category 2A
• Mitoxantrone§
• Abiraterone acetate§
• Enzalutamide§
• Palliative radiotherapy׀׀
• Clinical trial
• Best supportive care
Bone Health: Denosumab, ZoledronicAcid
*For asymptomatic or minimally symptomatic mCRPC with ECOG PS 0/1, no hepatic metastases, and life expectancy
≥6 months. †May be considered for rapid progression or hepatic metastases despite lack of symptoms. ‡For symptomatic
mCRPC with bone metastases; not approved in combination with chemotherapy. §For patients who are not candidates for
docetaxel-based regimens. ׀׀For symptomatic mCRPC with bone metastases.
National Comprehensive Cancer Network Guidelines in Oncology (NCCN Guidelines®)—Prostate Cancer. V.2.2014. Available at: http://www.nccn.org. AccessedMay 15, 2014.

31. 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.
• Evaluate for the best sequence  Biomarker
Studies.

32. Thank You