The document discusses the management of castration-resistant prostate cancer (CRPC), highlighting various therapeutic strategies, including androgen deprivation therapy (ADT), androgen receptor blockers, and cytotoxic chemotherapy. It details the efficacy of drugs such as abiraterone acetate and enzalutamide, supported by results from clinical trials, emphasizing their roles in improving overall survival and risk of disease progression. The author notes ongoing challenges in treatment selection and the necessity for proper patient assessment to optimize outcomes.

1. Management of CRPC
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Director of Advisory Board KOSC
2nd
KIOW
Khartoum – CORENTHIA Hotel
Saturday, 26/11/2016

2. Member of Advisory Board, Consultant, and Speaker for:
•Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag, Merck
Serono, Novartis, Pfizer, Mundipharma, MSD.
•The content of this presentation does not relate to any product of a
commercial interest.
•No Financial Disclosures for this presentation
Speaker Disclosures:

3. Prostate Cancer: Best Identity
Androgenic Disease
Androgen Deprivation
“Surgical or Medical”
Androgen Receptor
Blocking
Perfect Disease Control

4. Prostate Cancer:
Natural History:
Locoregional
Disease
Biochemical
Failure
Metastatic
“Sensitive”
Metastatic
“Refractory”
TIME
TumorBurden
Risk
Stratification
A.S.
Local Therapy
+/- Hormonal
Local Therapy
+ Hormonal
Hormonal
+/- Others
2nd
Hormonal
Others

5. Hypothalamus
LHRH
Hypothalamus
LHRH
PituitaryPituitary
TestesTestes Supra-renalSupra-renal
TestosteroneTestosterone
LHLH ACTHACTH
Blocking Androgen Biosynthesis:
LHRH
Analogue
LHRH
Analogue
Bilateral
Orchiectomy
Bilateral
Orchiectomy
+/- AR
Blockers
+/- AR
Blockers

6. Androgen Biosynthesis:
“More Clear Insight”
Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone
Androgen
ADT +/- AR Bocker

7. Androgen Receptor in Prostate Cancer:

8. CRPC: Therapeutic Strategy:
1. ADT: Should be maintained  avoid re-
evolution of hormone sensitive clones.
2. Tackling other targets:
 Biosynthesis; inhibition of CYP 17A1: Abiraterone
Acetate.
 Androgen Receptor Blocker: Enzalutamide.
 Induce Cytotoxicity: Docetaxel & Cabazitaxel.
 Bone Only Disease: Radium 223.
 Immunotherapy: Sipuleucel-T.
1. Bone Modifying Agents.

9. Prostate Cancer:
The Story: New Chapters:
2004 2010 2011 2012 2013 2014
Docetaxel
&
Zoladronic
Cabazitaxel
D-mab
Sip T.
Abi (Post) Abi (Pre) Enza (Post)
Radium 223
Enza (Pre)
OAS =
18.9 ms
OAS =
35.3 ms
2015 & Beyond
ADT + Cytotoxic in HSPC:
•Metastatic: CHAARTED & STAMPEDE
•Locally Advanced: RTOG 0521

10. Taxanes Beyond Cytotoxicity:
• Documented Effect:
Microtubule Stabilization  Blocking or Delaying
Mitosis at Metaphase – Anaphase of Cell Cycle 
Apoptosis.
• Anti-Androgen Effect:
de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med
2011; 364:1995-2005. Watson PA, Chen YF, Balbas MD, et al. Constitutively active androgen receptor splice variants expressed
in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci U S A 2010; 107:16759-65.

14. Sartor AO, Oudard S, Sengelov L, et al. Cabazitaxel versus docetaxel in chemotherapy-naïve patients with
metastatic castration-resistant prostate cancer: a three-armed phase III study (FIRSTANA). Abstract 5006,
American Society of Clinical Oncology 2016 meeting
Cabazitaxel versus Docetaxel:
FIRSTANA TRIAL
OAS
RRPFS = NS

15. 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

16. 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.

17. 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

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

19. COU-AA-302: Updated OS
Placebo +
prednisone,
30.1
months
Months From Randomization
Second interim analysis: 43% death1
Third interim analysis: 56% death2
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.

20. BTT and Abiraterone pre-chemo <br />

21. Abiraterone Acetate: Better Insight:
• Abi  5β HSD  D4A (Active Metabolite).
• D4A:
1. More potent inhibitor of CYP17A1.
2. Potent Inhibitor of 5@Reductase..
3. Potent inhibitor of AR (= Enzalutamide).
• Structural similarity to testosterone 
Reduced by 5@ & β Reductase  Agonist to
AR.
Li et al. Nature, 2015; 523(7560):347.
Nima Shariffi. ASCO GU 2016

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

23. 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

24. %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

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. Current Problems:
• Which drug or mechanism to start with?
– Sipuleucel T: Asymptomatic with low tumor burden
patients.
– R223: Bone only metastases.
• ARV7  Neither Abi nor Enza.
• Sequential use (Abi  Enza) or (Enza  Abi).
• The subsequent therapies:
– Abi and Enza are lacking activity after each other.
– Docetaxel & Cabazitaxel are still active in subsequent
therapies following Abi & Enza.

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

30. Met. CRPC: Treatment Allocations:
LancetOncology2015; 16: e279–92
ChemotherapyChemotherapy
2nd
Hormonal2nd
Hormonal

31. Take Home Message:
• CRPC is an increasing event in daily practice.
• Median OAS had increased (doubled) since
2004 till now.
• Proper assessment is crucial.
• ADT should be continued
• Proper sequence is not known but trials are
under way with increasing insight.

32. Thank You