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Management of crpc
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
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.
11.
12.
13.
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
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
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
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.