Describing the importance and how to choose the first line in CRPC emphasising the role of chemotherapy.

1. CRPC: The Paradigm of Sequence
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Fairmont Heliopolis Hotel & Towers
05/05/2016

2. Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma
• The content of this presentation does not relate to any product of a
commercial interest
Speaker Disclosures:

3. Basic Facts:
• 2nd most common cancer in men (27%).
• 1/6 men  prostate cancer.
• 2nd leading cause of cancer related death in men
(10%).
• World Wide: > 1000000 new case annually.
• > 300000 death/year.
• Closely related to age & Androgens
• Wide geographic and ethnic variations.
• Pre- and post-PSA era.
MJA 2008; 189: 315–318

4. Hypothalamus
LHRH
Pituitary
Testes Supra-renal
Testosterone
LH ACTH
Prostate Cancer is an Androgenic Disease:
Blocking Biosynthesis:
LHRH
Analogue
Bilateral
Orchiectomy

5. NTD DBDHingeLBD
Nuclear
& Steroid
Superfamily
Androgen
Estrogen
Glucocorticoid
Mineralocorticoid
Progesterone
Constitutively Active DNA
Promoter
Gene
Androgen N/C
HSP
Prostate Cancer is an Androgenic Disease:
Blocking AR:

6. Prostate Cancer:
Natural History:
Locoregional
Disease
Biochemical
Failure
Metastatic
“Sensitive”
Metastatic
“Refractory”
Death
TIME
TumorBurden
• Heterogeneous disease entity.
• Not only 1 cellular clone.
• Molecular players
• Other Targets.

7. Prostate Cancer:
The Story:
1940 - 1950 1970 - 1980 1980 - 1990 1990 - 2000
Bilateral
Orchiectomy + DES
LHRH Agonist
FDA APPROVAL
FLUTAMIDE + ADT
CRPC
Mitoxntrone +
Prednisone
OAS < 6 ms
OAS > 24 ms

8. 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

9. • 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

10. 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

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

12. 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

13. Management of CRPC:
Basic Principles:
1. ADT should be continued.
2. Keep an eye on the skeleton.
3. Choose between most active therapies
associated with survival benefit.

14. Therapies Associated with Survival
Benefit:

15. Trials Treatment of CRPC:
OAS = 2nd Hormonal Manipulation > Cytotoxic Therapy?
Comparison Across Treatment Trials Not Justified
2nd Hormonal Manipulation  Control Arm = PLACEBO
CYTOTOXIC Treatment  Control Arm = Active Treatment

16. Patients Population in CRPC Trials:
LancetOncology2015; 16: e279–92

17. CRPC: Subsequent Therapies:
LancetOncology2015; 16: e279–92

18. CRPC: Subsequent Therapies:
LancetOncology2015; 16: e279–92

19. Met. CRPC: Treatment Allocations:
LancetOncology2015; 16: e279–92
Chemotherapy
2nd Hormonal

20. 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.

21. Androgen Receptor Variants:
• Isoforms of AR within circulating tumor cells
 Active in the absence of Androgens.
• Claimed to be increased upon exposure to
Abiraterone Acetate and Enzalutamide.
• Heavy loads of ARV splices  indications to
start with Cabazitaxel.
Thadani-Mulero M, Portella L, Sun S, et al. Androgen receptor splice variants
determine taxane sensitivity in prostate cancer. Cancer Res 2014; 74:2270-82.

22. AR-V7: predictor of treatment response?

23. Future of Sequencing:

24. CRPC Biomarkers:

25. Take Home Message:
• Prostate cancer is a heterogeneous disease.
• No documented guideline for best sequence.
• Cytotoxic therapy might be indicated in heavy
tumor burden with grave symptomatology.
• 2nd hormonal manipulation is usually not
satisfactory a subsequent therapy following
each other, while cabazitaxel still retaining
some activity.
• Future = Clinical trials + Biomarker validation.

26. Thank you