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Crpc the paradigm of sequence
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
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.
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
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.
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.