crpc the paradigm of sequence
TRANSCRIPT
CRPC: The Paradigm of Sequence
Mohamed Abdulla M.D.Prof. of Clinical Oncology
Cairo University
Fairmont Heliopolis Hotel & Towers05/05/2016
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:
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
HypothalamusLHRH
Pituitary
Testes Supra-renal
Testosterone
LH ACTH
Prostate Cancer is an Androgenic Disease:Blocking Biosynthesis:
LHRH Analogue
Bilateral Orchiectomy
NTD DBDHingeLBD
Nuclear & Steroid
Superfamily
Androgen
EstrogenGlucocorticoidMineralocorticoid
Progesterone
Constitutively Active DNA
Promoter Gene
Androgen N/C
HSP
Prostate Cancer is an Androgenic Disease: Blocking AR:
Prostate Cancer:Natural History:
Locoregional Disease
Biochemical Failure
Metastatic “Sensitive”
Metastatic “Refractory”
Deat
h
TIME
Tum
or B
urde
n
• Heterogeneous disease entity.• Not only 1 cellular clone.• Molecular players• Other Targets.
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
Prostate Cancer:The Story: New Chapters:
2004 2010 2011 2012 2013 2014
Docetaxel &
Zoladronic
CabazitaxelD-mabSip 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
• 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
Castrate Resistant Prostate Cancer:Prognostic Factors:
1. Site of Metastases: 5 RCTs:
Liver
Lungs
Bone
LNs
0 5 10 15 20 25 30
OAS
Months
Halabi et al. Journal of Clinical Oncology, 2014 ASCO Annual Meeting Abstracts. Vol 32, No 15_suppl (May 20 Supplement), 2014: 5002
Castrate Resistant Prostate Cancer:Prognostic Factors:
Halabi et al. J Clin Oncol 32:671-677. © 2014
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
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.
Therapies Associated with Survival Benefit:
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
Patients Population in CRPC Trials:
LancetOncology2015; 16: e279–92
CRPC: Subsequent Therapies:
LancetOncology2015; 16: e279–92
CRPC: Subsequent Therapies:
LancetOncology2015; 16: e279–92
Met. CRPC: Treatment Allocations:
LancetOncology2015; 16: e279–92
Chemotherapy
2nd Hormonal
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.
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 variantsdetermine taxane sensitivity in prostate cancer. Cancer Res 2014; 74:2270-82.
AR-V7: predictor of treatment response?
Future of Sequencing:
CRPC Biomarkers:
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.
Thank you