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