Prostate cancer: “Keep Tackling The Androgenic Nature”

Mohamed Abdulla M.D.Prof. of Clinical OncologyCairo University

SUN Annual Urology MeetingASTRA Zeneca Symposium

Hilton Borg Al-Arab12/11/2015

Speaker DisclosuresMember of Advisory Board, Consultant, and Speaker for:● Amgen, Astellas, Astra Zeneca, Hoffman la Roche, Janssen

Cilag, Merck Serono, Novartis, Pfizer.

Speaker Disclosures:

Basic Facts:

● 2nd most 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

Prostate Cancer: The Story:

Dr. Huggins(1941): Orchiectomy and DES Effective Disease Control Noble Price 1966.

Dr. Shcally et al: (1977): LHRH Analogue Effective disease Noble Price

Prostate Cancer: Best Identity:

Natural History

Androgen Biosynthesis

Androgen Receptor Activity

Aggressiveness

AndrogenicDisease

HypothalamusLHRH

Pituitary

Testes Supra-renal

Testosterone

LH ACTH

Prostate Cancer is an Androgenic Disease:

LHRH Analogue

Bilateral Orchiectomy

Steroidogenesis & Prostate Cancer :

Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone

Prostate = Androgen Self Sufficient Organ

NTD DBD Hinge LBD

Nuclear & Steroid

Superfamily

Androgen

EstrogenGlucocorticoidMineralocorticoid

Progesterone

Constitutively Active DNA

Promoter Gene

AndrogenN/C

HSP

Prostate Cancer is an Androgenic Disease: “Androgen Receptor Structure”

Prostate Cancer is an Androgenic Disease: “Androgen Receptor Activity”

Testosterone DHT5@ Reductase

DHT+AR+HSP Active AR

Active AR Active AR Active AR

Proliferation

Angiogenesis

Metastases

AREAR

Degraded

Genomic ActivityPSA, IGF, …

Testosterone 5 α Reductase DHT + AR (LBD)

PI3KCaveolae

RTKGPCR

AR Activation & Dimerization

HSP

AKTSrc

MAPKERK1/2

Nuclear Transcription

Factors

• Proliferation, Angiogenesis, …• No AR Degradation.

Prostate Cancer is an Androgenic Disease: “Androgen Receptor Activity”

Non Genomic Activity

Androgen Receptor in Prostate Cancer:

Prostate Cancer: A Panoramic View:

Pre-Receptor

Level

Receptor Level

ANDROGEN

DISEASE PROGRESSION

Anti-Androgen

Synthesis:Abiraterone

Receptor:Enzalutamide

Cytotoxic Therapy

Androgen Deprivation Therapy (ADT)

Heemers HV> Int. J. Biol. Sci. 2014, Vol. 10

Long versus Short Term ADT:

Lancet Oncol 2015; 16: 320–27

Long versus Short Term ADT:

Lancet Oncol 2015; 16: 320–27

Long Term ADT > Short Term ADT

Biochemical Failure Free Survival

OAS

Metastasis Free Survival

Long versus Short Term ADT:

Lancet Oncol 2015; 16: 320–27

Practice Changing Guidelines:

Primary Hormonal Manipulation:1. Surgical Castration:

Bilateral Sub-

Capsular Orchiectomy

1 2 3 4 50

100

200

300

Serum Testosterone Following Bilateral

Orchiectomy

Days following Bilateral orchiectomySe

rum

Tes

tost

eron

e (n

g/m

l)

Primary Hormonal Manipulation:2. Medical Castration:

PituitaryLHRH Agonist LHRH Antagonist

+ LH & FSH

+ Testes

+ Testosterone

Neg

ativ

e Fe

ed B

ack

Mec

hani

sm

+ Symptoms FLARE

3 –

4 W

eeks

Castrate Level

Castrate Level

72 –

96

Hou

rs

Disease Control

Primary Hormonal Manipulation:

Medical Castration Surgical Castration Items

GnRH Agonists Bilateral Sub-Capsular Orchiectomy

Procedure

Reversible Irreversible Castration

3-4 weeks Rapidly Achieved Castrate Level of Testosterone

Elective Emergency Application

Yes no Flare

May be Required Not Required Prior Anti-Androgens

More Less Cost

More Preferred Less Preferred Psychological Element

Discussion

GnRH Antagonist versus Agonist:

Agonist Antagonist Item

3-4 weeks 96 Hours Castrate Level

Yes No Flare

14.1% 8.9% PSA Failure

1% 40% Local Injection Reaction

Similar Cardiovascular Complications

Every 3 Months Monthly AdministrationSchroder FH, Tombal B, Miller K, et al. Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study. BJU Int 2010; 106:182.Tombal B, Miller K, Boccon-Gibod L, et al. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol 2010; 57:836. Smith MR, Klotz L, Persson BE, et al. Cardiovascular safety of degarelix: results from a 12-month, comparative, randomized, open label, parallel group phase III trial in patients with prostate cancer. J Urol 2010; 184:2313.

Surgical versus Medical Castration?

Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2000; 132:566.

Meta-AnalysisOf 1908 Patients

Surgical Castration

Medical Castration

EquivalentOASPFSTTF

Maintaining testosterone <32 ng/dL was associated with significantly longer mean survival free of CRPC compared with levels >32 ng/dL

Survival free of CRPC in 73 patients with non-metastatic prostate cancer receiving ADT.*Patients with three serum testosterone determinations <32 ng/dL; †Patients with breakthrough increases >32 ng/dL.Serum testosterone was measured every 6 months. ADT=androgen-deprivation therapy; CRPC=castration-resistant prostate cancer.Figure adapted from Morote J, et al. J Urol 2007;178:1290–5.

100

80

60

40

20

0Cum

ulat

e su

rviv

al fr

ee o

f CR

PC (%

)

0 50 100 150 200 250

Follow up (months)

>32 ng/dL†

<32 ng/dL*

p=0.0258

Testosterone ≤30 ng/dL has been associated with longer overall survival versus >30 ng/dL

VariableTestosteroneContinuous

variable*

Testosterone<50 ng/dL

(n=94)

Testosterone≤30 ng/dL

(n=56)

Testosterone<20 ng/dL

(n=25)

Time to progressionHR (95% CI)p value

1.76 (0.62–5.01)0.29

0.84 (0.52–1.37)0.51

0.76 (0.46–1.26)0.30

0.58 (0.30–1.15)0.12

Overall survivalHR (95% CI)p value

2.47 (0.70–8.75)0.16

0.74 (0.42–1.33)0.32

0.45 (0.22–0.94)0.034

0.19 (0.04–0.76)0.020

*Testosterone was considered a continuous (values were measured on a continuous scale) not categorical variable in this analysis. CI=confidence interval; HR=hazard ratio.Bertaglia V, et al. Clin Genitourin Cancer 2013;11:325–30.

Maintaining testosterone levels at <20 ng/dL correlated with improved duration of response to ADT*

*Investigators defined CRPC as rising PSA >4 ng/mL with testosterone <3.0 nmol/L. Retrospective analysis of patients with biochemical failure after radiation or surgery plus radiation; n=626 patients with ≥3 testosterone levels in first year. Secondary analysis of PR-7 intermittent vs. continuous ADT trial. Conversion of testosterone values: 0.7 nmol/L=20 ng/dL; 1.7 nmol/L=50 ng/dL.ADT=androgen-deprivation therapy; CI=confidence interval; CRPC=castration-resistant prostate cancer; HR=hazard ratio.Figure adapted from Klotz L, et al. Nadir testosterone on ADT predicts for time to castrate resistant progression: A secondary analysis of the PR-7 intermittent vs continuous ADT trial. Poster. Presented at: 29th Annual Congress of the European Association of Urology, 11–15 April 2014, Stockholm, Sweden.

100

80

60

40

20

0

Perc

ent

0 2 4 6 8 12Time (years)

10

Log rank p=0.0092HR (95% CI): 0.7<testosterone<1.7/testosterone ≤0.7: 1.41 (1.07–1.84)Testosterone ≥1.7/testosterone ≤0.7: 1.91 (1.11–3.29)

Median testosterone ≤0.7 nmol/L0.7 nmol/L <median testosterone <1.7 nmol/LMedian testosterone ≥1.7 nmol/L

ADT: Key points from EAU guidelines 2014

ADT=androgen-deprivation therapy; EAU=European Association of Urologists; mCRPC=metastatic castration-resistant prostate cancer.Mottet N, et al. EAU Guidelines on Prostate Cancer 2014. Available at: http://www.uroweb.org. Last accessed January 2015.

Optimal castration testosterone level is defined as <20 ng/dL

In high-risk localised and locally advanced prostate cancer, the combination of radiotherapy and ADT is recommended because it

improves survival

First-line ADT is the standard of care for metastatic prostate cancer

Testosterone suppression should be continued indefinitely even when the disease becomes castration resistant

Second-line therapies for mCRPC should not be started unless patient testosterone levels are <50 ng/dL

Monitoring testosterone levels should be considered as partof routine clinical practice

NCCN GUIDELINES:

Management of CRPC:

1. ADT should be continued.2. Inhibition of bone resorption3. Risk Stratification.4. Choose between therapies associated with survival

benefit.

NCCN GUIDELINES:

NCCN GUIDELINES:

Take Home Message:

● Prostate cancer is a prevalent and lethal disease.● Prostate cancer is an ANDROGENIC disease.● Androgen receptors are ACTIVE & ADDICTED TO STIMULATION ADT is an

INTEGRAL part of therapy across disease spectrum after active surveillance.● Long term ADT (2-3 years) plus radiation therapy is mandatory for high risk and

very high risk patients.● Castrate level should be ensured for patients with CRPC.● Keep an eye on ADT related adverse events. ● Post-Receptor directed therapies would be of interest in the nearby future.

Localized Metastatic HRPC

Loco-Regional Treatment ADT ADT

ADT – Short Term +/- Anti-Androgen Biosynthesis Abiraterone Acetate

ADT – Long Term +/- Chemotherapy AR – Signaling Enzalutamide

Anti-Androgen (Flare) +/- Radiation Therapy Cytotoxic Docetaxel

Cabazitaxel Anti-Androgen + RTH Bone Targeted Agents Immunotherapy

Sipuleucel TBone Targeted

Radium 223

Take Home Message:

Thank You