2016 Urology UpdatesOncologist’s Perspectives:

“Focus on Prostate Cancer”

Mohamed Abdulla M.D.Prof. of Clinical Oncology

Cairo University

Sudanese Urology Association Annual MeetingCorinthia Hotel – KhartoumFriday, 25/03/2016

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

Prostate Cancer:Natural History:

Locoregional Disease

Biochemical Failure

Metastatic “Sensitive”

Metastatic “Refractory”

Deat

h

TIME

Tum

or B

urde

n

Risk Stratification

A.S.Local Therapy+/- Hormonal

Local Therapy+/- Hormonal

Hormonal+/- Others

2nd HormonalOthers

Prostate Cancer:Disease Progression:

Abnormal Cellular

Proliferation

Androgen Receptor Activity

Physiological Pathway Axis

Other Sources& Hormone

Independent Proliferation

Abnormal Receptor Activity

Disease Progression

Steroidogenesis & Prostate Cancer :

Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone

Prostate = Androgen Self Sufficient Organ

NTD DBDHingeLBD

Nuclear & Steroid

Superfamily

Androgen

EstrogenGlucocorticoidMineralocorticoid

Progesterone

Constitutively Active DNA

Promoter Gene

Androgen N/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:

Tips & Tricks for Daily Practice

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 Fol-lowing Bilateral Or-

chiectomy

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

ative

Fee

d Ba

ck M

echa

nism

+ Symptoms FLARE

3 –

4 W

eeks

Castrate Level

Castrate Level

72 –

96

Hour

s

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

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

0

Cum

ulat

e su

rviv

al fr

ee o

f CRP

C (%

)

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 part of routine clinical practice

Slide 5

Continuous (CAD) vs Intermittent Androgen Deprivation (IAD): Trials in mHNPC Patients & Survival End Point

Slide 7

Slide 10

Therapy Was Feasible:<br />Majority of Patients Received all 6 Cycles of Docetaxel

Slide 12

Chemotherapy in M0 HSPC?

Chemotherapy in non-metastatic prostate cancer

Results

More evidence for chemotherapy

Trial design

Disease free survival

Metastases free survival

Overall survival

Conclusion

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:

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.• Continuous ADT is the back – bone of therapy.

Thank You