To what extent we have to keep the castrate level of androgens in patients with prostate cancer during different disease phases.

1. Prostate cancer:
“Keep Tackling The Androgenic Nature”
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
SUN Annual Urology Meeting
ASTRA Zeneca Symposium
Hilton Borg Al-Arab
12/11/2015

2. Speaker Disclosures
Member of Advisory Board, Consultant, and Speaker for:
● Amgen, Astellas, Astra Zeneca, Hoffman la Roche, Janssen
Cilag, Merck Serono, Novartis, Pfizer.
Speaker Disclosures:

3. 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

4. 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

5. Prostate Cancer: Best Identity:
Natural History
Androgen
Biosynthesis
Androgen
Receptor Activity
Aggressiveness
Androgenic
Disease

6. Hypothalamus
LHRH
Pituitary
Testes Supra-renal
Testosterone
LH ACTH
Prostate Cancer is an
Androgenic Disease:
LHRH
Analogue
Bilateral
Orchiectomy

7. Steroidogenesis & Prostate
Cancer :
Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone

8. NTD DBD Hinge LBD
Nuclear
& Steroid
Superfamily
Androgen
Estrogen
Glucocorticoid
Mineralocorticoid
Progesterone
Constitutively Active DNA
Promoter
Gene
AndrogenN/C
HSP
Prostate Cancer is an Androgenic
Disease: “Androgen Receptor Structure”

9. Prostate Cancer is an Androgenic
Disease: “Androgen Receptor Activity”
5@ Reductase
Genomic Activity
PSA, IGF, …

10. Testosterone 5 α Reductase DH
T
+ AR
(LBD)
PI3K
Caveolae
RTK
GPCR
AR Activation
& Dimerization
HSP
AKT
Src
MAPK
ERK1/2
Nuclear
Transcription
Factors
• Proliferation, Angiogenesis, …
• No AR Degradation.
Prostate Cancer is an Androgenic
Disease: “Androgen Receptor Activity”
Non Genomic
Activity

11. Androgen Receptor in Prostate Cancer:

12. Prostate Cancer: A Panoramic View:
Pre-
Receptor
Level
Receptor
Level
A
N
D
R
O
G
E
N
DISEASE PROGRESSION
Anti-Androgen
Synthesis:
Abiraterone
Receptor:
Enzalutamide
Cytotoxic
Therapy
Heemers HV> Int. J. Biol. Sci. 2014, Vol. 10

13. Long versus Short Term ADT:
Lancet Oncol 2015; 16: 320–27

14. 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

15. Long versus Short Term ADT:
Lancet Oncol 2015; 16: 320–27

16. Practice Changing Guidelines:

17. Primary Hormonal Manipulation:
1. Surgical Castration:
Bilateral
Sub-
Capsular
Orchiectomy
0
100
200
300
1 2 3 4 5
SerumTestosterone(ng/ml)
Days following Bilateral orchiectomy
Serum Testosterone
Following Bilateral
Orchiectomy

18. Primary Hormonal Manipulation:
2. Medical Castration:
PituitaryLHRH Agonist LHRH Antagonist
+ LH & FSH
+ Testes
+ Testosterone
NegativeFeedBackMechanism
+ Symptoms
FLARE
3–4Weeks
Castrate Level
Castrate Level
72–96Hours
Disease
Control

19. Primary Hormonal Manipulation:
Medical CastrationSurgical CastrationItems
GnRH AgonistsBilateral Sub-Capsular
Orchiectomy
Procedure
ReversibleIrreversibleCastration
3-4 weeksRapidly AchievedCastrate Level of
Testosterone
ElectiveEmergencyApplication
YesnoFlare
May be RequiredNot RequiredPrior Anti-Androgens
MoreLessCost
More PreferredLess PreferredPsychological Element
Discussion

20. GnRH Antagonist versus Agonist:
AgonistAntagonistItem
3-4 weeks96 HoursCastrate Level
YesNoFlare
14.1%8.9%PSA Failure
1%40%Local Injection Reaction
SimilarCardiovascular
Complications
Every 3 MonthsMonthlyAdministration
Schroder 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.

21. 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-
Analysis
Of 1908
Patients
Surgical
Castration
Medical
Castration
Equivalent
OAS
PFS
TTF

22. 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
CumulatesurvivalfreeofCRPC(%)
0 50 100 150 200 250
Follow up (months)
>32 ng/dL†
<32 ng/dL*
p=0.0258

23. Testosterone ≤30 ng/dL has been associated with
longer overall survival versus >30 ng/dL
Variable
Testosterone
Continuous
variable*
Testosterone
<50 ng/dL
(n=94)
Testosterone
≤30 ng/dL
(n=56)
Testosterone
<20 ng/dL
(n=25)
Time to
progression
HR (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 survival
HR (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.

24. 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
Percent
0 2 4 6 8 12
Time (years)
10
Log rank p=0.0092
HR (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/L
0.7 nmol/L <median testosterone <1.7 n
Median testosterone ≥1.7 nmol/L

25. 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

26. NCCN GUIDELINES:

27. Management of CRPC:
1. ADT should be continued.
2. Inhibition of bone resorption
3. Risk Stratification.
4. Choose between therapies associated with survival
benefit.

28. NCCN GUIDELINES:

29. NCCN GUIDELINES:

30. 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.

31. 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 T
Bone Targeted 
Radium 223
Take Home Message:

32. Thank You