Prostate cancer is the second most common cancer in men and the second leading cause of cancer death in men worldwide. Maintaining low testosterone levels through medical or surgical castration is integral to treating prostate cancer across all disease stages. Clinical trials have shown that long-term androgen deprivation therapy in combination with radiation therapy improves survival outcomes for patients with high-risk or locally advanced prostate cancer compared to short-term therapy. Emerging evidence also supports the use of chemotherapy in combination with androgen deprivation for select non-metastatic prostate cancer patients. As the disease progresses to castration-resistant stages, novel anti-androgen and cytotoxic agents that target different pathways have improved outcomes compared to androgen deprivation alone.

1. 2016 Urology Updates
Oncologist’s Perspectives:
“Focus on Prostate Cancer”
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Sudanese Urology Association Annual Meeting
Corinthia Hotel – Khartoum
Friday, 25/03/2016

2. 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

3. 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

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

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

6. Prostate Cancer:
Natural History:
Locoregional
Disease
Biochemical
Failure
Metastatic
“Sensitive”
Metastatic
“Refractory”
Death
TIME
TumorBurden
Risk
Stratification
A.S.
Local Therapy
+/- Hormonal
Local Therapy
+/- Hormonal
Hormonal
+/- Others
2nd Hormonal
Others

7. Prostate Cancer:
Disease Progression:
Abnormal
Cellular
Proliferation
Androgen
Receptor
Activity
Physiological
Pathway Axis
Other Sources
& Hormone
Independent
Proliferation
Abnormal
Receptor
Activity
Disease Progression

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

9. NTD DBDHingeLBD
Nuclear
& Steroid
Superfamily
Androgen
Estrogen
Glucocorticoid
Mineralocorticoid
Progesterone
Constitutively Active DNA
Promoter
Gene
Androgen N/C
HSP
Prostate Cancer is an Androgenic Disease:
“Androgen Receptor Structure”

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

11. Testosterone 5 α Reductase DHT + 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

12. Androgen Receptor in Prostate Cancer:

13. Tips & Tricks for Daily Practice

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

15. 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

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

17. Practice Changing Guidelines:

18. 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

19. 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

20. 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

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 nmol/L
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. Slide 5

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

28. Slide 7

29. Slide 10

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

31. Slide 12

32. Chemotherapy in M0 HSPC?

33. Chemotherapy in non-metastatic prostate cancer

34. Results

35. More evidence for chemotherapy

36. Trial design

37. Disease free survival

38. Metastases free survival

39. Overall survival

40. Conclusion

41. 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:

42. 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.

43. Thank You