It describes the androgenic nature of prostate cancer and the androgenic axis should be tackled in all phases of prostate cancer. Also a special emphasis on recent data on management of metastatic hormone sensitive prostate cancer.

1. Prostate Cancer:
The Androgenic Dogma is still Fortified
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Asyut Cancer Center
Janssen Cilag Symposium
04/04/2018

2. Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma, MSD, Ely Lilly
Speaker Disclosures:

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
Androgenic Disease
Androgen Deprivation
“Surgical or Medical”
Androgen Receptor
Blocking
Perfect Disease Control

5. 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

6. 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.

8. Prostate Cancer:
Natural History:
Locoregional
Disease
Biochemical
Failure
Metastatic
“Sensitive”
Metastatic
“Refractory”
Death
TIME
TumorBurden

9. Why Progression is an Inevitable Event?
ADT +/- AR Blocking
1. Alternate Biosynthesis
2. Androgen Receptor Abnormality
3. Proliferation Cascade
4. Other Histology
Maintained ADT

10. Androgen Biosynthesis:
“More Clear Insight”
Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone
Androgen
ADT +/- AR Bocker

11. 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”

12. Prostate Cancer is an Androgenic Disease:
“Androgen Receptor Activity”
5@ Reductase
Genomic Activity
PSA, IGF, …
Microtubule
Prostate = Self Sufficient Organ

13. 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

14. AR Activity in Prostate Cancer:
Polymorphism Mutation Amplification
AR = Short a.a. + Other F.M. Soak A Traces
Tight Bond 
Continuous
Stimulation

15. AR Splice Variants:
Ciccarese et al. Cancer Treatment Reviews 43 (2016) 27–35

16. Non-Androgenic Proliferation Cascade
in Prostate Cancer:
Karantanos et al. Eur Urol. 2015 March ; 67(3): 470–479

17. Prostate Cancer:
Positioning of Available Therapies:
Locoregional
Disease
Biochemical
Failure
Metastatic
“Sensitive”
Metastatic
“Refractory”
Death
TIME
TumorBurden
Androgen Deprivation Therapy
1st Generation
Anti-Androgen
2nd Generation
Anti-Androgen
Biosynthesis
Cytotoxic
Anti-microtubule

18. CRPC: Current Definition:
Castrate Serum
Testosterone = < 50 ng/dL
or 1.7 nmol/L
Biochemical progression: 3 consecutive
rises in PSA 1 wk apart, resulting in two
50% increases over the nadir, and PSA >2
ng/ml
Radiologic progression: The appearance
of new lesions: either two or more new
bone lesions on bone scan or a soft
tissue lesion
Symptomatic
or Subjective
Progression

19. Summary of The Clinical Trials Outcome
(The Monotherapy Approach)
Pharmaceutical Setting Control
POAS
+ in median
(months)
HR P value
Docetaxel/P 1st Line Mitox/P 2.9 0.79 .004
Cabazitaxel/P Post-D Mitox/P 2.4 0.70 <.0001
Abiraterone/P Post-D Placebo/P 4.6 0.74 <.0001
Abiraterone/P Chemonaive Placebo/P 5.2 0.81 .0033
Enzalutamide Post-D Placebo 4.8 0.63 <.001
Enzalutamide Chemonaive Placebo 2.2 0.71 <.0001
Radium Bone Mets.
Pre & Post-D
Placebo 3.6 0.70 <.001
1. Berthold DR, et al. J Clin Oncol. 2008;26(2):242-245. 2. de Bono JS, et al. Lancet. 2010;376(9747):1147-1154. 3.
Fizazi K, et al. Lancet Oncol. 2012;13(10):983-992. 4. Rathkopf DE, et al. J Clin Oncol. 2013;31(Suppl 6): Abstract
5. 5. Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197. 6. Beer TM, et al. J Clin Oncol. 2014;32(Suppl 4):
Abstract LBA1. 7. Parker C, et al. N Engl J Med. 2013;369(3):213-223.

20. Available treatment options mentioned in 2015
guidelines for mCRPC
EAU ESMO AUA NCCN
Chemo-naïve
Abiraterone √ √ √ √
Docetaxel √ √ √ √
Sipuleucel-T √ √ √ √
Radium-223 √ √ √ √
Enzalutamide √ √ √ √
Post-docetaxel
Cabazitaxel √ √ √ √
Abiraterone √ √ √ √
Enzalutamide √ √ √ √
Radium-223 √ √ √ √
Bone-targeted agents reducing risk of SRE
Zoledronic
acid
√ √ √ √
Denosumab √ √ √ √

21. • Pain
• Bone vs visceral metastases
• Performance status
• Neuropathy & other Comorbidity
• “Early or late” CRPC
• Prior therapy exposure and response
• Response biomarkers
• Tumor characteristics
• Patient/Physician Preference
• Cost and Re-embarrassment
CRPC, castration-resistant prostate cancer

23. Refining the Approach to Treat mCRPC:

24. Loriot Y et al. Eur J Cancer 2015 sept ; 51(14):
1946-52
Study cohort consisted of 173 patients. Median duration of response to initial androgen
deprivation therapy (ADT) (time to castration resistance, TTCRPC) was 17.8 months.
Evaluation of AR axis targeted drugs for CRPC according to TTCRPC/12 mths.
PFS=7.5 mths
PFS=3.4 mths

25. AR-V7 seems a promising predictor of
treatment response
1. Antonarakis ES et al. N Engl J Med 2014;371:1028-38; 2. Antonarakis ES et al. JAMA Oncol 2015;
1:582-91
PSAchange,%
100
50
–50
–100
*
†
***
†
†
†
100
50
0
–50
–100
†
*
†
*
†
* †
† †
†
†
†† †
†
†
†
†
† † †
† †
100
50
0
–50
–100
Abiraterone1 Enzalutamide1 Taxane2
PSA response rate:
AR-V7 positive: 0% (95% CI: 0-26%)
AR-V7 negative: 52.6% (95% CI: 29-76%)
P=0.004
PSA response rate:
AR-V7 positive: 0% (95% CI: 0-46%)
AR-V7 negative: 68.0% (95% CI: 46-85%)
P=0.004
PSA response rate:
AR-V7 positive: 41% (95% CI: 18-67%)
AR-V7 negative: 65% (95% CI: 41-85%)
P=0.19
Docetaxel, n=30
Cabazitaxel, n=7
AR-V7 positive AR-V7 negative

26. Enzalutamide
Abiraterone Acetate
CYP3A4
CYP2D6
> 30 Drugs
20 Drugs
M. Del Re et al. / Cancer Treatment Reviews 55 (2017) 71–82

27. Abiraterone Acetate: Better Insight:
• Abi  5β HSD  D4A (Active Metabolite).
• D4A:
1. More potent inhibitor of CYP17A1.
2. Potent Inhibitor of 5@Reductase..
3. Potent inhibitor of AR (= Enzalutamide).
• Structural similarity to testosterone 
Reduced by 5@ & β Reductase  Agonist to
AR.
Li et al. Nature, 2015; 523(7560):347.
Nima Shariffi. ASCO GU 2016

28. Ueda et al. Clinical Genitourinary Cancer April 2017

30. Addition of docetaxel to first-line long-term<br />hormone therapy in prostate cancer (STAMPEDE): long-term survival, quality-adjusted survival and cost-effectiveness analysis.
Presented By Nicholas James at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

31. Docetaxel: Failure-free survival
Presented By Nicholas James at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

32. Docetaxel: Survival
Presented By Nicholas James at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

33. Docetaxel: Skeletal events (All patients)
Presented By Nicholas James at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

34. Fizazi et al. June 4, 2017, at NEJM.org.

35. LATITUDE TRIAL:
Fizazi et al. June 4, 2017, at NEJM.org.

36. Fizazi et al. June 4, 2017, at NEJM.org.
LATITUDE TRIAL:

37. LATITUDE TRIAL:
Fizazi et al. June 4, 2017, at NEJM.org.

38. LATITUDE TRIAL:
Fizazi et al. June 4, 2017, at NEJM.org.

39. mHSPC – High Risk  ADT + Abi = ADT + Docetaxel

41. Prostate Cancer (C61): 1971-2011
Age-Standardised Ten-Year Net Survival, England and Wales
De Angelis R, Sant M, Coleman MP, et al. Lancet Oncol 2014;15:23-34
PSA Era
Early
Diagnosis
Therapeutics
Enhanced
M & CRPC
Survival

42. Uptodate Accessed 05/10/2017

43. Still we need to know:
1. Which drug for which patient?
2. Which drug in subsequent lines?
3. Effect of initial natural history of disease on treatment
choice in CRPC phase?
4. Impact of drug resistance?
5. Impact of drug – drug interactions?
6. Impact of drug repositioning earlier in course of
mHSPC upon treatment selection for CRPC?
7. Impact of Molecular Key players in backstage of stage
on treatment selection for CRPC?
8. May be MORE QUESTIONS?
Although AA Offers Unmet Needs
in CRPC Patients with Better Insights,
but Definitely Still we are
in The Grey Zone in Management of CRPC