Exploring the landscape of metastatic prostate cancer.

1. Management of Metastatic
Prostate Cancer
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Menia Cancer Center
Astra Zeneca Symposium
09/07/2017

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. Basic Facts:
• 2nd most common 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. Geographic Variations:
MJA 2008; 189: 315–318
1. No National Registry.
2. Lacking of Screening &
Early Detection.
3. Delayed Diagnosis.

5. Jsamy et al. Journal of Cancer Epidemiology Volume 2014, Article ID 437971, 18 pages
Egypt Demographic Data:

6. 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

7. Prostate Cancer: Best Identity
Androgenic Disease
Androgen Deprivation
“Surgical or Medical”
Androgen Receptor
Blocking
Perfect Disease Control

8. Prostate Cancer:
Natural History:
Locoregional
Disease
Biochemical
Failure
Metastatic
“Sensitive”
Metastatic
“Refractory”
Death
TIME
TumorBurden
Effective Castration & AR Blocking
Serum Testosterone < 0.2 – 0.5 ng/ml

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

10. 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

11. 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

12. 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.

14. 1. 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

15. 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

16. 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

17. Primary Hormonal Manipulation:
2. LHRH Agonist versus Antagonist:
Hypothalamo-
Pituitary Axis
LHRH Agonist LHRH Antagonist
+ LH & FSH
+ Testes
+ Testosterone
NegativeFeedBackMechanism
+ Symptoms
FLARE
3–4Weeks
Castrate Level
Castrate Level
72–96Hours
Disease Control

18. 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.

19. ADT: Results of Treatment
Final Statement:

20. 2. When Do We Need CAB?
Surgical
Castration
Serum
Testosterone >
20 ng/dL
Medical
Castration
Serum
Testosterone >
50 ng/dL
Anti-Androgen

21. Antiandrogens:
• Competitive inhibition of peripheral androgen
receptors.
• No action on hypothalamic receptors.
• Inferior to ADT in phase III trials.
• Not suitable in hormone naive patients as a
mono-therapy.
• Used prior ADT to prevent flare & to manage
non-satisfactory results after ADT only.

22. Slide 5
Presented By Maha Hussain at Genitourinary Cancers Symposium 2016

24. Practical Considerations:
3. Intermittent Androgen Deprivation:
Prolonged ADT
CRPC
Side Effects
ADT
Maximum
Response
Treatment
Withdrawal
ProgressionRestart ADTOutcome??

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

26. Slide 7

27. • A 2007 meta-analysis combined the results
from 3065 patients in four randomized trials.
• Early ADT was associated with a statistically
significant decrease in prostate cancer-related
deaths (relative risk [RR] 0.84; 95% CI 0.77-
0.92.
• Although there was no significant benefit in
overall survival (RR 0.98; 95% CI 0.95-1.01).
Practical Considerations:
4. Timing of ADT:

28. • Loss of libido.
• Impotence.
• Hepato-splenomegaly.
• Hot flushes.
• Gynecomastia.
Complications of Short Term ADT:

29. • Obesity.
• DM & CVS.
• Insulin resistance.
• Osteoporosis and clinical fractures.
Complications of Long Term ADT:

30. ADT: Key points from EAU guidelines 2014:
“Oncologist & Urologist are Besides & Not A Side”
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

31. androgen-dependent cell
CRPC
Intrinsic Resistance to ADT

32. Slide 10

33. Slide 12

34. Role of Cytotoxics in HSPC:

35. Role of Cytotoxic Therapy in HSPC:
Effect of Adding Docetaxel on OAS in M1 Disease:

36. Role of Cytotoxic Therapy in HSPC:
Effect of Adding Docetaxel on FFS in M1 Disease:

37. Role of Cytotoxic Therapy in HSPC:
Effect of Adding Docetaxel on OAS in M0 Disease:

38. Role of Cytotoxic Therapy in HSPC:
Effect of Adding Docetaxel on FFS in M0 Disease:

39. Management of Oligometastatic
Disease:

40. 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”

41. Androgen Receptor in Prostate Cancer:

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

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

44. 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

45. Therapeutic Strategies Against CRPC:
• More effective Blocking of Androgen Biosynthesis:
 CYP 17A1  Abiraterone Acetate.
• More Effective AR Blocking: Triple Inhibition 
Enzalutamide.
• Direct Cell Killing: Chemotherapeutics  Anti-
Microtubule  Docetaxel & Cabazitaxel.
• Bone Only Disease “Symptomatic”: Radium 223.
• Immunotherapy: Sipuleucel T
Maintain Androgen Deprivation Therapy

46. Summary of Clinical Trials Outcome:

47. Discussion Points: Current Practice
• What drives current sequencing decisions in
patients with mCRPC ?
 Patient/doctor preference?
 Cost/reimbursement?
 Other reasons?
 Evidenced based data?
• What criteria would you use to determine a change
in the current therapy?
 Disease extent and anticipated survival?
 Symptomatology?

48. Chemotherapy in Advanced Prostate Cancer:
EARLY
M.C. Markowski, M.A. Carducci / Cancer Treatment Reviews 55 (2017) 218–224
LATE

49. Choice of Therapy:
Special Considerations:
• Heavy Tumor Burden, Highly Symptomatic,
Short PSA DT, Visceral Disease: Chemotherapy.
• Compromised Cardiac Functions, HTN,
Compromised Liver Functions: ? Abiraterone.
• Possibility of Seizures: No Enzalutamide.
• Drug Resistance: Androgen Receptor Splice
Variants and Cross Drug Resistance:
? Abiraterone/Enzalutamide.
Antonarakis E. Clinical Advances in Hematology & Oncology. 2016, 14(5)

50. Prostate Cancer:
The Story:
1940 - 1950 1970 - 1980 1980 - 1990 1990 - 2000
Bilateral
Orchiectomy + DES
LHRH Agonist
FDA APPROVAL
FLUTAMIDE + ADT
CRPC
Mitoxantrone +
Prednisone
OAS < 6 ms
OAS > 24 ms

51. Prostate Cancer:
The Story: New Chapters:
2004 2010 2011 2012 2013 2014
Docetaxel
&
Zoladronic
Cabazitaxel
D-mab
Sip T.
Abi (Post) Abi (Pre) Enza (Post)
Radium
223
Enza (Pre)
OAS =
18.9 ms
OAS =
35.3 ms
2015 & Beyond
ADT + Cytotoxic in HSPC:
• Metastatic: CHAARTED & STAMPEDE
• Locally Advanced: RTOG 0521
Current & Future Paradigm
• Sequencing of Available
Therapeutics.
• To Overcome Resistance.

52. Thank You