describes the management of prostate cancer in relation to the pathophysiology of disease

1. Current Dilemmas in Early
Management of CRPC
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Astellas Symposium
Hilton Heliopolis Hotel
Thursday, Jan. 17th 2019

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, Sanofi-Genzyme.
Speaker Disclosures:

3. 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

4. CRPC: an Overview

5. Prostate Cancer: Natural History:
Locoregion
al Disease
Biochemica
l Failure
Metastatic
“Sensitive”
Metastatic
“Refractory”
Death
TIME
TumorBurden
Effective Castration & AR Blocking
Serum Testosterone < 0.2 – 0.5 ng/ml

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

8. Genetic Insults in Prostate Cancer
Oliver Sartor, M.D., and Johann S. de Bono, M.B., Ch.B., Ph.D. N Engl J Med 2018;378:645-57.

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

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

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. Intracrine Androgen Metabolism &
Biosynthesis:
• Overproduction of 5α-Reductase  Excessive
conversion of Testosterone to DHT (Genetic
Predisposition in African).
• Cholesterol (CYP 11A1)  Pregnenolone (CYP
17A1)  Testosterone
Prostate is an androgen self – sufficient organ
Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral
androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res
2008;68:4447–54.
Pienta KJ, Bradley D. Mechanisms underlying the development of androgen- independent prostate cancer. Clin
Cancer Res 2006;12:1665–71.

13. Non-Genomic Activity of AR – Outlaw Pathway:
Growth Factors &
Receptors
IGF-1, EGF, IL-4&6, RTK
Enhanced Cellular
Proliferation & Survival
Oncogenic Signaling
Pathway RAS – RAF – PI3K -MPAK
Enhanced Cellular
Proliferation & Survival
Co-activator & Co-
suppressor Deregulation
ARA-70, SRC-1, PTEN,
RB, P53
Enhancing Sensitivity to
Ligands other than
Androgens & Loss of
Apoptosis
Neuroendocrine Cells No AR, Stimulated by IL-
6
No Role of ADT  Time
for Cytotoxic Therapy
Evident in Advanced Disease &
CRPC
Katsgia Cancer Treatment Reviews 41 (2015) 588–597

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

15. BRCA Genes:
Basic Knowledge
Eukaryotic Genome
Constant StressEndogenous Exogenous
Continuous Damage
Continuous Repair
Misrepair Perfect Repair No Repair
Mutations Apoptosis
Tumor Suppressor Genes
Peter J.O’Donovan and David M.Livingston. Carcinogenesis vol.31 no.6 pp.961–967, 2010
BRCA1 & BRCA2
• DNA Repair
• Control of Cell Cycle Checkpoints
• Control of Mitotic Activity
CANCER IS A HYPERMUTABLE
DISEASE

16. Cancer Risk in Carriers of Germline
Mutations in BRCA1 & BRCA2
Autosomal Dominant
Inheritance with High
Penetrance
• 50% Chance of Inheritance
• Lifetime Risk of Cancer =
30-70%

17. 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

18. M0 CRPC: New Chapter of Story
M0CRPC M1CRPC
Longer
• Symptomatic  QoL
• Survival.
Kirby et al. Int J Clin Pract 2011; 65(11): 1180–1192.
1ry endpoint  MFS

19. 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
ADT + Abiraterone Acetate
Prednisone in HSPC:
• LATITUDE Trial
ADT + Apalutamide/Enzalutamide
In M0 CRPC (++ MFS)
• SPARTAN & PROSPER Trials

20. • Start as early as possible
• Sequence

21. Presented By Mary-Ellen Taplin at 2018 ASCO Annual Meeting

22. PROSPER: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Enzalutamide in Men With Nonmetastatic Castration-Resistant Prostate Cancer
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

23. PROSPER Study Design
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

24. Baseline Patient Characteristics (N = 1401)
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

25. Adverse Events*
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

26. Primary Endpoint: MFS
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

27. Subgroup Analysis of MFS
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

28. Time to PSA Progression
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

29. Time to First Use of New Antineoplastic Therapy
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

30. SPARTAN, a Phase 3 Double-Blind, Randomized Study of Apalutamide vs Placebo in Patients With Nonmetastatic Castration-Resistant Prostate Cancer
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

31. Slide 5
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

34. Beer et al. N Engl J Med 2014;371:424-33.

36. Loriot et al. Lancet Oncol 2015; 16: 509–21

38. Patient population
375 men with mCRPC
who have progressed on
LHRHa therapy or after
bilateral orchiectomy
Asymptomatic/
mildly symptomatic
Chemotherapy-naïve
No requirement for
steroids
Enzalutamide
160 mg QD
(n=184)
Primary endpoint:
• PFS
– Radiographic progression
(central review)
– Skeletal-related event
– Initiation of new
antineoplastic therapy
– Death
Secondary endpoints:
• PSA response
• Time to PSA progression
R
1:1 Bicalutamide
50 mg QD
(n=191)

39. PSA Response by Week 13 with ENZA or BIC
100
80
60
40
20
0
-20
-40
-60
-100
-80
PercentageChangeinPSAfrom
Baseline
ENZA
BIC
PSA response: 21%
Observations
PSA response: 82%
Bicalutamide Enzalutamide
Shore ND, Lancet Oncol 2016: 17: 153-63

40. 100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30 33
Progression-Free Survival in TERRAIN
PatientswithoutPFSevent
(%)
184
191
159
133
131
85
107
61
86
44
71
30
52
13
33
7
21
4
13
2
8
2
5
1
ENZA
BIC
Time (months)ENZA
Patients at risk
BIC
Patients at risk
Enzalutamide
Median (95% CI):
15.7 months (11.5, 19.4)
Bicalutamide
Median (95% CI):
5.8 months (4.8, 8.1)
Hazard ratio (95% CI):
0.44 (0.34, 0.57); P <0.0001
Shore N, Lancet Oncol 2016; 17: 153-163

41. 41
Enzalutamide, n
Bicalutamide, n
184
191
121
88
91
50
71
30
55
20
45
15
33
10
19
6
12
4
6
1
3
1
2
1
1
0
0
0
HR=0.64 (95% CI: 0.46–0.88); p=0.0067100
0 3 6 9 12 15 18 21 24 27 30 33
Months
90
80
70
60
50
40
30
20
10
0
36 39
Enzalutamide: 13.8 months
(95% CI: 11.1–22.1)
Bicalutamide: 8.5 months
(95% CI: 5.8–11.3)
Patientswithout
deterioration(%)
TERRAIN: Quality of life
(Time to FACT-P deterioration)
CI=confidence interval; HR=hazard ratio; FACT-P=Functional Assessment of Cancer Therapy – Prostate.
Shore N, et al. AUA 2015; Oral presentation PII-LBA4.

43. 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.

44. 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 √ √ √ √

45. • Pain
• Bone vs visceral metastases
• Performance status
• Neuropathy & other Comorbidity (Cardiac & Hepatic)
• “Early or late” CRPC
• Prior therapy exposure and response
• Response biomarkers
• Tumor characteristics
CRPC, castration-resistant prostate cancer

46. Management of CRPC is still in
Infancy! (2010  2018 = 8 Years)
• Comparison across positive trials is NOT
JUSTIFIED.
• May be some better insight.
• RCT to answer a specific question are of
priority.

47. Patients Population in CRPC Trials:
LancetOncology2015; 16: e279–92

48. CRPC: Subsequent Therapies:
LancetOncology2015; 16: e279–92

49. CRPC: Subsequent Therapies:
LancetOncology2015; 16: e279–92

50. A randomized phase II cross-over study of abiraterone + prednisone vs enzalutamide for patients with metastatic, castration-resistant prostate cancer
Presented By Kim Chi at 2017 ASCO Annual Meeting

51. Study Schema
Presented By Kim Chi at 2017 ASCO Annual Meeting

52. Adverse Events of Interest
Presented By Kim Chi at 2017 ASCO Annual Meeting

53. Best PSA decline: 12 weeks
Presented By Kim Chi at 2017 ASCO Annual Meeting

54. Time to PSA Progression (Confirmed)
Presented By Kim Chi at 2017 ASCO Annual Meeting

55. Time to Progression
Presented By Kim Chi at 2017 ASCO Annual Meeting

56. ASCO – GU - 2018

58. Enzalutamide vs. Abiraterone:
The problem of cross-resistance
Zhang, et al, Expert Opin. Pharmacother., 2015

59. Resistance to 2nd Hormonal Manipulation:
Study Probability of 1ry Resistance
(Radiologic Progression
during 1st 3 months)
Pre-Chemotherapy:
• Abiraterone + Pred.
• Enzalutamide
• < 10%
• < 10%
Post-Chemotherapy:
• Abiraterone + Pred.
• Enzalutamide
• < 40%
• ≈ 20%
C. Buttigliero et al. / Cancer Treatment Reviews 41 (2015) 884–892

60. Enzalutamide vs Abiraterone:Asymptomatic/minimally symptomatic, pre-chemo pt
• Enzalutamide
• Androgen receptor signaling
• inhibitor
• Contraindicated in seizure history
• Side effects include:
– Fatigue (sometimes profound)
– Hypertension
– GI side effects
(constipation/diarrhea)
– Seizure risk
• Preferred in pts who cannot tolerate
systemic steroids (brittle DM, gastric ulcer
disease)
Abiraterone
• Androgen synthesis inhibitor (binds
the cytochrome P450 (CYP17) gene)
• Normally given with
corticosteroids (pred 5 bid)
• Side effects include:
– Hypertension & Liver Impairment
– Hypokalemia
– Fatigue
– Steroid-induced hyperglycemia
• Preferred in pts with seizure
history

61. Current Approach:
• Which drug or mechanism to start with?
– Sipuleucel T: Asymptomatic with low tumor burden
patients.
– R223: Bone only metastases.
• ARV7  Neither Abi nor Enza.
• Sequential use (Abi  Enza) or (Enza  Abi).
• Cytotoxics are indicated for heavy visceral or
symptomatic tumor burden,

62. AUA Clinical Scenarios:
Adapted from Cookson MS et al. Castration-resistant prostate cancer: AUA guideline. Update 2015
CRPC
Non Metastatic
“++ PSA”
Metastatic
No Prior
Docetaxel
Asymptomatic or Mildly
Symptomatic
Symptomatic
Good PSPoor PS
Prior Docetaxel
Good PSPoor PS

63. 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?
Better Insights, but Definitely Still
in The Grey Zone in Management of CRPC

64. • Survival of CRPC is well enhanced.
• Start Treatment as early as possible.
• Enzalutamide is a key player and is valid among different
patient scenarios and gaining access to earlier phases of
disease.
• The choice of 2nd hormonal manipulation depends on
1. The anticipated toxicity within the context of patient’s co-
morbidity.
2. Access to drug.
3. The anticipated sequelae of long term use of steroids.
We know:

65. Thank You