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Target Audience
The target audience for this activity is medical oncologists, urologists, radiation oncologists, radiologists, nuclear medicine physicians, and oncology specialty pharmacists involved in the management of individuals with CRPC.
Educational Objectives
At the conclusion of this activity, participants should be able to:
• Review the biology of bone metastases, skeletal morbidity, and recent advances in bone-targeted therapies for bone-metastatic CRPC
• Analyze the results of pivotal trials introducing radium-223 dichloride (R-223) for bone-metastatic CRPC and identify its impact on existing treatment algorithms
• Apply the benefits and limitations of contemporary strategies for the optimal treatment of men with bone-metastatic CRPC ineligible or unfit for chemotherapy into patient care recommendations
• Review ongoing and planned clinical trials evaluating novel bone-targeted therapies for bone-metastatic CRPC and the potential impact on the treatment landscape
This activity is supported by an educational grant from
Algeta US and Bayer HealthCare Pharmaceuticals, Inc.

3. Approved Therapies for mCRPC
Drug Class
Agent(s)
Basis of Approval
Androgen receptor antagonists
Enzalutamide
Prolonged survival
Androgen synthesis inhibitors
Abiraterone acetate
Bisphosphonates
Zoledronic acid
SRE reduction
Chemotherapy
Docetaxel
Cabazitaxel
Mitoxantrone
Pain reduction
Immunotherapy
Sipuleucel-T
RANK ligand inhibitors
Denosumab
Radioisotopes
Samarium-153 (153Sm)
Strontium-89 (89Sr)
Radium-223 dichloride
Bone pain reduction
RANK: nuclear factor kappa B ligand; SRE: skeletal-related event; SSE: symptomatic skeletal event
Food and Drug Administration. Available at:

4. Chronology of FDA Approvals in mCRPC
Docetaxel +
Prednisone
Abiraterone
+ Prednisone
Post-Docetaxel
Mitoxantrone +
Prednisone
Abiraterone
+ Prednisone
Pre-Docetaxel
Zoledronic
Acid
Sipuleucel-T
Strontium89
Samarium153
Denosumab
Radium-223
Estramustine
Cabazitaxel +
Prednisone
Enzalutamide
Post-Docetaxel

5. 2010-2013: OS Benefit in Recent CRPC Trials
Agent
Trial
Disease State
Comparator
Median OS (mo) HR
(P)
Sipuleucel-T
IMPACT
Chemo-naïve
CRPC
Placebo
25.8
0.759
(0.017)
Docetaxel
TAX327
Chemo-naïve CRPC
Mitoxantrone
Prednisone
18.9
0.76
(0.009)
Cabazitaxel
TROPIC
Post-docetaxel CRPC
15.1
0.70
(< )
Abiraterone acetate + prednisone
COU-AA-301
Post-docetaxel
Placebo Prednisone
14.8
0.646
Abiraterone acetate + prednisone
COU-AA-302
Progressive chemo-naïve CRPC
Placebo + Prednisone
Not Reached
0.75
(0.01)
Enzalutamide
AFFIRM
18.4
0.631
PREVAIL
32.4
Radium-223
ALSYMPCA
14.9
0.695
(0.002)
J Clin Oncol 31, 2013 (suppl 6; abstr 63)
Mark T. Fleming, Dana E. Rathkopf, Jackie Gibbons, Amy C. Peterson, Alison Hannah, David Forer, Howard I. Scher, Michael J. Morris; Virginia Oncology Associates, Norfolk, VA; Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY; Medivation, Inc., San Francisco, CA
CRPC, castration-resistant prostate cancer; HR, hazard ratio; OS, overall survival.
Kantoff PW, et al. N Engl J Med. 2010;363: ; Tannock IF, et al. N Engl J Med. 2004;351: ; de Bono JS, et al. Lancet. 2010;376: ; de Bono J, et al. N Engl J Med. 2011;364: ; Ryan CJ, et al. N Engl J Med. 2013;368(2): ; Scher HI, et al. N Engl J Med. 2012;367(13): ; Medivation and Astellas Press Release, October 22, 2013; Parker C, et al. N Engl J Med. 2013;369(3):

6. Metastatic CRPC: First-Line Options
Agents approved for first-line use
Sipuleucel-T
Abiraterone / prednisone
Docetaxel
Radium-223
Anticipated
Enzalutamide
To date, no head-to-head comparative studies of these agents

7. Bone Metastases in Prostate Cancer
Progressive disease
Bone pain
Pathologic fractures
Spinal cord compression
Marrow suppression
Slide that follows: Insert a set-up slide

8. Metastatic CRPC: Where Are We?

9. Sipuleucel-T vs Placebo: IMPACT Study Design (IMmunotherapy Prostate AdenoCarcinoma Treatment)
Treated at physician discretion P R O G E S I N
Asymptomatic or minimally symptomatic mCRPC
(N = 512)
R A N D O M I Z E D
2:1
Sipuleucel-T
q2 weeks x 3
Treated at physician discretion and / or salvage protocol
Placebo
q2 weeks x 3
Primary endpoint: Overall survival
Secondary endpoint: Objective disease progression
Kantoff PW, et al. N Engl J Med. 2010;363(5): 9

10. IMPACT: Overall Survival Final Analysis (349 events)
100%
80%
60%
Percent Survival S i pu l e u
cel - T ( n =
341)
40% M e d i a n s ur v i v a l : 25 . 8 mo 36 mo s ur v i v a l : 32 . 1 %
20% P l
ace bo ( n =
171) M e d i a n s ur v i v a l : 21 . 7 mo 36 mo s ur v i v a l : 23 . % 0% 12 24 36 48 60 72
Time From Randomization (months)
Median Follow-up = 36.5 months
HR = (95% CI, 0.606, 0.951), P = (Cox model)
Kantoff PW, et al. N Engl J Med. 2010;363(5): 10

11. IMPACT: Adverse Events
Sipuleucel-T (N = 338)
Placebo (N = 168)
All Grades
No. (%)
Grade 3-5
Any
334 (98.8)
107 (31.7)
162 (96.4)
59 (35.1)
Chills
183 (54.1)
4 (1.2)
21 (12.5)
Fatigue
132 (39.1)
64 (38.1)
3 (1.8)
Back pain
116 (34.3)
12 (3.6)
61 (36.3)
8 (4.8)
Pyrexia
99 (29.3)
1 (0.3)
23 (13.7)
Nausea
95 (28.1)
2 (0.6)
35 (20.8)
Arthralgia
70 (20.7)
7 (2.1)
40 (23.8)
5 (3.0)
Citrate toxicity
68 (20.1)
34 (20.2)
Vomiting
60 (17.8)
20 (11.9)
Headache
54 (16.0)
Pain
44 (13.0)
6 (1.8)
12 (7.1)
2 (1.2)
Influenza-like illness
33 (9.8)
6 (3.6)
Bone pain
32 (9.5)
3 (0.9)
18 (10.7)
Hypertension
25 (7.4)
Hyperhidrosis
18 (5.3)
1 (0.6)
Groin pain
17 (5.0)
4 (2.4)
Kantoff PW, et al. N Engl J Med. 2010;363(5):

12. Cabazitaxel + Prednisone vs Mitoxantrone + Prednisone: The TROPIC Study
R A N D O M I Z E D
Cabazitaxel 25 mg/m2 IV Q3wk
+ Prednisone for 10 courses
(N = 378)
Mitoxantrone 12 mg/m2 IV Q3wk
(N = 377)
Patients
Patients with mCRPC progressing during and after docetaxel
(N = 755)
Primary endpoint: Overall survival
Secondary endpoints:
 PFS
 Response rate
 Safety
de Bono J, et al. Lancet. 2010;376(9747):

13. TROPIC: Overall Survival
TROPIC slide deck. Slide5
Mitoxantrone
Prednisone
Cabazitaxel
Median OS (months)
12.7
15.1
Hazard ratio
0.72
95% CI
P value
<
100 80 60 40 20
Proportion of OS (%)
Censored MP
CBZP
Combined median follow-up: 13.7 months 6 12 18 24 30
Time (months)
de Bono J, et al. Lancet. 2010;376(9747):

14. TROPIC: Hematological Adverse Events
Mitoxantrone
(n = 371)
Cabazitaxel
All Grades
n (%)
Grade ≥ 3
Neutropenia
325 (88)
215 (58)
347 (94)
303 (82)
Febrile neutropenia 
5 (1)
28 (8)
Leukopenia
343 (92)
157 (42)
355 (96)
253 (68)
Anemia
302 (81)
18 (5)
361 (97)
39 (11)
Thrombocytopenia
160 (43)
6 (2)
176 (47)
15 (4)
de Bono J, et al. Lancet. 2010;376(9747):

15. TROPIC: Non-Hematological Adverse Events
Mitoxantrone (n = 371)
Cabazitaxel (n = 371)
All Grades
n (%)
Grade ≥ 3
Diarrhea
39 (11)
1 (< 1)
173 (47)
23 (6)
Fatigue
102 (27)
11 (3)
136 (37)
18 (5)
Asthenia
46 (12)
9 (2)
76 (20)
17 (5)
Back pain
45 (12)
60 (16)
14 (4)
Nausea
85 (23)
127 (34)
7 (2)
Vomiting
38 (10)
84 (23)
Hematuria
2 (1)
62 (17)
Abdominal pain
13 (4)
43 (12)
Pain in extremity
27 (7)
4 (1)
30 (8)
6 (2)
Dyspnea
3 (1)
44 (12)
5 (1)
Constipation
57 (15)
Pyrexia
Arthralgia
31 (8)
Urinary tract infection
Pain
20 (5)
Bone pain
19 (5)
de Bono J, et al. Lancet. 2010;376(9747):

16. Abiraterone + Prednisone vs Prednisone + Placebo: COU-AA-301 Study Design
Abiraterone acetate
mg tablets QD 1 hr
before or 2 hrs after meal +
Prednisone 5 mg BID x 28
days (N = 797)
R A N D O M I Z E D
1:1
Endpoints
Primary
Overall survival
Secondary
PSA response
rate
Time to PSA
progression
Radiographic
evidence of PFS
Patients
Histologically or
cytologically
confirmed prostate
cancer, previously
treated with
docetaxel
ECOG performance
status score ≤ 2
Placebo 4 tablets QD 1 hr
before or 2 hrs after meal +
Prednisone 5 mg BID x 28
days (N = 398)
Phase III, randomized, double-blind, placebo-controlled trial
conducted at 147 sites in 13 countries
de Bono J, et al. N Engl J Med. 2011;364: 16

17. COU-AA-301: Patient Characteristics
Abiraterone + Prednisone
(N = 797)
Placebo + Prednisone
(N = 398)
Median range (yr)
69 (42-95)
69 (39-90)
Disease location – no. of patients (%)
Bone
Node
Liver
709 (89)
361 (45)
90 (11)
357 (90)
164 (41)
30 (8)
Brief Pain Inventory (Short Form) score for pain
No. of patients
Median score (range)
792
3.0 (0-10)
394
No. of previous cytotoxic chemotherapy regimens – no. of patients (%) 1 2
558 (70)
239 (30)
275 (69)
123 (31)
ECOG performance status – no. of patients (%)
0 or 1
715 (90)
82 (10)
353 (89)
45 (11)
Prostate-specific antigen
Median (range) – ng/mL
788
128.8 ( )
393
137.7 ( )
ECOG: Eastern Cooperative Oncology Group
de Bono J, et al. N Engl J Med. 2011;364:

18. COU-AA-301: Overall Survival
Abiraterone acetate: 14.8 months
100 80
HR = ( )
P < 60
Survival (%) 40
Placebo: 10.9 months 20 AA
Placebo
100
200
300
400
500
600
700
Days From Randomization
de Bono J, et al. N Engl J Med. 2011;364:

19. COU-AA-301: Adverse Events
Abiraterone (N = 791)
Placebo (N = 394)
All Grades
No. (%)
Fatigue
346 (44)
169 (43)
Fluid retention and edema
241 (31)
88 (22)
Back pain
233 (30)
129 (33)
Nausea
124 (32)
Arthralgia
215 (27)
89 (23)
Constipation
206 (26)
120 (31)
Bone pain
194 (25)
110 (28)
Vomiting
168 (21)
97 (25)
Diarrhea
139 (18)
53 (14)
Hypokalemia
135 (17)
33 (8)
Pain in arm or leg
134 (17)
79 (20)
Cardiac disorder
106 (13)
42 (11)
Asthenia
104 (13)
52 (13)
Dyspnea
102 (13)
46 (12)
Abdominal pain
95 (12)
44 (11)
Urinary tract infection
91 (12)
28 (7)
Liver function test abnormalities
82 (10)
32 (8)
de Bono J, et al. N Engl J Med. 2011;364:

20. Prednisone + Abiraterone vs Prednisone + Placebo: COU-AA-302 Study Design
R A N D O M I Z E D
1:1
Abiraterone acetate
1000 mg daily +
Prednisone 5 mg BID
(N = 546)
Endpoints
Co-Primary:
rPFS by central review OS
Secondary:
Time to opiate use (cancer-related pain)
Time to initiation of chemotherapy
Time to ECOG-PS deterioration
TTPP
Patients
Progressive chemo-naïve mCRPC patients (Planned N = 1088)
Asymptomatic or mildly symptomatic
Placebo daily +
Prednisone 5 mg BID
(N = 542)
Phase III multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada
Stratification by ECOG performance status 0 vs 1
Ryan CJ, et al. N Engl J Med. 2013;368(2): 20

21. COU-AA-302: Radiographic Progression-Free and Overall Survival
Curatio PowerPoint Template
11/11/2018 6:47 AM
COU-AA-302: Radiographic Progression-Free and Overall Survival
Radiographic
Progression-Free Survival
Overall Survival
100
100
Hazard ratio, 0.75 (95% CI, )
Hazard ratio, 0.53 (95% CI, ) P
< 0.01 P
< 0.001 80 80
Abiraterone-prednisone,
not reached
Abiraterone-prednisone, 16.5 mo 60 60
Progression-Free Survival (%)
Overall Survival (%) 40 40
Prednisone alone, 8.3 mo
Prednisone alone, 27.2 mo 20
No. of Events 20
No. of Events
Fact check:
These data are similar to but not identical with those just published. Fig 1a (# at risk differences)
Other differences: OS
Abiraterone-prednisone: 271
Abiraterone-prednisone: 147
Prednisone alone: 336
Prednisone alone: 186 3 6 9 12 15 18 21 24 27 30 3 6 9 12 15 18 21 24 27 30 33
Months
Months
Ryan CJ, et al. N Engl J Med. 2013;368(2): 21 21

22. COU-AA-302: Adverse Events of Special Interest
Grade 3 or 4 Adverse Event
Abiraterone + Prednisone
N = 542, n (%)
Placebo + Prednisone
N = 540, n (%)
Fluid retention or edema
4 (< 1)
9 (2)
Hypokalemia
13 (2)
10 (2)
Hypertension
21 (4)
16 (3)
Cardiac disorder
31 (6)
18 (3)
Atrial fibrillation
7 (1)
5 (< 1)
ALT increased
29 (5)
AST increased
ALT: alanine aminotransferase; AST: aspartate aminotransferase
Ryan CJ, et al. N Engl J Med. 2013;368(2):

23. Enzalutamide vs Placebo: AFFIRM Study Design
R A N D O M I Z E D
2:1
Enzalutamide
160 mg daily
(N = 800)
Placebo
(N = 399)
Endpoints
Primary:
Overall survival
Secondary:
rPFS
Time to PSA
progression
Time to first SSE
Patients
1199 patients with
progressive mCRPC
Disease progression
after docetaxel
Phase III, double-blind, placebo-controlled trial conducted at 156 sites in 15 countries
Stratification according to:
 ECOG performance status (0 vs 1-2)
 Average pain over prior 7 days (Brief Pain Inventory [Short Form]; 0-3 [absent] vs
4-10 [present])
ECOG: Eastern Cooperative Oncology Group.
Scher HI, et al. N Engl J Med. 2012;367(13):

24. AFFIRM: Prior Hormonal and Chemotherapy Treatments
Enzalutamide
N = 800
Placebo
N = 399
Prior lines of hormonal drug therapy* 1 2
≥ 3
8.2%
42.3%
49.1%
8.8%
37.9%
53.1%
Number of prior chemotherapy regimens
72.4%
24.5%
3.1%
74.2%
23.8%
2.0%
Median number of prior docetaxel cycles
8.5
8.0
LEAVE THIS IN
*Abiraterone naïve.
Scher HI, et al. N Engl J Med. 2012;367(13):

25. AFFIRM: Overall Survival
100 90
Enzalutamide: 18.4 months
(95% CI: 17.3, NYR) 80 70 60
Survival, % 50 40
Placebo: 13.6 months
(95% CI: 11.3, 15.8) 30 20
Stephen to redraw 10 3 6 9 12 15 18 21 24
Duration of Overall Survival, Months
HR = (0.529, 0.752) P < , 37% reduction in risk of death
Scher HI, et al. N Engl J Med. 2012;367:

26. AFFIRM: Adverse Events
Enzalutamide (N = 800)
Placebo (N = 399)
Any Grade
No. (%)
Grade ≥ 3
≥ 1 adverse event
785 (98)
362 (45)
390 (98)
212 (53)
Any serious adverse event
268 (34)
227 (28)
154 (39)
134 (34)
Discontinuation owing to adverse event
61 (8)
37 (5)
39 (10)
28 (7)
Adverse event leading to death
23 (3)
14 (4)
Frequent adverse events more common
with enzalutamide
Fatigue
269 (34)
50 (6)
116 (29)
29 (7)
Diarrhea
171 (21)
9 (1)
70 (18)
1 (< 1)
Hot flash
162 (20)
41 (10)
Musculoskeletal pain
109 (14)
8 (1)
40 (10)
Headache
93 (12)
6 (< 1)
22 (6)
Clinically significant adverse events
Cardiac disorder
Any
49 (6)
7 (1)
30 (8)
8 (2)
Myocardial infarction
2 (< 1)
Abnormality on liver-function testing
3 (< 1)
6 (2)
Seizure
5 (< 1)
Scher HI, et al. N Engl J Med. 2012;367(13):

27. Enzalutamide vs Placebo in Chemotherapy-Naïve Metastatic Prostate Cancer: The PREVAIL Study
Progressive mCRPC
Asymptomatic or mildly symptomatic
Chemotherapy-naïve
Steroids allowed but not required
N = 1717
Enzalutamide
160 mg/day
(capsules)
n = 872
R A N D O M I Z E D
Co-Primary Endpoints OS
rPFS
Placebo
n = 845
Halted October 2010 halted by DMC and patient offered crossover Oct 2014
ClinicalTrials.gov identifier: NCT
mCRPC: metastatic castrate-resistant prostate cancer; OS: overall survival; rPFS: radiographic progression-free survival
Beer T, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA 1.

28. PREVAIL: Radiographic Progression-Free Survival
100 90
Hazard Ratio: 0.186
(95% CI: 0.15, 0.23) 80 P
< 70 60 50
Radiographic Progression-Free Survival (%) 40 30 20 10
Enzalutamide
Placebo 3 6 9 12 15 18 21
Radiographic Progression-Free Survival (Months)
Median rPFS: Enzalutamide, not reached
Placebo, 3.9 months
Beer T, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA 1.

29. PREVAIL: Radiographic PFS Across Subgroups
All patients
ECOG performance status at baseline = 0
Age < 75
Geographic region - North
America
Geographic region - Europe
Geographic region - Rest of world V
isceral disease (Lung and or liver) at screening - Y es
isceral disease (Lung and or liver) at screening - No
832 / 801
557 / 549
275 / 252
529 / 517
303 / 284
214 / 204
456 / 435
162 / 162
97 / 101
735 / 700
0.19 ( )
0.15 (0. 1
1-0.20)
0.27 ( )
0.20 ( )
0.17 ( )
0.17 ( )
0.21 ( )
0.14 ( )
0.28 ( )
0.17 ( )
Number of Patients
Enzalutamide / Placebo
Hazard Ratio
(95% CI)
1.0
0.5
Favors
Enzalutamide
Placebo
1.5
Beer T, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA 1.

30. PREVAIL: Overall Survival
100 90 80
Hazard Ratio: 0.706 70
(95% CI: 0.60, 0.84) 60 P
<
Survival (%) 50 40 30 20
Enzalutamide 10
Patients still alive at data cut off
Placebo
Enzalutamide: 72%; Placebo: 63% 3 6 9 12 15 18 21 24 27 30 33 36
Duration of Overall Survival (Months)
Median OS: Enzalutamide, 32.4 Months; Placebo, 30.2 months
Beer T, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA 1.

31. PREVAIL: Most Common Adverse Events
All Grades (%)
Grade ≥ 3 (%)
Enzalutamide
n = 871
Placebo
n = 844
Fatigue 36 26 2
Back Pain 27 22
2.5 3
Constipation 17
0.5
0.4
Arthralgia 20 16
1.4
1.1
Cardiac AE 10 8
Hypertension 13 4 7
↑ ALT
0.9
0.6
0.2
0.1
Seizure
Beer T, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA 1.

32. The Challenge of Bone Metastases

33. CRPC & Bone Metastases
Of the major solid tumors, prostate cancer is the most bone tropic
85-90% occurrence of bone metastases in phase III trials of CRPC
Bone metastases major cause of morbidity and mortality
 Pain most common
 Immobility / quality of life
 Cause pathologic fractures, spinal cord compression

34. Progress in Metastatic Prostate Cancer: Bone-Targeted Therapies
FDA Approvals in Castrate-Resistant Prostate Cancer
Radium-223
Survival
Enzalutamide
Cabazitaxel
Docetaxel
Abiraterone
Sipuleucel- T
1992
1996
2000
2004
2008
2012
Strontium-89
Samarium-153
Zoledronic acid
Denosumab
Mitoxantrone
Palliation 34

35. Strontium-89 vs Placebo The TransCanada Strontium-89 Study
R A N D O M I Z E D
Castrate-resistant
Bone metastases
(N = 126)
Strontium-89 (10.8 mCi x 1)
+ Local field radiotherapy
Placebo +
Local field radiotherapy
Primary Endpoint: Pain
Porter AT, et al. Int J Radiat Oncol Biol Phys. 1993;25(5):

36. The TransCanada Strontium-89 Study: Months Post-Treatment
New Pain Sites
Placebo Control
(n = 22)
1.4 –
1.2 –
1.0 –
0.8 –
0.6 –
0.4 –
0.2 –
(n = 42)
(n = 26)
(n = 23)
[P < 0.002]
Mean New Pain
Sites / Patient
(n = 46)
(n = 29)
(n = 25)
(n = 47)
(n = 44)
Strontium-89
(10.8 mCi)
(n = 34)
(n = 42)
(n = 48)
Months Post-Treatment
Porter AT, et al. Int J Radiat Oncol Biol Phys. 1993;25(5):

37. Samarium-153 EDTMP vs Placebo
Curatio PowerPoint Template
11/11/2018 6:47 AM
Samarium-153 EDTMP vs Placebo
R A N D O M I Z E D
2:1
Samarium-153
mCRPC
Bone metastases
(N = 152)
Placebo
Fact check:
In de Bono ESMO abstract- could not verify ECOG, pain, type of progression from abstract
This was a Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study conducted at 147 sites in the United States/Europe/Australia/Canada comparing the efficacy and safety of abiraterone acetate plus prednisone with placebo plus prednisone in men with metastatic CRPC who had failed 1 or 2 chemotherapy regimens, one of which contained docetaxel.
Subjects were randomized in a 2:1 ratio to receive abiraterone acetate plus prednisone or placebo plus prednisone, respectively, and were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs. 2), worst pain over the past 24 hours on The Brief Pain Inventory (BPI)-Short Form (0-3 [absent] vs [present]), prior chemotherapy regimens (1 vs. 2), and type of progression (PSA only vs. radiographic progression with or without PSA progression).
Subjects could receive treatment until documented disease progression (of all 3 types including 1) PSA progression, 2) radiographic progression and 3) symptomatic or clinical progression) or unacceptable toxicity.
Efficacy analysis set: ITT (intent-to-treat).
Primary efficacy endpoint: Overall survival (OS).
Secondary efficacy endpoints: prostate‑specific antigen (PSA) response rate, time to PSA progression, and radiographic progression-free survival (R_PFS).
Prospective, randomized, double-blind trial
Primary endpoint: pain response
Sartor O, et al. Urology. 2004;63(5): 37 37 37

38. Samarium-153 EDTMP vs Placebo: Palliative Effects
VAS Measured Pain Scores
PDS Measured Pain Scores -4
-12 -8
Week
0.5
1.5
2.0
2.5
3.0
3.5 -2 -6
-10
4.0
1.0
AUPC VAS -8 -4
Week
0.5
1.5
2.0
2.5
3.0
3.5 2 -2 -6
4.0
1.0
AUPC PDS
Analgesic Consumption 40
-40
Week
0.5
1.5
2.0
2.5
3.0
3.5 20
-20
4.0
1.0
Morphine Equiv/Day
Sartor O, et al. Urology. 2004;63(5):

39. Hematological Adverse Events of Strontium-89 and Samarium-153 Studies
TransCanada Study
Samarium-153 Study
Strontium-89
(n = 67)
n (%)
Placebo
(n = 58)
Samarium-153
(n = 93)
(n = 47)
Platelets
Grade 3
Grade 4
15 (22.4)
7 (10.4)
1 (1.72)
3 (3)
0 (0)
White blood cells
1 (1.49)
5 (5)
Porter AT, et al. Int J Radiat Oncol Biol Phys. 1993;25(5):
Sartor O, et al. Urology. 2004;63(5):

40. Time to First On-Study SSE
Bisphosphonates and Symptomatic Skeletal Event: Denosumab vs Zoledronic Acid
Time to First On-Study SSE
1.00
HR: 0.82 (95% CI: P = non-inferiority
P = superiority
Risk reduction
18%
0.75
Proportion of Subjects Without SSE
0.50
KM Estimate of Median Mos
0.25
No difference in overall survival or disease progression between denos and zole---delete Slide 38
CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier.
Denosumab
20.7
Zoledronic acid
17.1 3 6 9 12 15 18 21 24 27
Study Month
Pts at Risk, N
Zoledronic acid
951
733
544
407
299
207
140 93 64 47
Denosumab
950
758
582
472
361
259
168
115 70 39
SSE: symptomatic skeletal event
Fizazi K, et al. Lancet. 2011;377: 40

41. Summary of Adverse Events
Denosumab vs Zoledronic Acid: Adverse Events
Adverse Event
Zoledronic Acid (n = 945)
n (%)
Denosumab (n = 943)
Any adverse event
918 (97)
916 (97)
Most common adverse events in either arm
Anemia
341 (36)
337 (36)
Back pain
287 (30)
304 (32)
Decreased appetite
274 (29)
267 (28)
Constipation
251 (27)
236 (25)
Bone pain
245 (26)
235 (25)
Nausea
272 (29)
Asthenia
239 (25)
Fatigue
222 (24)
257 (27)
CTCAE Grade 3 or 4 adverse events
672 (71)
718 (76)
Serious adverse events
568 (60)
594 (63)
Adverse events leading to treatment discontinuation
138 (15)
164 (17)
Cumulative osteonecrosis of the jaw (total)
Year 1
Year 2
12 (1)
5 (1)
8 (1)
22 (2)
10 (1)
CTC, common toxicity criteria.
CTCAE: Common Terminology for Adverse Events (version 3.0)
Fizazi K, et al. Lancet. 2011;377: 41

42. Alpha Particle Treatment for
Bone-Metastatic CRPC

43. Critical Differences in Alpha- and Beta-Particles
Alpha Beta α β
Relative particle mass
7300 1
Initial energy (MeV) per particle
3-8
Range in tissue (μm)
40-100
LET (KeV/μm)
60-230
DNA hits to kill cells
1-10
LET = linear energy transfer Henriksen, et al. J Nucl Med. 2003;44:

44. Bone-Seeking Radiopharmaceuticals in
Human Clinical Trials
Radionuclide
Half-life
Targeting
Agents
Main Particle
Type
Maximum Energy (MeV)
Mean
Energy
Average
Penetration
Radium-223
11.4 days
None required
alpha
27.78
6.94
< 0.1 mm
Strontium-89
50.5 days
beta
1.46
0.58
2.4 mm
Samarium-153
1.9 days
EDTMP
0.81
0.22
0.5 mm
Phosphorus-32
14.3 days
1.71
0.69
3.0 mm
Yttrium-90
2.7 days
Citrate
2.27
0.93
4.0 mm
Lutetium-177
6.7 days
0.49
0.14
0.3 mm
Iodine-131
8.0 days
HDBP
0.61
0.19
0.8 mm
Rhenium-186
3.8 days
HEDP / etidronate
1.07
0.33
1.0 mm
Rhenium-188
0.7 days
HEDP
2.12
0.64
3.8 mm
Holmium-166
1.1 days
DOTMP / EDTMP
1.84
0.67
3.3 mm
Tin-117m
13.6 days
DTPA CE
0.15
0.2 mm

45. Radium Targets Osteoblastic Bone Metastases by Acting as a Calcium Mimetic
Strontium
Barium
Radium
McDevitt MR, et al. Eur J Nucl Med. 1998;25:

46. Radium: Bone-Seeking Calcium Mimetic That Binds to Hydroxyapatite [Ca10(PO4)6(OH)2]
Hydroxyapatite is intertwined with osteoid and cancer cells in the osteoblastic lesion
New Bone
Cancer Cells
Bruland, et al. Clin Cancer Res. 2006;12:6250s-6257s.

47. Note the short track length
Radium-223: Preferential Uptake in the Stroma of Osteoblastic Lesions Compared With Normal Bone and Bone Marrow
Normal bone Osteoblastic lesion
Bone marrow
Note the short track length
Studies in Dog Tumours
Bruland, et al. Clin Cancer Res. 2006;12:6250s-6257s. 47

48. Radium-223 Is Short-Range But High-Energy
2-10 cell diameter range of alpha-particle
Radium-223
Highly localized cell damage with minimal damage to
surrounding hematopoietic tissue
Perez, et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007.

49. Radium-223 vs Placebo: ALSYMPCA (ALpharadin in SYMptomatic Prostate Cancer) Study Design
STRATIFICATION
TREATMENT
PATIENTS R
A N D
OM I Z
E D
2:1
Confirmed symptomatic CRPC
≥ 2 bone metastases
No known visceral metastases
Post-docetaxel or unfit for docetaxel
(N = 922)
Radium-223 (50 kBq/kg) + Best standard of care
Total ALP: < 220 U/L vs ≥ 220 U/L
Bisphosphonate use: Yes vs No
Prior docetaxel: Yes vs No
6 injections at 4-week intervals
Placebo (saline) + Best standard of care
Statistical assumption
90% power
HR = 0.76
0.05 two-sided alpha
Planned Interim Analysis
Final Analysis
Events
320
640
Alpha
0.05
Parker C, et al. N Engl J Med. 2013;369(3):

50. ALSYMPCA Overall Survival (Updated Analysis)
Radium-223 Dichloride, n = 614
Median OS: 14.9 months
Placebo, n = 307
Median OS: 11.3 months
HR = 0.695
95% CI, 0.581, P = 10 20 30 40 50 60 70 80 90
100 %
Month 3 6 9 12 15 18 21 24 27 30 33 36 39
Radium-223
614
578
504
369
274
178
105 60 41 7 1
Placebo
307
288
228
157
103 67 14 4 2
May 2013, Radium-223 was FDA approved for patients with castrate-resistant prostate cancer who have bone metastases and no known visceral metastases
Parker C, et al. NEJM. 2013;369(3):

51. ALSYMPCA: Time to First SSE (Updated Analysis)
HR = 0.658
95% CI, 0.522, P =
Radium-223, n = 614
Median: 15.6 months
Placebo, n = 307
Median: 9.8 months 10 20 30 40 50 60 70 80 90
100 %
Months 3 6 9 12 15 18 21 24 27 30
Parker C, et al. NEJM. 2013;369(3):

52. ALSYMPCA: Subgroup Analysis
Parker C, et al. N Engl J Med. 2013;369:

53. ALSYMPCA: Adverse Events
All Grades
Grades 3 or 4
Radium-223
n = 600
n (%)
Placebo
n = 301
Hematologic
Anemia
187 (31)
92 (31)
77 (13)
39 (13)
Neutropenia
30 (5)
3 (1)
13 (2)
2 (1)
Thrombocytopenia
69 (12)
17 (6)
38 (6)
6 (2)
Non-hematologic
Bone pain
300 (50)
187 (62)
125 (21)
77 (26)
Diarrhea
151 (25)
45 (15)
9 (2)
5 (2)
Nausea
213 (36)
104 (35)
10 (2)
Vomiting
111 (19)
41 (14)
7 (2)
Constipation
108 (18)
64 (21)
6 (1)
4 (1)
At 1.5 years after the final injection, there were no reports of AML, MDS, or primary bone cancer
Aplastic anemia was reported in 1 patient in the radium-223 arm (considered treatment-related)
Primary cancers in other organs were identified in 2 radium-223 treated patients and 3 placebo-treated patients (deemed not study-drug related by investigators)
Parker C, et al. N Engl J Med. 2013;369(3): Nilsson S, et al. J Clin Oncol. 2014;32(suppl 4). Abstract 9.

54. Aspects of Ra-223 Therapy Administration
Outpatient therapy
Every 4 weeks x 6 (~ 6 months total), unless other therapy initiated for PoD
Hematologic toxicity comparable to placebo
Requires coordinated multidisciplinary care
Radium-223 will increase the role of nuclear medicine physicians in prostate cancer care

55. Future Challenges in the Management of CRPC
Sequencing and combination of newer therapies
Movement of newer therapies into earlier prostate cancer
Integrating novel targeted agents
Cost-effective management

56. What is the optimal sequence of therapy?
Practical Considerations for Treatment of Patients With Metastatic CRPC
How do we make treatment choices if there are no randomized comparisons?
How can we better stratify patients to increase their chances of responding?
What is the optimal sequence of therapy?

57. Practical Considerations: Patient Case Discussion

58. Metastatic CRPC Case
A 65-year-old man with a previous history of CAD presented with a PSA of 97 ng/mL
Biopsy showed a Gleason 3+4 adenocarcinoma of the prostate
Bone scan showed evidence of osteoblastic metastases
He was treated with an LHRH agonist
2 years later he develops castrate-resistant disease
His PSA has increased from 10 to 30 ng/mL
He complains of fatigue, difficulty urinating, and bone pain
Several new osseous metastases are detected

59. How would you treat this patient?
Key Takeaways?

60. Metastatic CRPC Case Continued
The patient was treated with docetaxel chemotherapy
After 6 cycles he developed painful peripheral neuropathy and discontinued treatment
His PSA increased from 16 to 38 ng/mL
His bone pain has worsened

61. How would you treat this
patient now?
Key Takeaways?

62. Case Takeaways Multiple active agents are now available for CRPC
Patients have treatment options. The first treatment is generally not the last treatment
The optimal sequence of treatments has yet to be determined
Data are unclear regarding the safety of radium-223 therapy following chemotherapy

63. Treatments for CRPC by Symptoms and Presence of Visceral Disease
Symptomatic
Asymptomatic
Visceral
Non-Visceral
Docetaxel √
Sipuleucel-T √*
Abiraterone acetate
Enzalutamide
Cabazitaxel
Mitoxantrone
Radium-223
*Mild symptoms.
Mohler JL, et al. J Natl Compr Canc Netw. 2013;11:

64. Thank You!
As a continuation of this activity, you will be invited to complete a post-assessment.
Your participation is needed to confirm the educational value of this program and is greatly appreciated.