Transcript Slide 1

‫תרופות וטיפולים חדשים בסרטן‬
‫ערמונית גרורתי עמיד לסירוס‬
‫דר' רענן ברגר‬
‫מנהל המכון האונקולוגי‬
‫ש שיבא‪ ,‬תל השומר”המרכז הרפואי ע‬
‫מהלך מחלה‬
‫הורדת רמת‬
‫הטסטוסטרון‬
‫כמותרפיה‬
‫טיפולים לאחר‬
‫הורדת רמת‬
‫הטסטוסטרון‬
‫פוסט‪-‬‬
‫כמותרפיה‬
‫טיפול מקומי‬
‫‪PSA‬‬
‫לא סימפטומטי‬
‫סימפטומטי‬
‫לא גרורתי‬
‫גרורתי‬
‫עמיד לסירוס‬
‫רגיש לסירוס‬
‫זמן‬
‫מטרות הטיפול כתלות בשלבי המחלה‬
‫הארכת חיים עם פליאציה‬
‫הארכת חיים עם מינימום רעילות‬
‫ריפוי‬
‫הורדת רמת‬
‫הטסטוסטרון‬
‫כמותרפיה‬
‫טיפולים לאחר‬
‫הורדת רמת‬
‫הטסטוסטרון‬
‫פוסט‪-‬‬
‫כמותרפיה‬
‫סימפטומטי‬
‫גרורתי‬
‫טיפול מקומי‬
‫לא סימפטומטי‬
‫לא גרורתי‬
‫עמיד לסירוס‬
‫רגיש לסירוס‬
‫זמן‬
‫אופציות טיפוליות‬
‫•מעקב אקטיבי‬
‫•הקרנות חיצוניות או‬
‫פנימיות‬
‫• ניתוח‬
‫התפתחות הטיפול התרופתי בסרטן‬
‫הערמונית‬
‫הארכת חיים עם פליאציה‬
‫הארכת חיים עם מינימום רעילות‬
‫ריפוי‬
‫הורדת רמת‬
‫הטסטוסטרון‬
‫כמותרפיה‬
‫‪Chemotherapy‬‬
‫פוסט‪-‬‬
‫כמותרפיה‬
‫טיפול מקומי‬
‫‪Tumor volume & activity‬‬
‫טיפולים לאחר‬
‫הורדת רמת‬
‫הטסטוסטרון‬
‫‪PSA‬‬
‫לא סימפטומטי‬
‫סימפטומטי‬
‫גרורתי‬
‫לא גרורתי‬
‫עמיד לסירוס‬
‫רגיש לסירוס‬
‫זמן‬
‫טקסוטר‬
‫‪Grey Zone‬‬
‫סטרואידים?‬
‫טיפול הורמונאלי (סירוס)‬
‫ניזורל?‬
‫אסטרוגנים‬
‫מרץ ‪2010‬‬
Current therapeutic landscape in
mCRPC
Docetaxel
Abiraterone
Abiraterone
Enzalutamide
(post-chemotherapy)
(pre-chemotherapy)
(post-chemotherapy)
Cabazitaxel
Mitoxantrone
2004
2010
2011
2012
2013
Sipuleucel-T
Zoledronic acid
Denosumab
Approval status in Europe
Radium-223
2004 ‫התפתחות הטיפול במחלה משנת‬
Testosterone < castrate serum levels
AND
‫תוספת של תוחלת חיים‬
OS benefit
‫ואיכות חיים‬
AND/OR
 Chemotherapy
 Bone-targeting therapy
 Docetaxel
 Cabazitaxel
 Zoledronic acid
 Denosumab
 Novel hormone therapy
 Abiraterone
 Enzalutamide
 Immunotherapy
 Sipuleucel-T
 Bone-targeting therapy
 Radium-223
Pain palliation & SRE
‫טיפול תומך עצם‬
prevention
‫לא בסל התרופות‬
Treatment options
with OS benefit
 Chemotherapy (docetaxel, cabazitaxel)
 Hormone therapy (abiraterone, enzalutamide)
 Bone-targeting therapy (radium-223)
 Sipuleucel-T
Cabazitaxel
Cabazitaxel
 Chemical structure: semi-synthetic taxane
 developed to overcome taxane resistance
docetaxel
cabazitaxel
 Indication
 in patients with mCRPC previously treated with docetaxel
Cabazitaxel:
Efficacy outcomes of TROPIC trial
Treatment
Probability of OS (%)
100
Cabazitaxel
15.1 mo
Mitoxantrone
12.7 mo
80
Cabazitaxel*
HR=0.70
95% CI: 0.59-0.83
P<0.0001
60
Mitoxantrone*
40
20
30% risk
reduction
0
No. at risk
Median OS
CBX
MTX
Time (mo)
0
6
12
18
24
30
377
378
300
321
188
231
67
90
11
28
1
4
de Bono JS et al. Lancet 2010;376:1147-54
*Prednisone in both arms
‫צ'רלס היגינס‬
1966 ‫חתן פרס נובל‬
 The first series of patients with prostatic cancer treated by
orchiectomy 16 comprised 21 patients with far advanced
metastases; only 4 of them survived for more than 12 years.
Despite regressions of great magnitude, it is obvious that there
were many failures of endocrine therapy to control the disease
but on the whole, the life span had been extended by the novel
treatments and there had been a decrease of man-pain hours.
 Stilbestrol, which had been discovered in 1938 by E. C. Dodds
et al. 15, was the first synthetic substance to control cancer;
hence the study of the prostate cancers was the start of
chemotherapy of malignant disease.
‫זולדקס‬
‫סופרפקט‬
‫דקהפפטיל‬
‫הציר ההורמונלי‬
‫‪LHRH‬‬
‫היפותלמוס‬
‫יותרת המוח‬
‫‪LH‬‬
‫טסטוסטרון‬
‫אבודרט‬
‫אשכים‬
‫סירוס‬
‫‪Adrenal‬‬
‫קטוקונזול‬
‫דיהידרוטסטוסטרון‬
‫גידול‬
‫בערמונית‬
‫קזודקס‬
‫התפתחות הטיפול התרופתי בסרטן‬
‫הערמונית‬
‫הארכת חיים עם פליאציה‬
‫הארכת חיים עם מינימום רעילות‬
‫ריפוי‬
‫הורדת רמת‬
‫הטסטוסטרון‬
‫כמותרפיה‬
‫‪Chemotherapy‬‬
‫פוסט‪-‬‬
‫כמותרפיה‬
‫טיפול מקומי‬
‫‪Tumor volume & activity‬‬
‫טיפולים לאחר‬
‫הורדת רמת‬
‫הטסטוסטרון‬
‫‪PSA‬‬
‫לא סימפטומטי‬
‫סימפטומטי‬
‫גרורתי‬
‫לא גרורתי‬
‫עמיד לסירוס‬
‫רגיש לסירוס‬
‫זמן‬
‫‪Grey Zone‬‬
‫טקסוטר‬
‫טיפול הורמונאלי (סירוס)‬
‫מרץ ‪2010‬‬
Abiraterone
Zytiga (Abiraterone)
 Mechanism of action
 Inhibits testosterone production in testis, adrenal glands, and prostate
CYP17
17α-hydroxylase
Pregnenolone
Progesterone
C17,20 lyase
17α-hydroxypregnenolone
17α-hydroxyprogesterone
Abiraterone
(steroidal)
DHEA
Androstenedione → Testosterone
Abiraterone (post-chemotherapy):
Efficacy outcomes of COU-AA-301 trial
Treatment
100
Abiraterone
15.8 mo
Placebo
11.2 mo
80
Overall survival (%)
Median OS
HR=0.74
Abiraterone+
prednisone
60
95% CI: 0.64-0.86
P<0.0001
Placebo+
prednisone
40
20
No.
at risk
ABI
PBO
0
6
12
18
24
30
797
398
657
306
473
183
273
100
15
6
0
0
Fizazi K et al. Lancet Oncol 2012;13:983-92
Time (mo)
Abiraterone (pre-chemotherapy):
Efficacy outcomes of COU-AA-302 trial
Treatment
Overall survival (%)
100
Abiraterone
35.3 mo
Placebo
30.1 mo
HR=0.79
Abiraterone+
prednisone
80
Median OS
95% CI: 0.66-0.95
P=0.0151*
Placebo+
prednisone
60
40
20
0
3
ABI 546 538
No.
at risk PBO 542 534
6
9
12
15
18
21
24
27
30
33
36
524
503
482
452
421 393
333
175
68
15
0
508
492
465
437
400 361
283
153
67
9
0
Rathkoph DE al. J Clin Oncol 2013;31(Suppl 6):abs. 5
Time (mo)
*pre-specified boundary of significance was not reached
Abiraterone (pre-chemotherapy):
Efficacy outcomes of COU-AA-302 trial
Patients without progression (%)
Treatment
100
Abiraterone
16.5 mo
Placebo
8.3 mo
HR=0.53
95% CI: 0.45-0.62
80
P<0.0001
Abiraterone
+prednisone
60
40
Placebo+
prednisone
20
0
No.
at risk
Median rPFS
3
6
9
12
15
18
21
24
27
30
ABI 546
485
389
311
240
195
157
131
117
66
20
PBO 542
406
244
176
133
99
78
62
45
20
7
Ryan CJ et al. N Engl J Med 2013;368:138-48
Time (mo)
Enzalutamide
Enzalutamide:
Mechanism of action and indication
 Mechanism of action
 androgen receptor (AR) signalling inhibitor
Enzalutamide
Inhibits nuclear
translocation of AR
2
Enzalutamide
Enzalutamide
1
3
AR
AR
Inhibits binding of
androgens to AR
Inhibits association
of AR with DNA
Cell
nucleu
s
Tumour death
Probability of Overalll Survival (%)
Enzalutamide (post-chemotherapy):
Efficacy outcomes of AFFIRM trial
No.
at risk
100
ENZ
PLB
80
Treatment
Median OS
Enzalutamide
18.4 mo
Placebo
13.6 mo
HR=0.63
95% CI: 0.53-0.75
P<0.001
Enzalutamide
60
Placebo
37% risk
reduction
40
20
0
0
3
6
9
12
15
18
21
24
800
399
775
376
701
317
627
263
400
167
211
81
72
33
7
3
0
0
Scher HI et al. N Engl J Med 2012;367:1187-97
Time (mo)
Radiographic PFS (secondary endpoint)

Radiographic PFS was significantly longer with enzalutamide compared
with placebo (8.3 vs. 2.9 months, respectively; p<0.001)
100
Survival (%)
80
Enzalutamide: 8.3 months
(95% CI: 8.2–9.1)
60
40
HR=0.40 (95% CI: 0.35–
0.47); p<0.001
20
Placebo: 2.9 months
(95% CI: 2.8–3.4)
0
No. at risk:
Enzalutamide, n=
Placebo, n=
0
3
6
800
399
583
176
447
86
9
12
15
Time to event (months)
287
86
140
20
58
7
18
21
24
13
3
1
0
0
0
Radiographic PFS defined on CT, MRI and bone scan according to RECIST 1.1 for soft tissue and Prostate Cancer Working
Group (PCGW2) for bone disease.
CI=confidence interval; CT=computed tomography; HR=hazard ratio; MRI=magnetic resonance imaging;
PFS=progression-free survival; RECIST=Response Evaluation Criteria In Solid Tumors guidelines.
De Bono J, et al. Presented at ASCO 2012; Oral presentation 4519.
HRQoL response rate
(secondary endpoint)
Significantly more enzalutamide-treated patients experienced an improvement in HRQoL
compared with placebo (43% vs. 18%; p<0.001)*
†
Enzalutamide (n=651)
60
54
Placebo (n=257)
Patients with improvement
(%)

50†
†
p<0.001
^ p=0.006
43
†
†
42
†
45
42
†
35
40
†
31
30
20
^
18
17
26
25
22
20
21
16
10
0
*Defined as a 10-point increase in score from baseline in FACT-P score; analysis includes all patients with baseline
and post-baseline assessments;
FACT-P=Functional Assessment of Cancer Therapy – Prostate; HRQoL=health-related quality of life;
PCS=Prostate Cancer Subscale; TOI=Trial Outcome Index; WB=well-being.
.Fizazi K, et al. Presented at ESMO 2012; Oral presentation 896O
17
Enzalutamide (pre-chemotherapy):
Efficacy outcomes of PREVAIL trial
Probability of Overalll Survival (%)
100
Median OS
Enzalutamide
32.4 mo
Placebo
30.2 mo
Enzalutamide
80
HR=0.71
95% CI: 0.60-0.84
P<0.0001
Placebo
60
40
29% risk
reduction
20
0
30
33
36 Time (mo)
ENZ 872 863 850 824 797 745 566 395 244 128 33
2
0
PBO 845 835 781 744 701 644 484 328 213 102 27
2
0
0
No.
at risk
Treatment
3
6
9
12
15
18
21
24
27
Radium-223
Radium-223:
Mechanism of action and indication
 Mechanism of action
 bone-seeking element, chemically similar to calcium
 induced double-strand DNA breaks in adjacent tumour cells by α-particles,
leading to highly localised tumour cell killing
Range of alpha-particle
Radium-223
Bone surface
 Indication
 in patients with symptomatic mCRPC, bone metastases and no known
visceral metastases
Radium-223:
ALSYMPCA study design
Double-blind, multi-centre, placebo-controlled phase III RCT 
N=921 patients 
symptomatic mCRPC 
≥2 bone metastases 
after docetaxel or chemo-naïve (ineligible for chemo) 
Received either radium-223 or placebo 
Primary efficacy endpoint 
OS 
Parker C et al. N Engl J Med 2013;369:213-23
Regulatory approvals
FDA: May 2013
EMA: November 2013
Radium-223:
Efficacy outcomes of ALSYMPCA trial
Treatment
Median OS
Radium-223*
14.9 mo
Placebo*
11.3 mo
HR=0.70
95% CI: 0.58-0.83
P=0.00007
Radium-223
Placebo
Time (mo)
No.
at risk
Ra-223
PBO
614
307
578 504 369
288 228 157
Parker C et al. N Engl J Med 2013;369:213-23
*administered with best standard of care
274
103
178
67
105
39
60
24
41
14
18
7
7
4
1
2
0
1
0
0
The T-cell antitumor response
2 Tumor antigens
presented to T cells
Tumor
cell
T cells are
3 activated and
proliferate
APC
Inactive
T cell
Tumor antigens
1 released by
tumor cells
Activated
T cell
Activated
T cell
‫חיסון‬
•Sipuleucel
•Prostvac
4
Tumor
cell
T cells recognize
tumor antigens
Tumor
cell
‫תרופות החדשות‬
5
T cells kill
tumor cells
Tumors use complex, overlapping mechanisms to
evade and suppress the immune system
1
Inhibition of tumor antigen presentation
e.g. down regulation of MHC I
APC
4
Recruitment of
immunosuppressive cell types
e.g. T-reg
2
Secretion of
immunosuppressive factors
Tumor
cell
e.g. TGF-ß
Activated
T cell
3
Inactive
T cell
MHC = major histocompatibility complex; TGF-ß = tumor growth factor-ß.
Drake CG, et al. Adv Immunol. 2006;90:51–81; Vesely MD, et al. Annu Rev Immunol. 2011;29:235–271.
Inhibition of attack by
immune cells
e.g. through T-cell
checkpoint pathways
Sipuleucel-T
Sipuleucel-T:
Mechanism of action and indication
 Mechanism of action:
 induces an immune response against prostatic acid phosphatase (PAP)
HARVEST
APCs FROM
PATIENT
PAP
antigen
AP
C
Recombinant PAP
antigen combines
with resting APC
APC takes up
the antigen
Antigen is processed
and presented on the
APC surface
Active
T-cell
T-cells proliferate and
attack cancer cells
INFUSE
BACK
INTO
PATIEN
T
Sipuleucel-T activates
T-cells in the body
 Indication
 Patients with asymptomatic (or minimally symptomatic) CRPC
Adapted from DeFrancesco L. Nat Biotechnology 2010;28:531-2 and www.dendreon.com
Fully activated,
the APC is now
sipuleucel-T
Efficacy results of IMPACT
study
Treatment
Probability of survival (%)
100
No.
SIP-T
at risk
PLB
Median OS
Sipuleucel-T
25.8 mo
Placebo
21.7 mo
80
HR=0.78
95% CI: 0.61-0.98
P=0.03
60
Sipuleucel-T
40
Placebo
20
0
12
24
36
48
60
341
274
129
49
14
1
171
123
55
19
4
1
Kantoff PW et al. N Engl J Med 2010;363:411–22
72
Time (mo)
Immune checkpoint inhibitors: mechanisms of action
Periphery
Tumour microenvironment
T-cell activation
Lymph Node
MHC
Dendritic
cell
B7
B7
(cytokines, lysis, proliferation,
migration to tumour)
TCR
+++
CD28
+++T cell
CTLA-4
MHC
PD-1
PD-L1
+ ++
T cell
---
---
Anti-CTLA-4
TCR
Tumour cell
Anti-PD-1/PD-L1
PD-1
PD-L2
--Anti-PD-1
CTLA-4 pathway blockade
Adapted from Wolchock J, et al. Presented at ASCO 2013 (abstr. 9012).
PD-1 pathway blockade
‫התפתחות הטיפול התרופתי בסרטן הערמונית‬
‫הארכת חיים עם פליאציה‬
‫הארכת חיים עם מינימום רעילות‬
‫ריפוי‬
‫הורדת רמת‬
‫הטסטוסטרון‬
‫כמותרפיה‬
‫‪Chemotherapy‬‬
‫פוסט‪-‬‬
‫כמותרפיה‬
‫טיפול מקומי‬
‫‪Tumor volume & activity‬‬
‫טיפולים לאחר‬
‫הורדת רמת‬
‫הטסטוסטרון‬
‫‪PSA‬‬
‫לא סימפטומטי‬
‫סימפטומטי‬
‫גרורתי‬
‫לא גרורתי‬
‫רגיש לסירוס‬
‫עמיד לסירוס‬
‫זמן‬
‫אבירטרון‬
‫‪MDV3100‬‬
‫ג'בטנה‬
‫רדיום ‪223‬‬
‫טקסוטר‬
‫‪XGEVA‬‬
‫‪Sipuleucel-T‬‬
‫‪Prostvac‬‬
‫אבירטרון‬
‫‪MDV3100‬‬
‫רדיום ‪223‬‬
‫טיפול הורמונאלי (סירוס)‬
‫מרץ ‪2012‬‬
‫אופציות הטיפול התרופתי בסרטן הערמונית‬
(2014 ‫העמיד לטיפול הורמונאלי )שנת‬
.1
Abiraterone
60%
Radium 223
15%
Taxotere
25%
.2
Radium 223 Taxotere
Taxotere
Abiraterone
Radium 223
Jevtana
.3
Taxotere
Jevtana
Taxotere
Jevtana
Radium
.4
Jevtana
Radium
Jevtana
Jevtana
2015 ‫סל‬
 Enzalutamide
 Firmagon
 expanded indication – Hormonal Naïve Pts
‫‪‬תודה רבה‬