Will Abiraterone replace LHRH Agonists?

Report
Castrate resistance prostate cancer:
Integrating novel agents into a
therapeutic algorithm
Charles J Ryan, MD
Associate Professor of Medicine and Urology
Helen Diller Family Comprehensive Cancer Center
University of California, San Francisco
1
U CSF
Since 2010…
• Four new drugs approved for advanced prostate
cancer by the US FDA
– Three based on improvements in survival (Cabazi,
Abiraterone, Sipuleucel T)
– (Initial phase I studies of abiraterone and Sip T done at
UCSF in GU Medical Oncology Program)
• Two Others- Alpharadin (Radium 223) and MDV3100 have shown OS Benefit in trials, FDA
approval not yet granted.
1. How do we define Castration Resistant Prostate Cancer?
500
ng/mL
50 ng/
mL
Testosterone
Progression of Disease despite
a suppressed (castrate)
testosterone level (<50ng/dL)
PSA
Castration
Therapy
Castration Resistance
5
2. What makes prostate cancer lethal and how do we assess
prognosis in patients?
500
ng/mL
50 ng/
mL
+
Testosterone
PSA
Castration
Therapy
Castration Resistance
5
=
Lethal Prostate
cancer
Prostate Cancer
Standards and Novel Therapies:
Clinically
Localized
Rising PSA
post RP/RT
ADT Resistant
Pre-Chemotherapy
Chemotherapy
CRPC
Docetaxel
Resistant
AR Targeted
Therapy
Chemotherapy
Immunotherapy
Targeted Therapy
UCSF
Prostate Cancer
Standards and Novel Therapies: 2009
Clinically
Localized
Rising PSA
post RP/RT
ADT Resistant
Pre-Chemotherapy
Chemotherapy
CRPC
Docetaxel
Resistant
AR Targeted
Therapy
Docetaxel
(Standard)
Chemotherapy
Immunotherapy
Targeted Therapy
Therapies showing a survival benefit
UCSF
New Treatments for Advanced Prostate Cancer
Targeting the T Cell
Androgen Synthesis Inhibitors
Second line chemotherapy
Alpha-emitting Radio-isotopes
UCSF
New Treatments for Advanced Prostate Cancer
Targeting the T Cell
UCSF
Theoretical Kinetics of Treatment Response:
Cytotoxic Therapy vs Immunotherapy
 Cytotoxic chemotherapy quickly
debulks tumors
Time on
treatment
– Resistance and tumor
regrowth may occur
Chemotherapy
– Clinical effect may take
time to develop
– Responses may be
sustained due to
immunologic memory
Tumor size
 Immunotherapy activates the
immune system
Progression
Immunotherapy
Time
Webster et al. J Clin Oncol. 2005;23:8262.
Sipuleucel-T: Background
APC8015
Precursor
APC
Sip-T
Antigen
Processing
Antigen-loaded
precursor APC
20
Maturing antigenloaded APC
PSA (ng/mL)
Antigen
Loading
s
Infuse
patient
15
10
5
0
T cells attack
tumor cells
In vivo
T cell activation
-10
0
10
20
Week
Small EJ et al., J Clin Oncol 18: 3894, 2000
30
Sipuleucel-T : (second) Pivotal Trial Results
Phase 3 design allowed for
crossover from placebo to vaccine
Adverse Events
PROVENGE
(n=338)
Adverse event
†
†
Control
(n=168)
All Grades
(%)
Grades 3–5
(%)
All Grades
(%)
Grades 3–5
(%)
Chills
54.1
1.2
12.5
0
Fever (pyrexia)
29.3
0.3
13.7
1.8
Headache
16.0
0.3
4.8
0
Influenza-like illness
9.8
0
3.6
0
Myalgia
9.8
0.6
4.8
0
Hypertension
7.4
0.6
3.0
0
Hyperhidrosis
5.3
0
0.6
0
Groin pain
5.0
0
2.4
0
• Primary endpoint: Overall survival1,2
• Secondary endpoint: Objective disease progression2
†Control
was nonactivated, autologous, peripheral blood mononuclear cells.
Kantoff PW et al. N Engl J Med. 2010;363:411-422.
UCSF
Sipuleucel-T in CRPC: How do we use it?
•
Sipuleucel-T prolongs life in patients with asymptomatic met CRPC
•
Sipuleucel-T is extremely well tolerated
•
For use only in asymptomatic CRPC with no visceral mets
•
Not remission inducing
•
My bias – use it early before advancing to prednisone-containing
regimens (abiraterone, docetaxel, cabazitaxel, mitoxantrone all require
steroids)
UCSF
FDA Approves Sipuleucel-T on April 29, 2010
You +1‘d
UCSF
New Treatments for Advanced Prostate Cancer
CYP-17 Inhibitors
UCSF
Keeping our eyes on the AR target……
“Despite regressions of great
magnitude, it is obvious that
there are many failures of
endocrine therapy to control
the disease.”
Charles Huggins MD
Nobel Lecture
Dec 13, 1966
Journal of Clinical Oncology 1997
Small and Vogelzang define
“secondary hormonal therapy”
Matching Biology to Therapy along the Path to AR signaling
Signaling Event
Pre -Receptor
Androgen
Production
Androgen
Transport/Ci
rculation/Up
take
Receptor
Conversion
to DHT
AR
Binding
Aberration
Intervention
Drugs
Intracrine
Production
SCC Inhibitors
CYP 17
Inihibitors
Ketoconazole Abiraterone
Tak-700
Tok-001
Polymorphisms
Block Transport
None
Amplified 5 Alpha
Reductase
Amplified AR
Splice Variant AR
5-Alpha
Reductase
inhibitors
Novel AR
Inhibitors
Dutasteride
MDV-3100
ARN-509
Tok-001
From Ryan and Tindall JCO 2011
Higher AR levels in CRPC tumors
CRPC samples have
robust AR expression
Mohler et al
AR expression in
Bone Marrow Mets
Stanbrough et al
Cancer Research
2006
Holzberlein et al Am J
Pathology
At autopsy – 73% of 15
samples exhibit AR
amplification.
Friedlander/Paris et al
17
UC
SF
Prostate Cancer can make its own
androgens
0
-5
P<0.0001
P=0.0091
-10
-15
-20
-25
BP
CP METS
3BHSD1
0
-5
BP
CP METS
3BHSD2
P=0.0005
-10
-15
-20
-25
BP
CP METS
CYP17A
5
0
-5
P<0.0001
P=0.0026
-10
-15
-20
BP
CP METS
AKR1C3
5
0
BP
CP METS
17BHSD3
P=0.0050
P=0.0004
-5
-10
-15
-20
BP
CP METS
SRD5A1
BP
CP METS
SRD5A2
P=0.0013
0
-5
-10
P=0.0031
-15
-20
-25
BP
CP METS
UGT2B15
Montgomery RB et alCancer Res.
2008 Jun 1;68(11):4447-54
BP
CP METS
UGT2B17
1.
Transcripts encoding steroidogenic enzymes are
detected within tumor
2.
Tumor androgens in CRPC metastases from anorchid
patients exceed levels in prostate cancer tissues from
eugonadal subjects
3.
These may be particularly relevant for tumors with
overexpressed AR
Abiraterone: Provides durable androgen
suppression
Abiraterone - no rise in
Androgens at PD.
Ketoconazole – Androgens
Rise at PD
Androgens during Rx with Ketoconazole (CALGB 9583)
1.2
Change from Baseline
1
DHEAS
0.8
DHEAS
0.6
Androstenedione
0.4
0.2
0
Baseline
Month 1
Progresion
TEST
Small et al JCO 2004
Ryan et al JCO 2010
UCSF
COU-AA-301: Abiraterone Acetate Improves
Overall Survival in post chemotherapy mCRPC
Abiraterone acetate: 14.8 months
100
80
HR = 0.646 (0.54-0.77)
P < 0.0001
Survival (%)
60
40
Placebo: 10.9 months
20
AA
Placebo
0
0
100
200
300
400
500
600
700
Days From Randomization
AA
797
728
631
475
204
25
0
Placebo
398
352
296
180
69
8
1
UC20SF
Survival Benefit Consistently
Observed Across Patient Subgroups
Variable
Subgroup
N
HR
95% CI
All subjects
All
1195
0.66
0.56–0.79
Baseline ECOG
0–1
1068
0.64
0.53–0.78
2
127
0.81
0.53–1.24
<4
659
0.64
0.50–0.82
4
536
0.68
0.53–0.85
1
833
0.63
0.51–0.78
2
362
0.74
0.55–0.99
PSA only
363
0.59
0.42–0.82
Radiographic
832
0.69
0.56–0.84
Baseline PSA above median
YES
591
0.65
0.52–0.81
Visceral disease at entry
YES
709
0.60
0.48–0.74
Baseline LDH above median
YES
581
0.71
0.58–0.88
Baseline ALK-P above median
YES
587
0.60
0.48–0.74
North America
652
0.64
0.51–0.80
Other
543
0.69
0.54–0.90
Baseline BPI
No. of prior chemo regimens
Type of progression
Region
Favors
AA
ALK-P, alkaline phosphatase
0.5 0.75
1
1.5
Favors
placebo
de Bono et al. N Engl J Med. 2011;364:21.
UCSF Study: Abiraterone Provides Durable and Complete
Responses in the chemotherapy naïve setting
Baseline
Ryan et al CCR 2011
Post Cycle 6
Response
n (%)
PSA Decline ≥30%
27/31 (87.1)
PSA Decline ≥50%
26/31 (83.9)
PSA Decline ≥90%
13/31 (41.9)
Undetectable PSA (≤0.1)
2/31 (6.0%)
UCSF
COU-AA-302: Does Abiraterone Improve Survival in its
physiologic space (pre-chemotherapy mCRPC)?
Progressive Prostate Cancer
WITHOUT prior Docetaxel
based chemotherapy
RANDOMIZE
•
Arm A
•Abiraterone plus
Prednisone
Arm B
Placebo plus Prednisone
Endpoints – PFS, Overall Survival
UCSF
Abiraterone in CRPC: How do we use it?
•
Abiraterone prolongs life in patients with met CRPC post chemotherapy
•
Does benefit translate into the pre-chemotherapy setting?
•
Can it be combined with other therapies? Should it be continued after
disease progression?
•
What are the mechanisms of resistance?
–
–
–
–
Pharmaco-kinetic?
Pharmaco-genomic?
Alternate signaling paths?
AR mediated progression?
UCSF
MDV3100
• Second-generation AR antagonist
• Binds AR more potently than does bicalutamide
• Not a partial agonist of AR
• Inhibits translocation of AR into nucleus and decreases
AR binding to DNA
• Oral agent; 160 mg daily (seizures at higher doses)
• Compared with placebo in ongoing randomized phase
3 trial (post-chemotherapy, ketoconazole-naïve)
Tran et al. Science. 2009;324(5928):787-790. Clinicaltrials.gov. NCT00974311. Accessed December
28, 2010. Scher et al. Lancet. 2010;375(9724):1437-1446.
MDV3100: Phase 1/2 Study Radiographic
Responses
No prior
chemotherapy
Total
Prior
chemotherapy
59
25
34
Partial response
13 (22%; 13%-35%)
9 (36%; 19%-57%)
4 (12%; 4%-28%)
Stable disease
29 (49%; 36%-62%)
11 (44%; 25%-65%)
18 (53%; 30%-70%)
109
41
68
61 (56%; 46%-65%)
26 (63%; 47%-77%)
35 (51%; 39%-64%)
22
12
10
≥25% ↓ from baseline
10 (45%; 25%-67%)
4 (33%; 11%-65%)
6 (60%; 27%-86%)
<25% ↓ from baseline
12 (55%; 33%-75%)
8 (67%; 35%-89%)
4 (40%;14%-73%)
Soft tissue
Bone scan (week 12)
Stable disease
FDG-PET (week 12)
MDV3100 induced >50% PSA declines in 56% of mCRPC patients, including those were
prechemotherapy (n = 65) and postchemotherapy (n = 75).
.FDG-PET, 2-¹⁸F-fl uoro-2-deoxy-D-glucose positron emission tomography.
Scher et al. Lancet. 2010;375(9724):1437-1446.
MDV-3100
Time to PSA Progression
Scher HI et al. Lancet. 2010;375:1437.
MDV3100: Phase 3 Trial (AFFIRM)
POSITIVE
N = 1170
Men with
docetaxelpretreated
mCRPC (ketonaïve)
R
A
N
D
O
M
I
Z
E
2
MDV3100 160 mg once daily +
prednisone 5 mg twice daily
1
Placebo once daily +
prednisone 5 mg twice daily
Primary objective: OS
Clinicaltrials.gov. NCT00974311. Accessed December 28, 2010.
MDV-3100 And Abiraterone both
extend survival post-docetaxel
Placebo
MDV-3100
P value
Overall
Survival
13.6 mo
18.4 mo
<0.001
Rx Duration
3.0 mo
8.3 mo
<0.001
Soft Tissue
resp
8.3%
2.9%
<0.001
Subsequent
therapy
-Abiraterone
-Cabazitaxel
24.3%
12%
21%
14%
*Seizures
0.6% (5cases)
0
Scher-Proc ASCO GU 2012 San Francisco 2/2/2012
New Treatments for Advanced Prostate Cancer
Second Line Chemotherapy
UCSF
SeSecond Line Chemotherapy
•CRPC patients inevitably progress following Docetaxel treatment1-5
•Despite Many studies (6,7,8):
– There has been no data showing that we can improve survival with second line
chemotherapy
– UCSF led early studies of second line chemotherapy (Rosenberg, Harzstark)
and helped establish this the estimates for survival and response in this
setting.
1. Petrylak DP, et al. N Engl J Med. 2004;351(15):1513-1520.
2. Tannock IF, et al. N Engl J Med. 2004;351(15):1502-1512.
3. Oudard S, et al. J Clin Oncol. 2005;23(15):3343-3351.
4. Nelius T, et al. BJU Int. 2006;98(3):580-585.
5. Nelius T, et al. Onkologie. 2005;28(11):573-578.
6. Garmey EG, et al. Clin Adv Hematol Oncol. 2008;6(2):118-132.
7. Rosenberg JE, et al. Cancer. 2007;110(3):556-563.
8. Sternberg CN, et al. J Clin Oncol. 2009;27(32):5431-5438.
Two Different Chemical Entities
Docetaxel
(C43H53NO14)
Docetaxel is an esterified product
of 10-deacetyl baccatin III
Cabazitaxel (XRP6258)
(C45H57NO14)
Cabazitaxel is a 7,10 dimethoxy
analogue of docetaxel
Mita AC, et al. Clin Cancer Res 2009;15:723-730; Ojima I, et al. J Med Chem 1996;39:3889-3896; Greenberger LM,
Sampath D. Resistance to taxanes. In: Teicher BA, ed. Cancer Drug Discovery and Development: Cancer Drug
Resistance. Totowa, New Jersey: Humana Press; 2006:329-358; Raub TJ. Mol Pharm 2005;3:3-25; www.Taxotere.com.
The TROPIC study: cabazitaxel or mitoxantrone with prednisone in patients
with metastatic CRPC previously treated with docetaxel (De Bono et al)
Men with metastatic CRPC
progressing during and after
docetaxel
(N=755)
R
A
N
D
O
M
I
Z
E
Cabazitaxel 25 mg/m² q 3 wk
+ prednisone for 10 courses (CBZP,
n=378)
Mitoxantrone 12 mg/m² q 3 wk
+ prednisone for 10 courses (MP,
n=377)
Primary objective: Overall survival
Secondary objectives: PFS (tumor progression, pain progression, PSA
progression, or death from any cause), response rate, safety
UCSF
Primary Endpoint (Overall Survival) Met
100
Median OS (months)
Hazard ratio
Proportion of OS (%)
80
MP
CBZP
12.7
15.1
0.72
95% CI
0.61–0.84
P-value
<.0001
60
40
Censored
MP
CBZP
20
Combined median
follow-up: 13.7 months
0
0
6
12
18
24
30
Time (months)
UCSF
3
7
Summary of Hematologic AEs
Hematologic AEsa
Neutropeniab
Febrile neutropenia
a In
JEVTANA® 25 mg/m² q 3 wk
+ prednisone 10 mg qd (n=371)
mitoxantrone 12 mg/m² q 3 wk
+ prednisone 10 mg qd (n=371)
Grade 1–4, n (%) Grade 3–4, n (%) Grade 1–4, n (%) Grade 3–4, n (%)
347 (94%)
303 (82%)
325 (87%)
215 (58%)
27 (7%)
27 (7%)
5 (1%)
5 (1%)
Anemiab
Leukopeniab
361 (98%)
355 (96%)
39 (11%)
253 (69%)
302 (82%)
343 (93%)
18 (5%)
157 (42%)
Thrombocytopeniab
176 (48%)
15 (4%)
160 (43%)
6 (2%)
≥5% of patients.
on laboratory values: JEVTANA® (n=369), mitoxantrone (n=370).
b Based
• Protocol did not permit primary prophylaxis with granulocyte colony-stimulating
factor (G-CSF) at cycle 1
JEVTANA® Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010.
Data on file. Clinical study report/EFC6193 (TROPIC).
Cabazetaxel: How do we use it?
1. Cabazitaxel significantly improved survival when
compared to mitoxantrone, in patients with metastatic
CRPC who had received prior docetaxel.
2. It may prolong sensitivity to taxane chemotherapy in
patients with acquired docetaxel resistance
3. Its use in the overtly taxane refractory patient may be
limited
UCSF
Cabazitaxel: Where do we go?
1. As an incremental step forward, it merits testing as front line chemotherapy
2. Combination studies are also warranted.
3. As before, a study of the mechanisms of resistance to this therapy are
warranted. (Friedlander/Paris project)
4. FDA mandated 25mg/m2 vs 20 mg/m2 study.
UCSF
XL184: Cabozantanib
XLOral Multi-targeted TKI
RET
MET
VEGFR2
KIT
3.8 nM
1.8 nM
0.035 nM
4.6 nM
How do we use it?
Where do we go?
Stay tuned….
New Treatments for Advanced Prostate Cancer
Radium 223
UCSF
Radium-223 Targets Bone
Metastases
• Radium-223
acts as a
calcium mimic
• Naturally
targets new
bone growth in
and around
bone
metastases
• Radium-223 is
excreted by the
small intestine
Ca
Ra
Radium-223 Targets Bone
Metastases
Range of alpha-particle
Radium-223
Bone surface
• Alpha-particles induce double-strand DNA breaks in adjacent
tumour cells1
– Short penetration of alpha emitters (2-10 cell diameters) =
highly localised tumour cell killing and minimal damage to
surrounding normal tissue
1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams &
Wilkins; 2007:103.
ALSYMPCA (ALpharadin in
SYMptomatic Prostate CAncer)
Phase III Study Design
TREATMENT
PATIENTS
STRATIFICATION
• Confirmed
symptomatic
CRPC
• ≥ 2 bone
metastases
• No known
visceral
metastases
• Total ALP:
< 220 U/L vs ≥ 220 U/L
• Bisphosphonate use:
Yes vs No
• Prior docetaxel:
Yes vs No
• Post-docetaxel
or unfit for
docetaxel
R
A
N
D
O
M
I
S
E
D
2:1
N = 922
Planned follow-up is 3 years
Clinicaltrials.gov identifier: NCT00699751.
6 injections at
4-week intervals
Radium-223 (50 kBq/kg)
+ Best standard of care
Placebo (saline)
+ Best standard of care
ALSYMPCA Patient Demographics and
Baseline Characteristics (ITT; N = 809)
Radium-223
(n = 541)
Placebo
(n = 268)
70.2
70.7
Race, n (%)
Caucasian
507 (94)
252 (94)
Baseline ECOG score, n (%)
≤1
2
467 (86)
71 (13)
229 (85)
37 (14)
Extent of disease, n (%)
< 6 metastases
6-20 metastases
> 20 metastases/superscan
88 (16)
235 (44)
217 (40)
33 (12)
129 (48)
106 (40)
WHO ladder,
cancer pain index ≥ 2, n (%)
294 (54)
142 (53)
Parameter
Age, y
Mean
ALSYMPCA Patient Baseline
Characteristics, cont (ITT; N = 809)
Parameter
Median (min, max)
Radium-223
(n = 541)
Placebo
(n = 268)
Haemoglobin, g/dL
12.2
(8.5-15.7)
12.1
(8.4-16.4)
40
(24-53)
40
(23-50)
Total ALP, µg/L
213
(32-4661)
224
(29-3225)
LDH, U/L
317
(76-2171)
328
(132-3856)
PSA, µg/L
159
(3.78-6026)
195
(1.5-14500)
Albumin, g/L
ALSYMPCA Overall Survival
100
HR 0.695; 95% CI, 0.552-0.875
P = 0.00185
90
80
70
60
%
Radium-223, n = 541
Median OS: 14.0 months
50
40
30
Placebo, n = 268
Median OS: 11.2 months
20
10
0
Month
Radium- 223
Placebo
0
3
6
9
12
15
18
21
24
27
541
268
450
218
330
147
213
89
120
49
72
28
30
15
15
7
3
3
0
0
The Future – My predictions
1. Oral, Well tolerated therapies will extend the option of treatment for m
CRPC to more patients than previous….(only about 50% of CRPC pts
get docetaxel)
2. Prostate cancer will become a model for ( or a victim of ?) cost
effectiveness research.
3. Management of CRPC will be done by those most capable of
understanding biology and the integration of therapies – no matter
what their prior training.
4. Combined oral therapies will push therapy and survival further – e.g
with better survival more patients will be available for therapy (“If you
build it, they will come”)_
5. New targeted therapies will need to be developed in conjunction with
biomarkers that predict response (e.g. Her 2  trastuzumab in breast
cancer)
UCSF
Thank You
UCSF

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