Transcript Placebo - The Prostate Net

MANAGEMENT PROTOCOLS
FOR ADVANCED PROSTATE
CANCER:
Walter Stadler, MD, FACP
University of Chicago
Disclosures
•
(All Non-University &/or Financial Dealings with
Potential, Real, or Perceived Conflicts of Interest)
Consultant:
– Novartis, Pfizer/Wyeth, GSK, Roche/Genentech, Takeda, Caremark/CVS,
Aveo, Ligand Pharmaceuticals, NCI/SAIC-Frederick
• Speakers Bureau:
– CME providers (sponsorship unknown): Imedex, CME Innovations, Researchto-Practice, NOCR, Clinical Care Options, Medical Communications Media,
– Pfizer, Bayer
• Grant/Research Support:
– Active Biotech, Bayer, Bristol-Myers-Squibb, Boerhinger-Ingelheim, Novartis,
Genentech (Roche), Glaxo-Smith-Kline, Medivation, Solvay (Abbott), Pfizer,
ImClone (Lilly), Amgen, Takeda (Millenium), NIH, CALGB
• Stockholder:
– Abbott (Spouse)
• Expert Witness
– None
• Miscellaneous:
– Kidney Cancer Assoc, Bladder Cancer Advocacy Network, Up-To-Date,
NexCura, Demos Medical Publishing
Castrate Resistant Disease
• Not really “hormone refractory”
• AR still a relevant target
• Other potential targets
– Immune system
– DNA and DNA repair
• Mechanisms of castrate resistance
–
–
–
–
–
AR amplification
AR mutation
AR modification
Ligand availability
AR interactions
AR Activation in Castrate Patients
Scher and Sawyers, JCO, 2005
What we know…
•
Prostate cancer requires AR signaling for
development and sustenance.
•
AR activation is required throughout the natural history
of prostate cancer.
•
AR activation in CRPC occurs via many mechanisms.
•
Successful blockade of the receptor pathways will
confer greater therapeutic control on metastatic
prostate cancer.
Abiraterone/TAK-700
Abiraterone Phase II
Attard JCO 2009
Pre-Chemo
Ryan ASCO 2009
Danila ASCO 2009
Post-Chemo
Reid ASCO 2009
COU-AA-301 Study Design
Patients
• 1195 patients with
progressive mCRPC
• Failed 1 or
2 chemotherapy
regimens, one of
which contained
docetaxel
R
A
N
D
O
M
I
Z
E
D
2:1
•
•
Abiraterone 1000 mg daily
Prednisone 5 mg BID
n=797
Efficacy endpoints (ITT)
Primary end point
• OS (25% improvement; HR
0.8)
Secondary endpoints (ITT)
Placebo daily
Prednisone 5 mg BID
n=398
• TTPP
• PFS
• PSA response
Phase III, multinational, multicenter, randomized, double-blind, placebo-controlled
study (147 sites in 13 countries; USA, Europe, Australia, Canada)
Stratification according to
–
–
–
–
ECOG performance status (0-1 vs 2)
Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs 4-10 [present])
Prior chemotherapy (1 vs 2)
Type of progression (PSA only vs radiographic progression with or without PSA progression)
Abbreviations: BPI=Brief Pain Inventory; TTPP=time to PSA progression; ITT=intent to treat;
mCRPC=metastatic castrate-resistant prostate cancer.
Source: Clinicaltrials.gov identifier: NCT00638690.
COU-AA-301 Patient Disposition
Abiraterone
(n=797)
Placebo
(n=398)
791
394
8 (1-21)
4 (1-21)
Treatment ongoing, n (%)
222 (28.1)
54 (13.7)
Treatment discontinued, n (%)
569 (71.9)
340 (86.3)
Subjects treated
Median number of cycles of
therapy (range)
COU-AA-301 Baseline Demographics
Abiraterone
(n=797)
69.0
(42-95)
Placebo
(n=398)
69.0
(39-90)
Total
(n=1195)
69.0
(39-95)
White
93.3
92.7
93.1
Black
3.5
3.8
3.6
Asian
1.4
2.3
1.7
ECOG PS 2, %
10.7
11.1
10.8
Significant pain present, %
44.3
44.0
44.2
2 Prior chemotherapies, %
28.2
28.4
28.3
Median age, years
(range)
Race, %
COU-AA-301 Baseline
Disease Characteristics
Abiraterone
(n=797)
Placebo
(n=398)
Bone
89.2
90.4
Node
45.4
41.5
Liver
11.3
7.6
Lung
13.0
11.4
Primary site of disease, %
COU-AA-301: Abiraterone Acetate
Improves OS in mCRPC
100
HR=0.646 (0.54-0.77) P <0.0001
Abiraterone: 14.8 months
(95% CI: 14.1, 15.4)
Overall Survival, %
80
60
40
Placebo: 10.9 months
(95% CI: 10.2, 12.0)
20
1 Prior Chemo OS:
15.4 months abiraterone vs 11.5 months placebo
0
0
100
200
300
500
400
Days from Randomization
600
Abiraterone
797
728
631
475
204
25
0
Placebo
398
352
296
180
69
8
1
700
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
0.5 0.75
Abbreviations: HR=hazard ratio;
ALK-P=alkaline phosphatase.
Favors
Abiraterone
1
1.5
Favors
Placebo
COU-AA-301: Secondary End Points
Achieved Statistical Significance
Abiraterone
(n=797)
Placebo
(n=398)
HR
(95% CI)
P Value
TTPP, mo
10.2
6.6
0.58
(0.46, 0.73)
<0.0001
rPFS, mo
5.6
3.6
0.67
(0.59, 0.78)
<0.0001
38.0
10.1
PSA response rate
(>50% reduction), %
Total
<0.0001
COU-AA-301: Summary of AEs
Abiraterone
(n=791)
Placebo
(n=394)
All Grades
Grades 3/4
All Grades
Grades 3/4
All treatment-emergent AEs, %
98.9
54.5
99.0
58.4
Serious AEs, %
37.5
32.1
41.4
35.3
AEs leading to discontinuation, %
18.7
10.5
22.8
13.5
Deaths within 30 days of last dose, %
10.5
13.2
Underlying disease
7.5
9.9
Other specified cause
2.9
3.3
0
0
Drug-related AEs
COU-AA-301: AEs of Special Interest
Abiraterone
(n=791)
Placebo
(n=394)
All Grades
Grades 3/4
All Grades
Grades 3/4
Fluid retention
30.5
2.3
22.3
1.0
Hypokalemia
17.1
3.8
8.4
0.8
LFT abnormalities
10.4
3.5
8.1
3.0
Hypertension
9.7
1.3
7.9
0.3
Cardiac disorders
13.3
4.1
10.4
2.3
AE, %
Novel More Potent AR Antagonists
• BMS-641988 (development discontinued)
• ARN-509 : in phase 1/2
• MDV3100
– Phase I/II trial
– Phase III trial initiated (docetaxel refractory)
60 mg
(n=22)
150 mg
(n=23)
2 pt off study
<12 wk
3 pt off
study
<12 wk
240 mg
(n=28)
7 pt off study
<12 wk
Scher, et al,
ASCO 2009
Castrate Resistant Disease
Non-Hormonal Treatment Options
• Good prognosis (asymptomatic, “low
volume”)
– Standard docetaxel chemotherapy
– ? Immunotherapy (Provenge, sipuleucel-T)
– Investigational therapy
• Poor prognosis
– Standard docetaxel chemotherapy
– Standard cabazitaxel
– Investigational chemotherapy combinations
Sipuleucel-T: Autologous APCs
Cultured with Antigen Fusion
Protein
Recombinant Prostatic
Acid Phosphatase
(PAP) fusion antigen
combines with resting
antigen presenting cell
(APC)
APC takes up
the antigen
Antigen is
processed and
presented on
surface of the APC
Fully activated, the
APC is now
sipuleucel-T
INFUSE PATIENT
Inactive
T-cell
Active
T-cell
T-cells proliferate
and attack
cancer cells
sipuleucel-T
activates T-cells
in the body
The precise mechanism of sipuleucel-T in prostate cancer has not been established.
23
Sipuleucel-T: Logistics of Therapy
Day 1
Leukapheresis
Apheresis Center
Day 2-3
sipuleucel-T is manufactured
Central Processing
Day 3-4
Patient is infused
Doctor’s Office
COMPLETE COURSE OF THERAPY:
Weeks 0, 2, 4
24
Randomized Phase 3 IMPACT
Trial
(IMmunotherapy Prostate AdenoCarcinoma
Treatment)
Asymptomatic or
Minimally
Symptomatic
Metastatic
Castration
Resistant
Prostate Cancer
(N=512)
Sipuleucel-T
Q 2 weeks x 3
2:1
Placebo
Q 2 weeks x 3
P
R
O
G
R
E
S
S
I
O
N
Treated at
Physician
Discretion
S
U
R
V
I
V
A
L
Treated at
Physician
Discretion
and/or Salvage
Protocol
Primary Endpoint: Overall Survival
Secondary Endpoint: Objective Disease Progression
25
IMPACT Overall Survival
Final Analysis (349 events)
36.5 mo median f/u
HR = 0.759 (95% CI: 0.606, 0.951)
p = 0.017 (Cox model)
Sipuleucel-T (n = 341)
Median Survival: 25.8 mo.
36 mo. survival: 32.1%
Placebo (n = 171)
Median Survival: 21.7 mo.
36 mo. survival: 23.0%
No. at Risk
Sipuleucel-T
Placebo
341
171
274
123
142
59
56
22
18
5
3
2
26
Adverse Events More Commonly1
Reported in Sipuleucel-T Group
Preferred Term
Chills
Pyrexia
Headache
Influenza-Like Illness
Myalgia
Hypertension
Hyperhidrosis
Groin Pain
Sipuleucel-T
N = 338
%
54.1
29.3
16.0
9.8
9.8
7.4
5.3
5.0
Placebo
N = 168
%
12.5
13.7
4.8
3.6
4.8
3.0
0.6
2.4
1 Reported
by ≥ 5% of sipuleucel-T patients and having a ≥ 2-fold difference from placebo.
The majority of the most common AEs were mild or moderate in severity.
Safety results obtained from primary analysis did not substantively change with additional
data obtained after study closure.
27
Challenges
• Why no effect on prostate cancer progression?
– Ability to measure disease progression sucks
– Something “bad” happened in control group
– Something “good” happened in treated group that is
unrelated to cancer
– Important: no effect on symptoms
• Cost
– $93,000 not include all apheresis and infusion costs
• Logistics
– Limited apheresis capacity
– Limited processing capacity
Other Immune Therapy Approaches
• Anti-CTLA4: Ipilimumab
– “Turn off the brake”
• Potential for severe auto-immune disease
• Auto-immune diarrhea
• Anti-tumor activity in phase II trials
– Castrate/Docetaxel resistant pts:
• Phase II External beam RT ± ipilimumab
• Based on possible immune enhancing effects of RT
– Castrate resistant pre-chemo pts:
• Placebo vs Ipilimumab
Other Immune Therapy Approaches (2)
• A true vaccine: PSA-TRICOM
– “Prime” and “boost” vaccinations
– Castrate/Docetaxel resistant patients
– Quadramet ± PSA-TRICOM
How do we Measure “Immune
Activation”
• Ongoing blood collection study to:
– Analytically validate HMBG1 in serum as
marker of “danger signal”
– Analyze serum antibodies to identify new
immune targets
– Store serum for evaluating other possible
biomarkers
CABAZITAXEL PHASE III
mCRPC patients who progressed during
and after treatment with a docetaxel-based
regimen
(N=755)
Stratification factors
ECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease
cabazitaxel 25 mg/m² q 3 wk
+ prednisone* for 10 cycles
(n=378)
mitoxantrone 12 mg/m² q 3 wk
+ prednisone* for 10 cycles
(n=377)
*Oral prednisone/prednisolone: 10 mg daily.
Primary endpoint: OS
Secondary endpoints: Progression-free
survival (PFS), response rate, and safety
32
Inclusion: Patients with measurable
disease must have progressed by
RECIST; otherwise must have had new
lesions or PSA progression
Summary of Demographics and
Patient Characteristics
Age
Median (years)
≥65 (%)
ECOG PS (%)
0, 1
2
PSA (ng/mL)
Median
Measurability of disease (%)
Measurable disease
Non-measurable disease
Disease Site (%)
Bone
Lymph node
Visceral
PSA: Prostate-specific antigen.
33
MP (n=377)
CBZP (n=378)
67.0
57.0
68.0
64.9
91.2
8.8
92.6
7.4
127.5
143.9
54.1
45.9
53.2
46.8
87.0
44.8
24.9
80.2
45.0
24.9
Primary Endpoint: Overall Survival
Proportion 100
of OS (%)
MP
12.7
15.1
0.70
0.59–0.83
<.0001
Median OS
(months)
Hazard Ratio
95% CI
P-value
80
CBZP
60
40
20
0
0 months
Number
at risk
34
MP
CBZP
377
378
6 months
12 months
18 months
24 months
30 months
300
321
188
231
67
90
11
28
1
4
Most Frequent Grade ≥3 TreatmentEmergent AEs*
MP (n=371)
All grades (%) Grade ≥3 (%)
Any adverse event
CBZP (n=371)
All grades (%) Grade ≥3 (%)
88.4
39.4
95.7
57.4
Febrile neutropenia
1.3
1.3
7.5
7.5
Diarrhea
10.5
0.3
46.6
6.2
Fatigue
27.5
3
36.7
4.9
Asthenia
12.4
2.4
20.5
4.6
Back pain
12.1
3
16.2
3.8
Nausea
22.9
0.3
34.2
1.9
Vomiting
10.2
0
22.6
1.9
Hematuria
3.8
0.5
16.7
1.9
Abdominal pain
3.5
0
11.6
1.9
*Sorted by decreasing frequency of events grade ≥3 in the CBZP arm.
35
Total Deaths During Study
Safety Population
MP (n=371)
CBZP (n=371)
Total deaths during study
275 (74.1%)
227 (61.2%)
Due to progression
253 (68.2%)
197 (53.1%)
Due to AEs
7 (1.9%)
18 (4.9%)
Due to other reasons
15 (4.0%)
12 (3.2%)
FDA Mandated studies
• 25 mg/m2 vs 20 mg/m2 in docetaxel resistant pts
• Cabazitaxel vs Docetaxel in chemotherapy naïve pts
36
Hussain, et al: Cabozantinib (abstract 4516)
PR or CR
12-Week
Lead-In Stage:
Open-Label
Cabozantinib
100 mg PO,
QD
Week 12
SD
Tumor
Staging
PD
Open-Label
Extension
Cabozantinib
Blinded
Randomized Stage
Cabozantinib vs.
Placebo (1:1)
Discontinue
Cabozantinib
Discontinue
Cabozantinib
Unblind at
Progression
Placebo
Cross-Over
to Cabozantinib
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease
(per mRECIST 1.0)
mCRPC Patient Disposition
Enrolled: N = 171
Randomization was suspended after
122 patients because of early clinical benefit
Open-Label Extension
≥ Week 12a
n = 79 (46%)
Randomized
at Week 12
n = 31 (18%)
Off Study Treatment
≤ Week 12
n = 61 (36%)
Active
52
Active
4
Disease
Progression
28 (16%)
Discontinued
27
Discontinued
13
Adverse Event
25 (15%)
Cross-over to
Cabozantinib
14
a Includes
Death
1 (1%)
Otherb
7 (4%)
patients with SD at Week 12 following suspension of randomization
b Includes withdrawal (n = 2), not compliant (n = 1), request (n = 3), lost to follow up (n = 1)
Progression-Free Survival for Patients
Randomized to Placebo or Cabozantinib (N = 31)
Median PFS
Proportion
Progression-Free
1.00
Cabozantinib (n = 14)
Placebo (n = 17)
0.75
21 weeks
6 weeks
(HR 0.13; log-rank p-value 0.0007)
0.50
0.25
-12 12-Week 0
Lead-in
Stage
10
20
30
50
40
60
PFS per mRECIST, Post Randomization (Weeks)
Cabozantinib
Placebo
PFS (95% CI) # Events
(11, NE)
6
11
(5, 12)
Bone Scan Effects: Representative
Images
Baseline
Week 12
Docetaxel-pretreated
Baseline
Week 12
Docetaxel-pretreated
Baseline
Week 12
Docetaxel-pretreated
Baseline
Week 12
Docetaxel-naïve
Each Patient had PR + Pain Improvement
Best Overall Effect on Bone Scan
Bone scan evaluable (N = 108)a
n (%)
Complete resolution
21 (19)
Partial resolution
61 (56)
Stable
23 (21)
Progressive disease
3 (3)
a Bone
metastases at baseline and ≥ 1 post-baseline bone scan available
A Met/VEGFR inhibitor?
• VEGF pathway inhibition not effective
– CALGB docetaxel ± bevacizumab
– Prednisone/Sunitinib vs. Prednisone (abstract 4515)
• No similar dramatic reports in early phase
studies of reported Met or HGF inhibitors
– Others being tested
• Ongoing cabozantinib trials
– Phase 3 efficacy with pain endpoints
– Imaging & biopsy trials to understand stromal vs.
tumor specific effects
FDA Grants Fast Track Designation For
Alpharadin (Ra-223)
“Alpharadin's Phase III ALSYMPCA trial met its primary endpoint by
considerably improving overall survival of patients with castrationresistant prostate cancer (CRPC) and symptomatic bone
metastases.
An Independent Data Monitoring Committee recommended that the
study be stopped and that the patients on placebo be offered
Alpharadin therapy. Bayer wrote that the "overall survival result was
statistically significant (two-sided p-value = 0.0022, HR = 0.699, the
median overall survival was 14.0 months for Alpharadin and 11.2
months for placebo)."
Alpharadin's safety and tolerability in the Phase III trial was similar
with those in Phases I and II.”
Prostate Cancer 2011
• Advanced prostate cancer pts can have a long history
– Opportunity for multiple therapies
– Toxicities and quality of life important
– Issues of co-morbid disease and aging
•
•
•
•
•
Philosophy of chronic d. management
Androgen receptor pathway targeting is key
DNA targeted chemotherapy plays a role
Immunotherapy may play a role
Bone stromal targeting plays a role
– Bisphosphonates/denosumab for bony morbidity
– Radioactive bone targeting nuclides
– Met inhibitors?
What do we need to know?
• When do we start ADT?
• How early do we start more potent AR
targeting agents?
• When do we introduce non-AR targeting
therapy?
• Can we afford “personalized” long-term
therapy?
–$
– Toxicity