SYSTEMIC THERAPY OF
PROSTATE CANCER:
Androgen Receptor and Immune System
Targeting
Walter Stadler, MD, FACP
University of Chicago
Androgen Ablation
Androgen Ablation & Prostate Ca
• The androgen receptor is the most important
therapeutic target in PCa
– Targeting AR is effective in >90%
– The AR is critical even in the “hormone refractory”
state
– Targeting AR is not curative
• Androgen ablation has toxicity
– Bone, muscle, sex
– Toxicity minimal in comparison to other cancer
therapies
Natural History of Rising PSA
Makarov, et al; J Urol:179:156, 2008
Prostate Ca System Therapy
Philosophy
• Natural history can be very long
– Chronic disease management
– Competing mortality/morbidity
– Therapy toxicity can have significant functional
signficance
• Natural history is highly variable
– Some patients have rapid disease progression
– Disease mortality and morbidity not insignificant
• Care is often fragmented
– Urologists
– Medical oncologists
– Primary care
Endocrine Axis in Prostate
Cancer
GnRH agonist
Adrenal Blockade
Antiandrogens
Orchiectomy
Tumor Androgens
Androgen Ablation: Early vs Late
• VA studies early vs delayed orchiectomy (1960’s)
– Advanced metastatic cancer
– No survival differences
• MRC trial of delayed vs immediate hormonal therapy
– 934 pts, asymptomatic clinical mets
– Immediate LHRH/orchiectomy vs at symptoms
– Decreased morbidity, improved survival with immediate
• DOD prostate cancer database
– Early hormonal therapy delayed clinical metastases in patients with
Gleason >7 and PSA doubling < 12 mo
• Swiss immediate vs delayed orchiectomy
– 197 pts no primary tumor therapy, most without mets
– Immediate delayed time to pain, urinary obstruction, or mets
EORTC 30891: Immediate vs Delayed
• T0-4, N0-2, no mets
• Refused or ineligible for definitive local rxn
• Immediate androgen ablation vs. at
symptomatic progression
• 1002 pts randomized
• Reasons for starting deferred (n=245)
– Symptoms  objective findings: 56%
– Asymptomatic objective findings: 10%
– Asymptomatic marker rise: 26%
EORTC 30891: Survival
HR: 1.25 (1.05 – 1.48)
EORTC 30891: Causes of Mortality
Prostate Ca Mortality
Non-Prostate Ca Mortality
But in meta-analysis of RT  ADT pts on ADT had higher
incidence of fatal MI (D’Amico, et al, JCO 25:2420, 2007)
Adjuvant Data Supports “Early” ADT
• Prostatectomy LN positive immediate vs delayed
ADT
– Improved survival (Messing, et al, Lancet Oncol, 2006)
• Clinical T3 (or high risk) radiotherapy
– Survival advantage with long term adjuvant (EORTC,
RTOG 85-31) (Bolla, et al, Lancet, 2002; Pilepich, et al Int J Rad Oncol Biol
Phy, 2005)
– Survival advantage with long vs short term ADT
(EORTC) (Bolla, et al NEJM, 2009)
– Disease-free and metastases-free survival advantage
with combined plus long term versus combined plus short
term (RTOG 92-02) (Horwitz, et al, J Clin Oncol, 2008)
Morbidity of Androgen Ablation
•
•
•
•
•
•
•
•
Hot flashes
Loss of libido and impotence
Gynecomastia
Weight gain and loss of muscle mass
Exacerbation of hypertension and diabetes
Fatigue
Osteoporosis and fractures
Cognitive effects (?)
Unadjusted Fracture-free Survival among
Patients with Prostate Cancer
Shahinian, V. et al. N Engl J Med 2005;352:154-164
Timing of Bisphosphonates
• Risk of osteonecrosis and renal failure
– Increases with duration of exposure
– Risk benefit of use for hormone sensitive
disease unclear
• CALGB 90202
– Immediate versus delayed zoledronate for
hormone sensitive bone scan positive pts.
Fatigue, Muscle Loss and Elderly
Prostate Cancer Patients
Bylow, et al, Cancer, 2007
Diabetes and CV Risk ADT
• Case control,
– Ontario (Alibhai, JCO, 2009)
• Median 6.5 yr follow up
• DM HR (time to event): 1.16 (1.12 – 1.21)
• MI HR: 0.91 (0.84 – 1.00)
– US claims based
• Incident DM HR: 1.36 (Lage, et al; Urology, 2007)
• Incident DM HR: 1.44 (p<0.001), MI HR: 1.11 (p=0.03)
• Adjuvant ADT (RTOG 85-31) (Efstatstiou, JCO, 2009)
– Median 8.1 yr follow up
– No increased risk MI/sudden death
Intermittent ADT As a New Drug
Screen
• Drug x vs. placebo during “off” period
• Need to monitor testosterone and DHT
recovery
• Drugs in study
– Thalidomide – no major effect (Figg, ASCO 2008)
– Pazopanib (VEGFR/PDGFR TKI)
• Closed, too toxic
– Dutasteride (5- reductase inhibitor)
• UC/NU SPORE clinical trial and others
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
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.
Testosterone
• Actually a growth inhibitory and
differentiating agent in normal prostate
• Cells adapted to androgen depleted
environment
– AR upregulation
– Growth inhibited by androgen
– Tumor shrinkage in xenograft models
• Randomized phase II trial initiated
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)
• 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
240 mg
(n=28)
3 pt off study
<12 wk
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.
44
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
45
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
46
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
341
274
142
56
18
3
Placebo
171
123
59
22
5
2
47
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.
48
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
53
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.
54
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
55
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.
56
Total Deaths During Study
Safety Population
57
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%)
XL184
• MET/VEGF pathway targeted
• Dramatic changes in bone scan
• Clinical implications to be determined
Conclusions
• 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
New therapies need to be identified