Download Treatment of Advanced Prostate Cancer

Treatment of Advanced Prostate Cancer:
The Changing Landscape
Wm. Kevin Kelly, DO
Professor, Medical Oncology and Urology
Director, Division of Solid Tumor Oncology
Thomas Jefferson University
Disclosures
Sanofi – Aventis: Research support
Outline
1. Evolving Biology of CRPC
2. Novel Agents for the treatment of CRPC
•
Androgen Biosynthesis Inhibitors (ABI’s)/novel antiandrogens
–
•
Cytotoxics
–
•
Cabazitaxel
Immunotherapies
–
•
Abiraterone, Enzalutamide (MDV-3100)
Sipuleucel-T
Bone\micro-environment directed therapies
–
Alpharadin
3. “Picking the right treatment for the right patients at the
right time”
Prostate Cancer:
Growth Rate and Progression
Prostate Cancer Death
Metastatic
Disease
Localized
Disease
Early
Detection
Onset of
Cancer
Life Expectancy
Natural
Death
Prostate Cancer Clinical States: A Framework for Clinical
Practice, Drug Development, and Biomarker Qualification
Diagnoses
Non-Castrate
Androgen depletion /
blockade (bicalutamide)
Castration resistant:
deaths from disease
186,320
Clinically
Localized
Disease
28,660
Rising PSA
Clinical
Metastases:
Non-Castrate
1
Rising PSA:
Castrate
2
Clinical
Metastases:
Castrate
Pre-
3
Clinical
Metastases:
Castrate
1st Line
Docetaxel
Standard
4
Clinical
Metastases:
Castrate
2nd Line
No Standard
With detectable metastases:
deaths from cancer exceed
that from other causes
Docetaxel – CRPC
Overall Survival—TAX 327
1.0
Docetaxel 3 wkly
Probability of Surviving
0.9
Docetaxel wkly
0.8
Mitoxantrone
0.7
0.6
0.5
0.4
0.3
Combined:
D 3 wkly:
D wkly:
Mitoxantrone
0.2
0.1
Median
survival
(mos)
Hazard
ratio
P-value
18.2
18.9
17.3
16.4
0.83
0.76
0.91
–
0.03
0.009
0.3
–
0.0
0
6
12
18
Months
Eisenberger M, et al. ASCO Annual Meeting Proceedings. June 2004. Abstract 4.
24
30
What to do when first line
Docetaxel treatment fails?
Three years ago the choices were limited
VS.
Palliative Chemotherapy
Phase I study
Beach
Understanding the Biology of CRPC
Driver Pathways of Dependency of PC
Primary
Mets
Androgen Receptor (AR)
55%
100%
PTEN loss
25%
80%
PI3K/Akt, Ras/Raf, RB
42%
100%
TMPRSS2-ETS fusion
50%
33%
Genetic variants of androgen transporter genes
Tomlins, S. A. Eur Urol 2009
Taylor, B et al, Cancer Cell 2010
Kong D. Cancer Sci 2008
Jenkins, R. B. Cancer Res 1997
Khor, L. Y. Clin Cancer Res 2007
Intratumoral Androgen Levels Are Increased Due To
Overexpression of The Androgen Synthetic Enzymes
Squaline Monoxygenase
Non-castrate
LIVER
Positive control metastatic
Castrate
metastatic
Gerald et al, Amer J Pathol 164:217, 2004
Testosterone
4.0
Benign prostate
3.5
Testosterone (ng/gm)
Primary prostate cancers
3.0
Control tissues (bladder, liver, lung)
2.5
Metastatic prostate cancers
2.0
1.5
1.0
0.5
0.0
P1 P2
P3
P4 P5
Prostate samples
( eugonadal)
P6
C1 C2 C3
Steroid content
M1 M2 M3 M4 M5 M6 M7 M8
Control and Metastatic autopsy
samples (castrate)
Montgomery et al. Cancer Res 68:4447, 2008
Prostate Cancer:
“Adapting” to castrate environment
Hormone Therapy
AC
AR
T
CoACT
P
selective
pressure
Sumo
ABERRANT
•gain of function MODIFICATION
•GF, cytokines
•Src
MUTATION
ALTERN.
SPLICING
COFACTOR
PERTURBATION
•CoAct gain
INTRACRINE
ANDROGEN
SYNTHESIS
•CoR loss/dismissal
AR
DEREGULATION
•amplification
•overexpression
adaptation
>30% CRPC
RESTORED AR ACTIVITY
(rising PSA)
RECURRENT TUMOR DEVELOPMENT
CRPC
Penning & Knudsen
2010
Targeting the Androgen Pathway
• Androgen Biosynthesis Inhibitors
– *Abiraterone Acetate
– TAK 700
– VN/124-1 (TOK-001)
• Novel Anti-Androgens
– *MDV3100
– RD 162
– EPI-001 (AR N-Terminal)
– SNARE-1 (selective nuclear receptor exporter-1)
* FDA approved
Hormonal Impact of Abiraterone
Low-dose steroid replacement minimizes
mineralocorticoid-related toxicity
OH
O
O
O
HO
P450 S CC
HO
Aldosterone
HO
Choles terol
O
Pregnenolone
P45017a
(17α-hydroxylase)
O
Proges terone
Corticos terone
21-hydroxylase
OH
11bb-hydroxylase
O
Abiraterone
OH
HO
HO
OH
17αa-Hydroxyproges terone
Cortis ol
P45017a
(C17,20 -lyas e)
O
OH
O
O
17α-Hydroxypregnenolone
O
O
tes tos terone
5α-reductas e
O
OH
OH
Abiraterone
HO
Dehydroepiandroserone
O
O
O
Andros tenedione
Tes tos terone
H
5α-Dihydrotes tos terone
Abiraterone Suppresses Steroids Downstream of
C17,20-lyase: Proof-of-Concept Phase I Trial
3
nmol/L
ng/dL
5
4
2
Testosterone
(by LC-MS/MS)
6
Lower Limit
of Sensitivity
Androstenedione
1
2
1
0
Start of 10
Treatment
1
12.5
0.07
20
60
Days
DHEA
28
56
Days
At
Progression
Estradiol
10.0
ρmol/L
Nmol/L
10.0
7.5
5.0
2.5
0
Start of
Treatment
0
Start of
Treatment
12.5
70
At
Progression
7.5
5.0
2.5
0
28
56
Days
At
Progression
10
20
30
40
50
Days Post Treatment
Confidential. For Internal Use Only. Do not distribute.
60
Phase II Trials of Abiraterone Acetate in
Castration Resistant Prostate Cancer
Patient population
CRPC: Chemotherapy
naïve1
CRPC: Prior docetaxel2
CRPC: Prior docetaxel3
No prior ketoconazole
Prior ketoconazole
ECOG PS
Improvement
(at least one
level)
N
PSA decline
≥ 50%
Tumor
response
(RECIST)
33
24 (73%)
PR: 9 (27%)
SD: 19 (58%)
8 (61.5%)
47
24 (51%)
PR: 6 (13%)
SD: 25 (53%)
11 (35%)
(n = 18)
PR: 3 (17%)
SD: 11 (61%)
16 (48%)
31
27
16 (52%)
8 (30%)
1Ryan
et al. J Clin Oncol 2009; 27(suppl):245s (abstract 5046)
2Reid et al. J Clin Oncol 2009; 27(suppl):246s (abstract 5047)
3Danila et al. J Clin Oncol 2009; 27(suppl):246s (abstract 5048)
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, placebocontrolled 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.
deBono N Engl J Med. 2011 May 26;364(21):1995-2005
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
deBono N Engl J Med. 2011 May 26;364(21):1995-2005
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
deBono N Engl J Med. 2011 May 26;364(21):1995-2005
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 deaths
deBono N Engl J Med. 2011 May 26;364(21):1995-2005
Overall Study Design of COU-AA-302
Patients
• Progressive chemonaïve mCRPC
patients
(Planned N = 1088)
• Asymptomatic or
mildly symptomatic
R
A
N
D
O
M
I
Z
E
D
Efficacy end points
AA 1000 mg daily
Prednisone 5 mg BID
(Actual n = 546)
Placebo daily
Prednisone 5 mg BID
(Actual n = 542)
1:1
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
• Phase 3 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 et al. ASCO 2012
Statistically Significant Improvement in rPFS
Primary End Point
100
AA + P (median, mos):
NR
PL + P (median, mos):
8.3
HR (95% CI):
Progression-Free (%)
80
P value:
0.43 (0.35-0.52)
< 0.0001
60
40
20
AA + P
PL + P
0
0
3
6
9
12
15
18
Time to Progression or Death (Months)
AA
PL
546
542
489
400
340
204
164
90
46
30
12
3
0
0
Data cutoff 12/20/2010.
NR, not reached; PL, placebo.
Ryan et al. ASCO 2012
Strong Trend in OS Primary End Point
100
Survival (%)
80
60
40
AA + P (median, mos):
NR
PL + P (median, mos):
27.2
HR (95% CI):
20
AA + P
PL + P
P value:
0.75 (0.61-0.93)
0.0097
0
0
3
6
9
12
15
18
21
24
27
30
33
0
2
0
0
Time to Death (Months)
AA 546
PL 542
538
534
524
509
503
493
482
465
452
437
412
387
258
237
120
106
Updated GU ASCO 2013: Rathkopf et al. Abstract # 5
-r PFS
16.5 vs. 8.3 mo.
HR 0.53 (0.45-0.62)
- OS
35.3 vs. 30.1 mo. HR 0.79 (0.66-0.96)
27
25
p = <0.0001
p= 0.0151
No New Safety Concerns Identified with
Longer AA Treatment than in 301 Study
AA + P
(n = 542)
%
Placebo + P
(n = 540)
%
All Grades
Grades 3/4
All Grades
Grades 3/4
Fatigue
39
2
34
2
Fluid retention
28
0.7
24
1.7
Hypokalemia
17
2
13
2
Hypertension
22
4
13
3
Cardiac disorders
19
6
16
3
4
1.3
5
0.9
ALT increased
12
5.4
5
0.8
AST increased
11
3.0
5
0.9
Atrial fibrillation
Most ALT and AST increases occurred during the first 3 months of treatment
Ryan et al. ASCO 2012
Subsequent Therapy Was Common
and Still a Survival Trend Observed
AA + P
(n = 546)
n (%)
Placebo + P
(n = 542)
n (%)
242 (44.3)
327 (60.3)
207 (37.9)
287 (53.0)
Cabazitaxel
45 (8.2)
52 (9.6)
Ketoconazole
39 (7.1)
63 (11.6)
Sipuleucel-T
27 (4.9)
24 (4.4)
Abiraterone acetate*
26 (4.8)
54 (10.0)
No. with selected subsequent
therapy for mCRPC
Docetaxel
*Prior to unblinding (e.g. not per protocol)
Ryan et al. ASCO 2012
TAK-700 (Ortoronel) in mCRPC:
PSA Response and Safety
•
•
•
inhibit the enzyme 17,20-lyase
53% with PSA decreases ≥ 50% at 12 wks
Serious AEs in 25 patients (26%): hypokalemia (n = 3), acute renal failure
(n = 3), pneumonia (n = 2), urinary tract infection (n = 2), hypotension (n = 2),
neutropenia (n = 2), fatigue (n = 2)
Efficacy and tolerability demonstrated with TAK-700 administered with or
without prednisone, suggesting feasibility of a steroid-free regimen
PSA Change at 12 Wks (%)
•
275
250
225
200
175
150
125
100
75
50
25
0
-25
-50
-75
-100
-125
xx x
Treatment
x
Xxx
x x
x
x x
x
x
Xx x
xx x
xxx
300 mg BID (n = 23)
400 mg BID + prednisone (n = 24)
600 mg BID + prednisone (n = 26)
600 mg QDAM (n = 24)
X Previous ketoconazole therapy
Agus DB, et al. ASCO 2011. Abstract 4531.
Novel anti-androgens
“Development of Enzalutamide”
• Built of the scaffolding of the
non-steroidal agonist RU59063
• Screened ~ 200 derivatives
• Derivatives were optimized –
RD162 and MDV3100
Enzalutamide (MDV3100)
Tran et al. Science 324:787-790, 2009
MDV3100 (Enzalutamide) Was Designed to Overcome
Deficiencies of Available Anti-Androgens and Has Several
Unique Mechanisms of Action and No Agonist Effects
1. MDV3100 is an oral
investigational drug rationally
designed as a new hormonal
agent to target androgen
receptor (AR) signaling, a key
driver of prostate cancer
growth.
2. MDV3100 is the first in a
new class of Androgen
Receptor Signaling
Inhibitors that affects
multiple steps in the
androgen receptor
signaling pathway.
Tran et al. Science 2009;324:787–90.
T
T
1
Inhibits Binding of
Androgens to AR
Enzalutamide
AR
Cell cytoplasm
2
Inhibits Nuclear
Translocation of AR
Cell nucleus
3
Inhibits Association
Of AR with DNA
AR
Bicalutamide vs. Enzalutamide
Enzalutamide has a 5-8
fold increased affinity to
AR than bicalutamide
Enzalutamide does not
have agonists effects in
castrate resistant setting
Enzalutamide
suppressed growth and
induced apoptosis in
cells lines with AR gene
amplications
Tran et al. Science 324:787-790, 2009
Anti-tumor activity if MDV3100 in castrationresistant prostate cancer: a phase 1-2 study
Post-chemotherapy
N=75
Pre-chemotherapy
N=65
Grade 3-4 adverse events in >2 patients
N (%)
Adverse event
All doses
(n = 140)
≤ 240mg/day
(n = 87)
Fatigue
16 (11%)
5 (17%)
Anemia
4 (3%)
3 (3%)
Arthralgia
3(2%)
2(2%)
3 (2%)
0
Scher et al. Lancet 375:1437-1446, 2010 Seizure
AFFIRM: Phase 3 Trial of Enzalutamide vs
Placebo in Post-Chemotherapy CastrationResistant Prostate Cancer (CRPC)
Patient
Population:
1199 patients with
progressive CRPC
* Failed docetaxel
chemotherapy
R
A
N
D
O
M
I
Z
E
D
Enzalutamide
160 mg daily
n = 800
Placebo
n = 399
2:1
*Glucocorticoids were not required but allowed
Tran et al. Science 2009;324:787–90.
ASCO June 2012
Primary
Endpoint:
Overall Survival
AFFIRM: Clinical Outcomes
Variable
Enzalutamide
(800 pts.)
Placebo
(399 pts.)
Hazard Ratio
P -value
OS
(months)
18.4
13.6
0.631
<0.0001
PSA
progression
(months)
8.3
3.0
0.218
<0.0001
rPFS
(months)
8.3
2.9
0.404
<0.0001
1st SRE
(months)
16.7
13.3
0.621
<0.0001
CR + PR
28.9%
3.8%
-
<0.0001
FACT-P
43.3%
17.8%
-
<0.0001
De Bono et al. ASCO 2012
Favorable Adverse Risk Profile
All Grades
Grades >3*
Enzalutamide
(n = 800)
Placebo
(n = 399)
Enzalutamide
(n = 800)
Placebo
(n = 399)
AEs
98.1%
97.7%
45.3%
53.1%
Serious AEs
33.5%
38.6%
28.4%
33.6%
Discontinuations
due to AEs
7.6%
9.8%
4.6%
7.0%
AEs leading to
death
2.9%
3.5%
2.9%
3.5%
All Grades
Seizure
Grade ≥ 3 Events
Enzalutamide
(n = 800)
Placebo
(n = 399)
Enzalutamide
(n = 800)
Placebo
(n = 399)
0.6%
0.0%
0.6%
0.0%
De Bono et al. ASCO 2012
Association of PSA progression and rPFS
AFFIRM
PSA
COU-AA-301
rPFS
De Bono et al. ASCO 2012
de Bono JS et al. N Engl J Med 2011;364:1995-2005
Novel Agents Targeting the Androgen Pathway
Agent
Function
Phase
Abiraterone Acetate
CYP 17 α-hydroxylase\12,20-lyase
inhibitor
FDA approved
TAK-700
CYP 17,20 lyase inhibitor
-Phase III
Enzalutamide (MDV3100)
Anti-androgen\androgen receptor -Completed Phase III
signaling inhibitor
-Ongoing Phase III in
non-castrate disease
ARN-509
Anti-androgen
AZD3514
AR down-regulator\anti-androgen -Phase I
TOK-001
Anti-androgen\CYP 17 inhibitor
-Phase I-II
EPI-001
Anti-androgen\N-terminal
Domain
-pending clinical
trials
-Phase III
Cabazitaxel
• Microtubule stabilizer
• Developed in docetaxelresistant prostate cancer cell
lines
• a favorable pharmacokinetic
and safety profile
• decreased propensity for Pglycoprotein (Pgp)-mediated
drug resistance.
• inhibited cell growth in a wide
range of human cancer cell
lines, including tumor models
expressing Pgp.
TROPIC – Cabazitaxel vs Mitoxantrone
• CRPC
• PD during or
after
docetaxel
RANDOMIZE
Cabazitaxel 25 mg/m2 Q 21 d
Prednisone 10 mg daily
146 Sites /
26 Countries
Abbreviation: PD=progressive disease.
Source: deBono et al. Lancet. 2010;376:1147-1154.
N=755
Mitoxantrone
Prednisone 10 mg daily
TROPIC Primary Endpoint – OS
(ITT Analysis)
100
Proportion of OS (%)
Median OS (months)
MP
CBZP
12.7
15.1
Hazard Ratio
80
95% CI
0.70
0.59–0.83
P Value
<.0001
60
40
20
0
0 months
Number
at Risk
MP
377
CBZP 378
6 months
12 months
18 months
24 months
30 months
300
321
188
231
67
90
11
28
1
4
Abbreviation: ITT=intent-to-treat.
Source: deBono et al. Lancet. 2010;376:1147-1154.
Most Frequent Grade ≥3
Treatment-Emergent AEs*
MP (n=371)
All Grades (%) Grade ≥3 (%)
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
Any AE
*Sorted by decreasing frequency of events grade ≥3 in the CBZP arm.
deBono et al. Lancet. 2010;376:1147-1154
Immunotherapy Approaches in PC
 Active immunotherapy
 tumor associated antigen is directly targeted by loading in that
antigen in APC or into vaccine vector at protein or DNA level
 Antigen specific immunotherapy
 Sipuleucel-T
 Poxvirus-based vectors
 DNA based vaccines
 Passive immunotherapy
 Antibodies to specific receptors/antigens
 Prostate Specific Membrane Antigen (PSMA)
 Immune Checkpoint Inhibitors
 Strategies to maintain activated tumor specific T-cells by neutralizing
co-inhibitory receptors
 Anti-cytotoxic T lymphocyte protein 4 (CTLA 4)
 Ipilumimab, tremelimumab
 Anti- program death 1 (PD-1)
 MDX-1106
Active Cellular Immunotherapy
(Sipuleucel-T)
Patient’s white blood
cells harvested
Short-term culture with protein
“cassette”
GMCSF
Prostatic acid
phosphatase
Shipping
Cells infused back into
patient (IV)
Sipuleucel-T in Prostate Cancer
Overall Survival
Median, Months
(95% CI)
Hazard Ratio
(95% CI)
P
Study
D9902B
Study
D9902A
Study
D9901
Sip-T
Placebo
Sip-T
Placebo
Sip-T
Placebo
25.8
21.7
19
15.7
25.9
21.4
(22.8, 27.7)
17.7, 23.8)
(13.6, 31.9)
(12.8, 25.4)
(20.0, 32.4)
(12.3, 25.8)
0.775
0.786
0.568
(0614,0.979)
(0.484, 1.278)
(0.388, 0.884)
0.032
0.010
0.331
Cheever and Higano., Clin Cancer Res 2011;17:3520-3526
CD54 is a surrogate marker of antigen presenting cell activation
Serum cytokines or humoral responses
by ELISA have limited utility
Second Generation Anti-PSMA Abs: J591
2nd generation mAbs
– Bind extracellular domain
– Bind viable PSMA+ cells
– Rapidly internalized
– May be conjugated
Capromab binding site
J591
binding site
Liu H et al. Cancer Res 1997; 57: 3629
Liu H et al. Cancer Res 1998; 58: 4055
Tagawa et al, ASCO 2008
177Lu-J591
Rx: Excellent Targeting & PSA Response
30/32 (94%) with accurate targeting of known sites of disease
99mTc-MDP
bone scan
177Lu-J591
mAb
PSADT=3.9 mo
6 months
Log scale
90% decline
Arithmetic scale
Ant
Post
Ant
Post
Defining the Future:
Ongoing Immumotherapy Trials
Study
Phase
Study
Population
Treatment
Outcome
PROTECT
P-11
III
Non-metastatic ADPC
3 mo. ADT + SipT vs. control
PSADT,
Distant Failure,
OS
NeoACT
P07-1
II
Localized PC
Sip-T x 3 prior to
RP
Post-op Boost
vs. no Boost
Immune
response,
Safety
ProACT
P07-2
II
Asymptomatic or
minimally symptomatic
CRPC
3 different dose
levels of PA2024
CD54 upreg.,
Immune
response,
QOL, CTC, OS
Cornell
177Lu-J591
II
High risk non-metastatic
CRPC
Ketoconazole +
hydrocortisone
± active 177LuJ591
PFS, OS, PSA,
RECIST
BMS CA 184043
Ipi\Prostate
III
CRPC post docetaxel
XRT + Ipi vs.
XRT + placebo
OS, PFS, Pain,
Safety
Radioisotopes Targets Bone
Metastases
• Naturally targets
new bone growth
in and around
bone metastases
• Most acts as a
calcium mimic
• Strontium-89
• Samrarium-153
• Radium-223
Ca
Ra
Radium-223 (AlpharadinTM )
•
•
•
•
Based on alpha emitter Radium-223
ideal half-life of 11.4 days
Excreted via small bowel
Safe and easy to produce, deliver and handle
Alpha
Beta
7000
1
Initial energy (MeV)
3-8
0.01-2.5
Range in tissue (µm)
40-90
50-5000
60-230
0.015-0.4
+2
-1
2000-7000
5-20
1-5
100-1000
Relative particle mass
LET (KeV/µm)
Charge
Ion pairs/µm
DNA hits to kill cell
Range of alpha-particle
Radium-223
Encouraging Phase II results
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 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
EORTC 2011
ALSYMPCA Secondary Endpoints:
ALP and PSA
Hazard ratio
95% CI
P-value
Time to Total ALP progression
0.163
(0.121 – 0.221)
< 0.00001
Time to PSA progression
0.671
(0.546 – 0.826)
0.00015
Radium-223
n (%)
Placebo
n (%)
P-value
Total ALP response
(30% reduction)
165 (43)
4 (3)
< 0.001
Total ALP normalisation*
83 (33)
1 (1)
< 0.001
*In patients who had elevated total ALP at baseline.
EORTC 2011
ALSYMPCA Adverse Events
All Grades
Grades 3 or 4
Radium-223
(n = 509)
n (%)
Placebo
(n = 253)
n (%)
Radium-223
(n = 509)
n (%)
Placebo
(n = 253)
n (%)
136 (27)
69 (27)
54 (11)
29 (12)
Neutropenia
20 (4)
2 (1)
9 (2)
2 (1)
Thrombocytopenia
42 (8)
14 (6)
22 (4)
4 (2)
Bone pain
217 (43)
147 (58)
89 (18)
59 (23)
Diarrhoea
112 (22)
34 (13)
6 (1)
3 (1)
Nausea
174 (34)
80 (32)
8 (2)
4 (2)
Vomiting
88 (17)
32 (13)
10 (2)
6 (2)
Constipation
89 (18)
46 (18)
6 (1)
2 (1)
Haematologic
Anaemia
Non-Haematologic
EORTC 2011
Targeting the micro-environment
• Bevacizumab (monoclonal VEGF)
• Sunitinib (TKI VEGF 1,2,3)
• Aflibercept (VEGF 1 and 2 domains fused to
Fc portion IgG1
– VENICE Trial-completed
• Lenalidomide (Immunomodulatory derivative
of thalidomide)
– MAINSAIL Trial
• Tasquinimod (quinolone-3-carboxamide)
• Cabozantinib (VEGFR2/MET inhibitor)
• Dasatanib (SRC inhibitor)
Cabozantinib, Dual MET/VEGFR TKI,
vs Placebo in mCRPC
PR or
CR
(n = 79)
Open-Label Extension
Cabozantinib
100 mg/day PO
12 wks
Randomization
Patients with
mCRPC and
measurable
disease; rising
PSA only,
not eligible
Lead-in Stage
Cabozantinib
100 mg/day PO
(n = 171)
*At progression, patients on placebo could
cross-over to cabozantinib (n = 14).
SD
(n = 31)
Cabozantinib
100 mg/day PO
(n = 14)
Until PD*
Placebo daily
(n = 17)
PD
(n = 61)
Hussain M, et al. ASCO 2011. Abstract 4516.
Discontinue
cabozantinib
Cabozantinib vs Placebo in
mCRPC: Efficacy and Safety
Median PFS, Wks
Cabozantinib (n = 14)
21
Placebo (n = 17)
6
Proportion
Progression Free
1.00
0.75
0.50
0.25
-12
0
12-Wk
Lead-in Stage
(HR 0.13; log-rank P = .0007)
10
20
30
40
50
PFS per mRECIST,
Postrandomization (Wks)
60
• Authors concluded that
cabozantinib has substantial
antitumor activity in progressive
mCRPC
– Disease control at Wk 12: 68%
– Measurable disease
regression: 74%
– Evidence of improvement on
bone scan: 76%
– Pain improvement: 67%
– Moderate but manageable
toxicity profile; similar to other
TKIs
Hussain M, et al. ASCO 2011. Abstract 4516.
Phase III Trials for CRPC
(First line chemotherapy trials)
Sponsor
Treatment
*Novacea
Docetaxel ± DN101
*SWOG
*CALGB
*Sanofi-Aventis
NCI
Docetaxel ± atrasentan
Docetaxel ± bevacizumab
Docetaxel ± aflibercept
Docetaxel or KAVE
Doxorubicin ± Strontium-89
Docetaxel vs. GVAX
*Cell Genesys
*Cell Genesys
*Zeneca
*Bristol
OncGeneX
Docetaxel ± GVAX
Docetaxel ± zibotentan
Docetaxel ± dasatinib
Docetaxel ± Custirsen
No improvement of Survival
*Closed
to accrual
*Closed
to accrual
OS Benefit in Recent CRPC Trials
Trial/
Agent/
Date
Approved
Mechanism
AFFIRM
Enzalutamide
2012
Androgen
Receptor
Signaling
Inhibitor
Placebo
18.4 vs. 13.6
COU-AA-301
Abiraterone +
prednisone
2011
CYP17 Inhibitor
Placebo +
prednisone
14.8 vs. 10.9
0.646
<0.0001
TROPIC
Cabazitaxel +
prednisone
2010
Cytotoxic
Mitoxantrone +
prednisone
15.1 vs. 12.7
0.70
<0.0001
Alpharadin*
2012
Alpha-particle
emitting
radionuclide
Placebo
14.9 vs. 11.3
0.69
0.0018
Comparator
Survival
(months)
Hazard
Ratio
P-value
Would suggest the
0.631
<0.0001
post-chemotherapy
population remains
heterogonous
* Only 60% of these patients were post-docetaxel patients
De Bono et al. ASCO 2012
1. Who is the right
patient for which
novel therapy?
2. What is the optimal
sequencing of these
agents? Does it
matter?
3. How long do I give
these agents?
4. Why are patients still
relapsing?
Baseline Serum Adrenal Androgens Are Prognostic and
Predictive of Overall Survival in Patients With mCRPC:
Results from the COU-AA-301 Phase 3 Randomized Trial
Multivariate Model: Higher Baseline Androgens Associate With
Improved OS:
Testosterone
Androstenedione
DHEA
HR
p Value
0.667
< 0.0001
HR
p Value
0.679
< 0.0001
HR
p Value
0.691
< 0.0001
• Treatment effect: Robust
• Laboratory parameters: All significant (LDH, Hgb, ALP, PSA)
*Including 1 androgen at a time (dichotomized) and other lab parameters (dichotomized).
Ryan et al Proc AACR 2012
Effects of Abiraterone Acetate on Androgen Signaling in
Castrate-Resistant Prostate Cancer in Bone
• androgen\enzyme tissue levels
(A) Pretreatment intense nuclear
androgen receptor (AR)
expression in combination with
CYP17 expression in the bone
marrow–infiltrating tumor of a
patient with treatment duration
more than 4 months.
• Serum Androgen Levels
Efstathiou E et al. JCO 2012;30:637-643
Molecular characterization of CTCs in CRPC
(N= 89 patients treated with Abiraterone)
1.
2.
3.
4.
5.
CTC collected by
Immunicon system
57% had CTC ≥ 4
(40% chemo naïve;
82% Docetaxel
treated)
ERG rearrangement
was associated with
magnitude of PSA
decline on
abiraterone
Concordance in
ERG gene status of
CRPC tumor biopsy
and CTC’s
Heterogeneity in AR
copy number and
PTEN loss noted
Attard, G. et al. Cancer Res 2009;69:2912-2918
The RB loss signature should be developed as a
metric to direct therapeutic intervention for CRPC
•Feb 2011:
Gene Chip to readout for RB function
& other key prostate-specific
markers generated & validated
RB+ gene signature
RB- gene signature
Direct toward therapies that
hyperactivate RB function
Capitalize on loss of cell cycle
checkpoints
e.g. CDK4 inhibitors
e.g. a subset of chemotherapeutics
that induce DNA damage
Sharma et al,
J. Clin Investigation
A phase II multicenter trial combining Cabazitaxel and
Abiraterone Acetate in treatment of metastatic
Castration Resistant Prostate Cancer
(Knudsen\Kelly)
Registration
C
T
C
S
e
r
u
m
Interquartile range
RB target genes
Lower quartile
B
i
o
p
s
y
RB+/RBtumors
Cabazitaxel +
abiraterone acetate
Upper quartile
Androgen Profiles
•Testosterone
•Androstenedione
•DHEA
RB Prostate Signature
Conducted in PCCTC
The Changing Landscape in
Prostate Cancer
Clinically
Localized
Disease
Rising PSA
Clinical
Metastases:
Non-Castrate
1
Rising PSA:
Castrate
2
Clinical
Metastases:
Castrate
Pre-
3
Clinical
Metastases:
Castrate
1st Line
Docetaxel
Standard
4
Clinical
Metastases:
Castrate
2nd Line
Therapies with a Clinical Benefit
Bicalutamide
Flutamide
Nilutamide
LhRH agonists
LhRH antagonists
Bicalutamide
Flutamide
Nilutamide
LhRH agonists
LhRH antagonists
Alpharadin
Sipuleucel-T
Zolendronic Acid
Denosumab
Samarium
Docetaxel
Mitoxantrone
Enzalutamide
Abiraterone
Cabazitaxel
Alpharadin
Sipuleucel-T
Need for biomarker driven trials to direct patient treatment
Novel Agents in CRPC
17α hydrolase/17, 20 lyase inhibitor
Anti-angiogenic/immunomodulatory
Anti-CTLA4\PD-1 antibody
Anti-CCL2
Anti-FGFR3
Anti-Il-6 antibody
Anti-insulin-like GFR antibody
Anti-integrin anti-body
Anti-PSMA immunoconjugate
Anti-prostate stem cell antibody
Anti-VEGF
Cytotoxic agent
Clusterin inhibitor
EGFR antibodies\TKI
Faranesyl protein transferase inhibitor
GMP phospodiesterase inhibitor
HSP-90 inhibitor
HDACi
HGF inhibitor
Hypoxia activated pro-drug
IGF inhibotors
Integrin receptor antagonist
Il-11 inhibitor
JAK inhibitor
M-TOR inhibitor
Multi-targeted TKI
MMP-9 inhibitor
Pro-apoptotic agent
Proteosome Inhibitor
RANKL inhibitor
SRC kinase inhibitor
Signal Transduction inhibitor
Survivin suppressant
Abiraterone, TAK 700
CC-4047,Lenalidomide, ABR-215050, cediranib, AS1404
Ipilimumab, MLN2704
CNTO 888
TKI 258
CNTO 95
IMC-A12
CNTO 95
MLN2704, 177 Lu-J591
AGS-PSCA
Bevacizumab, Alfibercept
ABT-751, abraxane, E7389, SB-715992, carbazitaxel
Irofulven, Paclitaxel poliglumex, TPI 287, E7389
OGX-11
Pertuzumab, Cetuximab, Erlotinib, Gefitnib,
R115777
Exisulind
17-AAG, IPI-504
LBH589, Vorinostat, Belinostat, SB939
AMG 102
TH 302
Citutumumab, figitumumab, octreotide, pasireotide
Cilengitide
BMTP-11
INCB-18424
Temsirolimus
Sunitinib, Sorafenib, CEP 701, vatalinib, DMXAA
PCK 3145
AT-101
Bortezomib
Denosumab
KX2-391
PCK-3145
YM155
GU-Investigator Initiated Trails at KCC
 Phase I Trial of Weekly Cabazitaxel with Concurrent Intensity Modulated Radiation
Therapy and Androgen Deprivation Therapy for the Treatment of Locally Advanced
High Risk Adenocarcinoma of the Prostate.- Lin
 A Phase II Study of Cabazitaxel in Patients with Urothelial Carcinoma Who Have
Disease Progression Following Platinum-Based Chemotherapy. -Hoffman
 Phase I Trial of High Dose Rate Brachytherapy Combined with Stereotactic Body
Radiation Therapy for Intermediate Risk Prostate Cancer Patients.-Den
 A Pilot Phase II Study of Digoxin in Patients with Recurrent Prostate Cancer as
Evident by a Rising PSA.-Lin
 A Multi-Institutional Translational Clinical Trial of Disulfiram in Men with
Recurrent Prostate Cancer as Evident by a Rising PSA.-Lin
 A Phase I/II multicenter trial combining Cabazitaxel and Abiraterone Acetate in
Treatment of Metastatic Castration Resistant Prostate Cancer. -Kelly
 A Phase I/II Study of MLN8237 in combination with Abiraterone for patients with
castration- resistant prostate cancer after progression on Abiraterone.-Lin
Genitourinary Oncology Team
Medical Oncology
•Jean Hoffman-Censits, MD
•Jianqing Lin, MD
•Gwen Slakind, RN
•Diane Woodford, APRN
Radiation Oncology
•Adam Dicker, PhD, MD
•Robert Den, MD
•Mark Hurwitz, MD
Urology
•Lenny Gomella, MD
•Edouard Trabulsi, MD
•Costas Lallas, MD
Pathology
•Peter McCue, MD
•Ruth Birbie
Clinical Trials Office\Data Collection
•Monica Byrnes
•Christine Huberts
•Brooke Kennedy
•Deborah Kilpatrick, RN
•Zachary Foerst
Basic Science
•Allessandro Fatalis, MD
•Karen Knudsen, PhD
•Lucia Languino, PhD
•Marja Nevalainen, PhD
•Eric Wickstrom, PhD
Administrative Support
•Teresa Bryant
•Beth Schade
Thank You