Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY Management of advanced hormonesensitive and castrationresistant prostate cancer Overview Early chemotherapy in patients with metastatic hormonesensitive prostate cancer ID: 704375
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Slide1
Matthew D. Galsky, MDDirector, GU Medical OncologyTisch Cancer InstituteIcahn School of Medicine at Mount Sinai New York, NY
Management of advanced hormone-sensitive and castration-resistant prostate cancerSlide2
OverviewEarly chemotherapy in patients with metastatic hormone-sensitive prostate cancerNew generation “hormonal” therapies for castration-resistant diseaseIntegration of immunotherapy and radiopharmaceuticalsSlide3
New Drug Approvals in Prostate CancerGalsky et al, CA: A Cancer Journal for Clinicians, 2012 Slide4
Early chemotherapy in patients with metastatic hormone-naïve diseaseSlide5
Huggins: ADT for Prostate CancerSlide6
Docetaxel in Prostate CancerThe standard of care for CRPC changed from mitoxantrone/prednisone to docetaxel/prednisone based on SWOG 99-16 and TAX-327 studies
Petrylak
N
Engl
J Med
.
2004
Tannock
,
N
Engl
J Med
. 2004
SWOG
99-16
TAX-327
HR: 0.83,
P
=0.03Slide7
Early Chemotherapy +ADT for metastatic prostate cancer?ProAttack de-novo testosterone independent clones early - allow ADT to keep PrCa in remission longerS
ome patients at the time of progression are too frail for chemo.Con
ADT will take cells out of cycle and be less responsive to cytotoxicsSome patients respond for a long time and never need chemotherapy
Androgen Deprivation Therapy
Regression Re-emergence
Sweeney et al, ASCO, 2014Slide8
E3805 – CHAARTED TreatmentStratificationExtent of MetsHigh
vs LowAge≥70
vs < 70yo
ECOG PS
- 0-1
vs
2
CAB> 30 days
-Yes
vs
No
SRE Prevention
-Yes
vs
No
Prior Adjuvant ADT
≤12
vs
> 12 months
RANDOMIZe
ARM A:
ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles
ARM B:ADT (androgen deprivation therapy alone)
Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks
Evaluate every 12 weeks
Follow
for time to progression and overall survival
Chemotherapy at investigator’s discretion at
progression
ADT allowed
up to 120 days prior to randomization.
Intermittent
ADT dosing
was not
allowed
Standard dexamethasone premedication but no daily prednisone
High volume:
visceral metastases and/or 4 or more bone metastases
(at least 1 beyond pelvis and vertebral column)Slide9
Primary endpoint: Overall survivalHR=0.61 (0.47-0.80)
p=0.0003Median OS:
ADT + D: 57.6 monthsADT alone: 44.0 months
Sweeney et al, ASCO, 2014Slide10
In patients with high volume metastatic disease, there is a 17 monthimprovement in median overall survival from 32.2 months to 49.2 months
OS by extent of metastatic disease at start of ADT
High volume
Low volume
p=0.0006
HR=0.60
(
0.45-0.81)
Median OS:
ADT + D: 49.2 months
ADT alone: 32.2 months
p=0.1398
HR=0.63 (0.34-1.17)
Median OS:
ADT + D: Not reached
ADT alone: Not reached
Sweeney et al, ASCO, 2014Slide11
Clinical States of Prostate Cancer
Clinically
localized
“Rising PSA”
state
Non-metastatic,
hormone-
sensitive
Metastatic,
hormone-sensitive
Non-metastatic
CRPC
Metastatic
CRPC
10-15 years +
Death from other causes
Death from prostate cancerSlide12
New generation of “hormonal therapies” for castration-resistant diseaseSlide13
Testosterone
500 ng/mL
50 ng/mL
Castration Therapy
PSA
Castration Resistance
CRPC is NOT Hormone
Refractory
Cancer,
but is frequently Hormone
Ultra-Sensitive
What is
castration-resistance?Slide14
Androgen Deprivation Therapy
RESTORED AR ACTIVITY
(rising PSA)
adaptation
selective
pressure
CRPC
ALTERN.
SPLICING
INTRACRINE
ANDROGEN
SYNTHESIS
T
ABERRANT
MODIFICATION
GF, cytokines
Src
Sumo
AC
P
COFACTOR
PERTURBATION
CoAct gain
CoR loss/dismissal
CoACT
MUTATION
gain of function
AR
AR
DEREGULATION
amplification
overexpressionSlide15
Androgen Deprivation Therapy
RESTORED AR ACTIVITY
(rising PSA)
adaptation
selective
pressure
CRPC
ALTERN.
SPLICING
INTRACRINE
ANDROGEN
SYNTHESIS
T
ABERRANT
MODIFICATION
GF, cytokines
Src
Sumo
AC
P
COFACTOR
PERTURBATION
CoAct gain
CoR loss/dismissal
CoACT
MUTATION
gain of function
AR
AR
DEREGULATION
amplification
overexpressionSlide16
Enzalutamide
Oral
drug rationally designed to target AR signaling, impacting multiple steps in AR signaling pathway.
No demonstrated agonist effects in pre-clinical models.
Enzalutamide
1
T
AR
T
Tumor
Death
Cell nucleus
Inhibits Binding of
Androgens to AR
Inhibits Nuclear
Translocation of AR
Inhibits Association
Of AR with DNA
AR
Cell cytoplasm
Tran et al. Science
2009;324:787–90
.
Charles Sawyers & Michael Jung
2
3Slide17
Androgen Deprivation Therapy
RESTORED AR ACTIVITY
(rising PSA)
adaptation
selective
pressure
CRPC
ALTERN.
SPLICING
INTRACRINE
ANDROGEN
SYNTHESIS
T
ABERRANT
MODIFICATION
GF, cytokines
Src
Sumo
AC
P
COFACTOR
PERTURBATION
CoAct gain
CoR loss/dismissal
CoACT
MUTATION
gain of function
AR
AR
DEREGULATION
amplification
overexpressionSlide18
Abiraterone (CYP-17 Inhibitor)Reduce adrenal androgen synthesis by inhibition of 17α-hydroxylase and C17,20-lyase. These enzymes are needed to produce the precursors of the sex steroids in both the adrenal cortex and testicles….and in prostate cancer cells……
Attard, JCO, 2008Slide19
Expected Toxicities of CYP17 InhibitionACTH increasesDOC and Corticosterone increaseExpected side effect profile mineralocorticoid excessHypokalemiaHypertensionFluid overload
Attard, JCO, 2008
Rise in ACTH blunted with co-administration of steroidsSlide20
Abiraterone
and
Enzalutamide
:
Four Positive Studies!
PREVAIL
COU-AA-301
Co-Primary Endpoints: OS,
rPFS
Primary Endpoint:
OS
AFFIRM
COU-AA-302
mCRPC
Pre-chemotherapy
mCRPC
1
st
Line
Chemotherapy
mCRPC
Post-chemotherapySlide21
PREVAIL: Radiographic Progression-Free Survival
Median rPFS
: Enzalutamide
, not reached
Placebo, 3.9 months
Beer T, et al.
J
Clin
Oncol
. 2014;32(
suppl
4): Abstract LBA 1.Slide22
COU-AA-302:
Abiraterone
Acetate ~Doubles
rPFS
in
Pre-Chemo
mCRPC
100
80
60
40
20
0
0
Subjects Without Progression
or Death (
%)
6
12
18
30
36
24
546
542
389
244
240
133
157
78
20
7
0
0
Abiraterone
Prednisone
117
45
Months From Randomization
Abiraterone
Prednisone
Abiraterone
(median, mos):
16.5
Prednisone (median, mos):
8.3
HR (95% CI):
0.53
(0.45-0.62)
p
Value:
< 0.0001
15
9
3
21
27
33
485
406
311
176
195
99
131
62
66
20
4
0
Rathkopf
GU ASCO 2013Slide23
COU-302PREVAIL
Abiraterone/PrednisonePrednisone
EnzalutamidePlacebo
Prednisone Use?
Y
Y
N
N
Visceral Disease
N
N
Y
Y
Grade 3/4
AE
48%
42%
43%
37%
PSA RR62%24%78%3%rPFS16.5 mo8.3 mo15-18 mo3.9 mo
OS34.7 mo30.3 mo32.4 mo30.2 mo
Time to chemo25 mo16.8 mo28 mo10.8 mo
Time to PSA progression11.2 mo
5.6 mo11.1 mo
2.8 mo
Zhang
Expert
Opin
Pharmacother
2015
COU-302
vs
PREVAILSlide24
Substantial (but incomplete) cross-resistance between these therapiesAuthor
YearNMedian Duration
PSA Decline > 50%ENZA
ABI
Loriot
2013
38
3 mo
3%
Noonan
2013
30
3.2
mo
3%
ABI
ENZA
Schrader
2013
354.9 mo29%Badrising201461
3 mo21%Bianchini201439
2.9 mo23%Schmid201435
2.8 mo10%
Brasso2014
1373.2 mo
18%Slide25
Phase III Enzalutamide +/- Abiraterone Acetate + Prednisone in Treating Patients With Metastatic CRPCAvailable at http://www.clinicaltrials.gov/NCT01949337
Patients with mCRPC with no prior docetaxel
R
A
N
D
O
M
I
Z
E
D
2:1
Enzalutamide
160 mg daily
days 1-28
Enzalutamide
160 mg daily
Abiraterone Acetate
1000 mg daily
Prednisone
5 mg BID
Endpoints
Primary:
OS
Key Secondary:
PFS and rPFS
PSA response
Toxicity
Enrollment Goal
N = 1224
PI: Michael Morris, MDSlide26
Can patients be identified that will not respond to abiraterone and enzalutamide?Slide27
Androgen Deprivation Therapy
RESTORED AR ACTIVITY
(rising PSA)
adaptation
selective
pressure
CRPC
ALTERN.
SPLICING
INTRACRINE
ANDROGEN
SYNTHESIS
T
ABERRANT
MODIFICATION
GF, cytokines
Src
Sumo
AC
P
COFACTOR
PERTURBATION
CoAct gain
CoR loss/dismissal
CoACT
MUTATION
gain of function
AR
AR
DEREGULATION
amplification
overexpressionSlide28
Androgen Receptor Splice VariantsNelson, NEJM, 2014Slide29
Antonarakis et al, NEJM, 2014ARV7 is associated with lack of response to enzalutamide and abirateroneSlide30
Galeterone Decreases AR and AR-V7
0
1
2.5
5
AR
AR-V7
b-Actin
–
110
kDa
–
80
kDa
–
45
kDa
µM
Galeterone
(72
hr
)
CWR22rv1 Cells
CWR22rv1 cells express wild type AR and AR-V7
Taplin
et al, 26
th
EORTC-NCI-AACR Symposium
Castration (Cx)
Cx + Galeterone 250 mg/kg QD, PO 5x/wk
Galeterone
Treatment
Initiated
LuCaP136 Castration Resistant
XenograftSlide31
ARMOR2: Galeterone Activity in Patients with AR C-terminal
Loss
M0 and M1 Treatment Naïve Arms
Maximal PSA, %
*
Time to PSA Progression (PCWG2):
Median 7.3 months (95% CI 2.8–NE)
Taplin
et al, 26
th
EORTC-NCI-AACR Symposium Slide32
ARMOR3-SV Trial Schematic: Phase 3 Trial
Secondary EndpointsOverall survival
Skeletal related events
Time to cytotoxic therapy
Primary Endpoint
Radiographic progression free survival
Key Inclusion Criteria
M1 disease
Progressive disease on androgen deprivation therapy based on PCWG2
Detectable AR-V7 from CTCs
ECOG 0 or 1
Key Exclusion Criteria
Prior treatment with second generation
antiandrogens
(abiraterone, enzalutamide)
Prior treatment with chemotherapy for CRPC
Galeterone
2550 mg/day
Randomize
Enzalutamide
160 mg/day
Other Endpoints
Safety
PSA50
Time to progression and ECOG deterioration
Best overall response by RECIST 1.1
CTC characterization
Pharmacokinetics
Quality of life
Taplin
et al, 26
th
EORTC-NCI-AACR Symposium Slide33
The role of immunotherapy in metastatic CRPC?Slide34
Sipuleucel-T: Autologous APCs Cultured with Antigen Fusion Protein
APC takes up the antigen
Recombinant Prostatic Acid Phosphatase (PAP) fusion antigen combines with resting antigen presenting cell (APC)
Fully activated, the APC is now
sipuleucel
-T
Antigen is processed and presented on surface of the APC
INFUSE PATIENT
T-cells proliferate and attack
cancer cells
sipuleucel-T activates T-cells in the body
Active T-cell
Inactive T-cellSlide35
Sipuleucel-T Survival BenefitSipuleucel-T was approved based on HR 0.775 (~4 month OS benefit)Survival curves separate after 6 monthsTreatment is done in 5 weeks
Well tolerated
Kantoff
NEJM
2010Slide36
IMPACT: Overall Survival by Baseline PSA
Baseline PSA
≤22.1 >22.1–50.1
>50.1–134.1
>134.1
n
128
128
128
128
Median OS, months
-Sipuleucel-T
41.3
27.1
20.4
18.4
-Control
28.3
20.1
15.0
15.6
-Difference
13.0
7.1
5.4
2.8
HR
0.51
(0.31, .85)
0.74
(0.47, 1.17)
0.81
(0.52, 1.24)
0.84
(0.55, 1.29)
Survival Benefit of Sip-T is Greater When PSA is Lower
Schellhammer
Urology
2013Slide37
Radium-223 Is For Symptomatic Patients With Bone MetsSlide38
Radium-223 Targets Bone MetastasesRadium-223 acts as a calcium mimic Naturally targets new bone growth in and around bone metastasesRadium-223 is excreted by the small intestine
Ca
Sr
Ba
RaSlide39
Radium-223 Targets Bone MetastasesAlpha-particles induce double-strand DNA breaks in adjacent tumour cellsShort penetration of alpha emitters (2-10 cell diameters) = highly localized tumour cell killing and minimal damage to surrounding normal tissue
Range of alpha-particle
Radium-223
Bone surfaceSlide40
ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design
TREATMENT
6 injections at
4-week intervals
Radium-223 (50 kBq/kg) + Best standard of care
Placebo (saline)
+ Best standard of care
R
A
N
D
OM
I
S
E
D
2:1
N = 921
PATIENTS
Confirmed symptomatic CRPC
≥ 2 bone metastases
No known visceral metastases
Post-docetaxel or unfit for docetaxel
Total ALP:
< 220 U/L vs ≥ 220 U/L
Bisphosphonate use:
Yes vs No
Prior docetaxel:
Yes vs No
STRATIFICATION Slide41
ALSYMPCA Updated AnalysisOverall SurvivalRadium-223, n = 614Median OS: 14.9 months
Placebo, n = 307
Median OS: 11.3 months
HR = 0.695
95% CI, 0.581, 0.832
P
= 0.00007
Month
0
3
6
9
12
15
18
21
24
27
30
33
36
39
Radium-223
614
578
504
369
274
178
105
60
41
18
7
1
0
0
Placebo
307
288
228
157
103
67
39
24
14
7
4
2
1
0
0
10
20
30
40
50
60
70
80
90
100
%Slide42
Local
Therapy
Androgen
Deprivation
Death
Treatment Landscape
Surgery / Radiation
Standard Androgen Deprivation Therapy
Sipuleucel-T
Docetaxel
Cabazitaxel
Radium-223
Denosumab, Zoledronic Acid
Abiraterone
EnzalutamideSlide43
The next few years…..More agentssome will be “me too” drugs?Increased understanding of the biology of CRPCEarlier use of therapiesAdjuvant, neoadjuvant, rising PSA, non-mets CRPCMore molecular diagnostics and personalization of prostate cancer subtypesTrue “hormone refractory” disease