Transcript monoclonal antibody-based therapy of prostate cancer

Update on the Treatment
of Prostate Cancer
David M. Nanus, MD
Chief, Division of Hematology and Medical Oncology
Weill Medical College of Cornell University
New York Presbyterian Hospital
Demographics
 238,590 estimated new cases in 2013
- 27.9% of all cancers in males
- most common cancer in men
- Lifetime risk: 16% (1 in 6)
 29,720 estimated deaths
- 9.7% of cancer deaths in males
- second to lung cancer in men
Death from other causes
Clinically
Localized
Disease
Adapted from Scher et al.
Rising
PSA
Death from
Prostate cancer
Clinical
Metastases
Non-Castrate
Castrate
Rising
PSA
Castrate
Metastatic
Disease
PSA – Like a Clint Eastwood Movie
 The Good
PSA-based early detection decreases
mortality
 The Bad
Not perfectly sensitive or specific
 Over-detection compounded by
Over-treatment
 The Ugly
Treatment arbitrary, variable, often
unnecessary and increasingly costly
Screening Recommendations
 Shared decision making
 Annual PSA and DRE
- from age of 40 (AUA); age 50 (ACS)
- High risk: 40-45 (African American; 1rst degree relative)
 Frequency
- AUA: annually (based on initial PSA)
- ACS: annually (every 2 year if PSA < 2.5 ng/ml)
 Discontinue: life expectancy <10 years
The Changing Face of Prostate Cancer
in the United States
Cooperberg et al. J Urol 2007; 178:S14
Significance of cancer:
Determining need for treatment
 Patient (age, comorbidities)
 Gleason score
- sum of two predominant areas
 Tumor characteristics
- Number of positive cores
- Percent positive within each core
 Molecular profile
Active Surveillance
Rationale
Hypotheses
 Screening results in the
detection of very early
stage/grade lesions - many
indolent
 Surveillance in low risk
patients is feasible and
associated with a limited risk
of progression
 Current staging/grading
techniques accurate
 Progression can be
quantitated
 Natural history prolonged
and can be measured
 Predictors of progression
and treatment can be
identified
Intervention
Overall Survival
1.0
0
2
4
6
8
10
12
14
97% at 10 years
N=452
0.0
0.0
0.2
0.4
Survival distribution function
0.6
0.8
1.0
0.8
0.6
0.4
0.2
Survival distribution function
Ca-Specific Survival
0
2
Surveillance Survival (years)
62% free of intervention at 10 y
Klotz L, et al. J Clin Oncol 2010;26:126–31
4
6
8
10
12
14
Overall Survival (years)
5/452 patients
All PSADT ≤ 1.6 years
Defining the Triggers for Intervention
• Change in PSA kinetics: PSADT <3 y
• Progression on follow-up biopsy
• Increase in Gleason grade
• Increase in tumor volume
–
–
–
–
Increase in absolute cores involved with cancer
Increase in percent of positive cores >33%
Increase in absolute tumor length (mm)
Increase in percent of tumor tissue >50% within single core
• Patient preference
• Clinical/radiographic evidence of local/distant progression
What’s new in prostate cancer therapy?




Targeting the androgen axis
Immunotherapy
Chemotherapy
Bone targeted therapies
 Molecular genetics
 Circulating prostate cancer tumor cells
Intermittent versus continuous androgen deprivation in
hormone sensitive metastatic prostate cancer patients:
Results of S9346 (INT-0162), An international phase III trial
 3040 hormone naïve metastatic patients
-
PS 0-2
PSA ≥ 5 ng/ml
treated with 7 months of goserelin + bicalutamide
 1535 pts PSA ≤4 ng/ml
- randomized to CAD or IAD
 Primary objective: non-inferior
 Median Follow up: 10 years
Management of Castrate Resistant
Metastatic Prostate Cancer
 Androgen Signaling Axis Therapy
- Abiraterone
- Enzalutamide (MDV3100)
 Chemotherapy
- Docetaxel
- Cabazitaxel
- Mitoxantrone
 Bone Targeted
- Radium-223
Intra-cellular androgen
Alternatively-spliced AR
Adapted from Harris et al. Nature Reviews Clin Onc 2009
Simplified view of cholesterol  testosterone synthesis
cholesterol
Occurs in: Testes,
Adrenal Gland,
Prostate cancer cells
pregnenolone
CYP17
Mineralocorticoids
17α-hydroxypregnenolone
CYP17
Cortisol
DHEA
androstenedione
Testosterone
DHT
Montgomery et al. Cancer Res 2008
Locke et al. Cancer Res

Abiraterone
Acetate
cholesterol
Oral irreversible inhibitor of
CYP17
- 17α –hydroxylase
- C17,20-lyase
 Inhibits testosterone
production in testis, adrenal,
and prostate
pregnenolone
CYP17
Mineralocorticoids
17α-hydroxypregnenolone
CYP17
Cortisol
DHEA
androstenedione
Testosterone
DHT
Montgomery et al. Cancer Res 2008
Locke et al. Cancer Res
COU-AA-301Abiraterone Acetate + prednisone vs Placebo + prednisone
in men with progressive metastatic CPRC after docetaxel
Overall survival HR=hazard ratio. AA=abiraterone acetate. P=prednisone.
de Bono JS et al. N Engl J Med 2011;364:1995-2005.
Fizazi et al. Lancet Oncol 2013;13:983.
Secondary End Points
de Bono JS et al. N Engl J Med 2011;364:1995-2005.
Hazard Ratios for the Risk of Death, According to Subgroup
de Bono JS et al. N Engl J Med 2011;364:1995-2005.
COU-AA-302
Chemo-naïve CRPC
(n=1088)
Asymptomatic or
mildly symptomatic
Abiraterone 1000 mg/d
Prednisone mg bid
Placebo daily
Prednisone mg bid
Primary endpoint: Radiographic PFS, OS
Secondary endpoints: Time to – opiate use; chemotherapy; EOCS-PS
deterioration; progression
COU-AA-302: Updated interim results
Prednisone
Abiraterone +
Prednisone
Radiographic
PFS
8.3 mos
16.5 mos
HR 0.53;
p < 0.0001
Overall Survival
30.1 mos
35.3 mos
HR 0.79;
p = 0.0151*
69%
29%
Median Time to
Chemotherapy
16.8 mos
26.5 mos
HR: 0.61
p < 0.0001
Median Time to
Opiate Use
23.7 mos
NR
HR 0.71
p = 0.0002
> 50% PSA
decline
* did not cross the prespecified boundary for significance (p = 0.0035)
Ryan CJ et al. N M2013;368:138-148 + GU ASCO 2013
Adverse Events of Special Interest.
Ryan CJ et al. N Engl J Med 2013;368:138-148.
AFFIRM: Enzalutamide (MDV3100)
Scher HI et al. N Engl J Med 2012;367:1187-1197.
Subgroup Analyses of Hazard Ratios for Death in the Two Study Groups
Scher HI et al. N Engl J Med 2012;367:1187-1197.
Enzalutamide
• PREVAIL trial: Phase 3 CRPC before chemotherapy
• TERRAIN trial: Phase 2 comparing Enzalutamide with
bicalutamide in men who have progressed on LHRH analogue
therapy or following surgical castration
 Other studies:
Enzalutamide + docetaxel
Enzalutamide + abiraterone
Cabazitaxel/Prednisone vs Mitoxantrone/Prednisone
de Bono et al, Lancet 2010: 1147-54
Immunotherapy
 Cancer vaccines
 Modulation of immune regulatory mechanisms
- Blocking CTLA-4
- Blocking PD-1 or PDL-1
 Monoclonal antibody targeting of tumour
growth
IMPACT Trial
HR=0.759 (95% CI: 0.606, 0.951)
P=.017 (Cox model)
Median Survival Benefit: 4.1 months
Sipuleucel-T (n=341)
Median Survival: 25.8 months
36-months survival: 32.1%
Control (n=171)
Median Survival: 21.7 months
36-months survival: 23.0%
Kantoff et al, ASCO GU 2010
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
Parker et al; ECCO-ESMO 2011
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
6 injections at
4-week intervals
Radium-223 (50 kBq/kg) +
Best standard of care
Placebo (saline)
+ Best standard of care
2:1
N = 922
Clinicaltrials.gov identifier: NCT00699751.
Parker et al; ECCO-ESMO 2011
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
Parker et al; ECCO-ESMO 2011
CRPC Therapeutic Options
Increase in
median survival
Relative
reduction in risk
of death
Hazard ratio
(95% CI; P-value)
3. 9 mos
35%
0.65
(0.54-0.77;
P<0.001)
Enzalutamide vs.
placebo
4.8 mos
37%
0.63
(P<0.0001)
Docetaxel(q3w)/P
vs. Mitoxantrone/P
2.4 mos
24%
0.76
(0.62-0.94;
P=0.009)
Cabazitaxel/P vs.
mitoxantrone/P
2.8 mos
30%
0.70
(0.59-0.83;
P<0.0001)
Sipuleucel T vs.
placebo
4.1 mos
22%
0.78
(0.61- 0.98;
P:0.03)
Alpharadin vs.
placebo
2.8 mos
31%
0.70
(0.55-0.88;
P:0.00185)
Abiraterone/P vs.
placebo/P
Phase III Randomized Trials vs. Docetaxel + Prednisone
Primary Endpoint: Overall Survival
Trial Name
Arm B: DocPred plus
Mechanism
ASCENT-2
DN101
Calcitriol
CALGB 90401
Bevacizumab
VEGF
SWOG 0421
Atrasentan
Endothelin receptor antagonist
MAINSAIL
Lenalinomide
Anti-angiogenic; immune
VENICE
Aflibercept
Soluble VEGF fusion protein
ENTHUSE 33
Zibotentan
Endothelin receptor antagonist
READY
Dasatinib
SRC kinase inhibitor
SYNERGY
OGX-11
Antisense to clusterin
(cell survival protein)
FIRSTANA
vs. Cabazitaxel
(unTxed)
Taxane Chemotherapy
Molecular Markers
 Beyond the microscope
 May be diagnostic, prognostic, and/or predictive
 Gene fusions
TMRPSS2-ERG
 Expression of abnormal proteins
Many may be targetable
 Circulating Tumor Cells (CTCs)
Molecular Classification of
Prostate Cancer
* Discoveries led by NYP-Weill Cornell Medical College
Frequency
Therapy
Ets gene fusion
50-60%
PARP inhibitor
PTEN/MAGI2
25-40%
PI3K inhibitor
BRAC2/ATM
20%
PARP inhibitor
Spink1
10-15%
EGFr inhibitor
Aurora kinase A
5-40%
AURK inhibitor
SPOP
10%
?
BRaf fusion
1%
Raf inhibitor
Frequency
Therapy
Ets gene fusion
50-60%
PARP inhibitor
PTEN/MAGI2
25-40%
PI3K inhibitor
BRAC2/ATM
20%
PARP inhibitor
Neuroendocrine or
Spink1
10-15%
EGFr inhibitor
Aurora kinase A
5-40%
AURK inhibitor
anaplastic prostate cancer
SPOP
10%
?
BRaf fusion
1%
Raf inhibitor
Multi-institutional Phase II Trial of The Aurora kinase A inhibitor
MLN8237 for Patients with Neuroendocrine Prostate Cancer
 Inclusion Criteria:
- Pathologic diagnosis
- Clinical diagnosis: visceral metastases in absence
of PSA progression, elevated serum
neuroendocrine marker
 MLN8237 50 mg bid orally x 7 d on 21 day cycle
 Molecular biomarkers
- Tumor biopsies
- CTC analyses
- Exome/transcriptome sequencing
TAXSYNERGY: Phase II Trial to Evaluate Benefit of Early Switch from first-Line
Docetaxel/Prednisone to Cabazitaxel/Prednisone and the opposite sequence,
exploring molecular markers and mechanisms of taxane resistance in men with
Metastatic mCRPC who have not received prior chemotherapy
100 men with
Chemotherapy
naïve metastatic
CRPC
R
A
N
D
O
M
I
Z
E
Docetaxel
75 mg/m2
2:1
>30% PSA
reduction
Docetaxel
Continued
<30% PSA
reduction
Switch to
Cabazitaxel
>30% PSA
reduction
Cabazitaxel
Continued
<30% PSA
reduction
Switch to
Docetaxel
4 cycles
Cabazitaxel
25 mg/m2
Primary Objective: Explore benefit of an early switch from DOC to CBZ
Evaluate the association of biomarkers with clinical response/resistance to Rx
- Molecular Drug Target Engagement (DTE) in CTCs
- RNA sequencing on CTCs to assess for tubulin mutations and AR isoforms
100 men with
Chemotherapy
naïve metastatic
CRPC
R
A
N
D
O
M
I
Z
E
Docetaxel
75 mg/m2
2:1
>30% PSA
reduction
Docetaxel
Continued
<30% PSA
reduction
Switch to
Cabazitaxel
>30% PSA
reduction
Cabazitaxel
Continued
<30% PSA
reduction
Switch to
Docetaxel
4 cycles
Cabazitaxel
25 mg/m2
GEDI CTCs
Baseline: Multiplex confocal, AR Taqman variant, RNA-Seq, ex-vivo predictive assays
Cycle 1/Day 8 : Multiplex confocal (enumeration; AR subcellular localization; endogenous DTE)
C4 Crossover :Mutliplex confocal, AR Taqman variant, ex-vivo predictive assays
C5/Day 8: Multiplex confocal
Relapse: Mutliplex confocal, AR Taqman variant, RNA-Seq
Bone Targeted Therapy
CALGB 90202: A Randomized, Double-Blind, Placebo-Controlled Phase III
Study of Early versus Standard Zoledronic Acid (ZA) to Prevent Skeletal
Related Events in Men with Prostate Cancer Metastatic to Bone
 Eligibility:
> 1 bone metastasis, ADT therapy within 6 mos of enrollment
 Therapy:
Zoledronic acid or placebo q 4 weeks
 Median time to first SRE (skeletal-related event)
32.5 vs 29.8 mos (HR = 0.96 [0.76-1.22]; P=0.74)
 > Grade 3 toxicity same (15% vs. 12% in ZA and P)
 Overall survival (HR= 0.89 [0.70-1.14]; P=0.34)
Smith MR et al. 2013 GU Cancers Symposium
Targeted Therapy: Denosumab vs zoledronic acid for
Skeletal Related Events risk-reduction in CRPC
Fizazi et al, Lancet 2011; 377: 813
Denosumab vs placebo to improve
bone-metastases free survival
Smith et al, Lancet 2011
Management of Metastatic CRPC
Sequencing???
 Chemotherapy
- Docetaxel, Cabazitaxel, Mitoxantrone
 Androgen Signaling Axis Therapy
- Abiraterone
- Enzalutamide
 Bone Targeted
- Denosumab
- Alpharadin
Prostate cancer clinical states model
enzalutamide
Scher H I et al. JCO 2011;29:3695-3704
Prostate cancer clinical states model
enzalutamide
Scher H I et al. JCO 2011;29:3695-3704
Cabozantinib (XL184): orally bioavailable tyrosine kinase inhibitor
against MET and VEGFr2 in men with CRPC
Smith D C et al. JCO 2013;31:412-419
PFS in (A) randomly assigned patients with CRPC; and
(B) patients with CRPC by docetaxel pretreatment status
Smith D C et al. JCO 2013;31:412-419
Bone scan effects of cabozantinib treatment on study patients
Smith D C et al. JCO 2013;31:412-419
Where We Are Now: Positive Phase 3 Trials in Met CRPC
Trial
Canadian
N = 161
Design
Mitoxantrone/prednisone vs
prednisone
HR
Endpoint
Comment
NR
Palliation in 29% vs
12% (duration 42 vs
Approval of mitoxantrone (also
CALGB 9182)
18 wks)
TAX 327
N = 1006
Docetaxel/prednisone vs
mitoxantrone/prednisone
0.76
OS 18.9 vs
16.5 mo
Docetacel/pred approved as
new standard
SWOG 9916
N = 770
Docetaxel/estramustine vs
mitoxantrone/prednisone
0.80
OS 17.5 vs
15.6 mo
Support docetaxel as new
standard
ZAPCSG
N = 643
Zoledronic acid vs placebo
NR
SRE 33.2% vs
44.2%
Zoledronic acid reduces SRE’s
IMPACT
N = 512
Sipuleucel-T vs Control
0.78
OS 25.8 vs
21.7 mo
Sip-T approved min
symptomatic metCRPC
Dmab 103
N = 1904
Denosumab vs zoledronic acid
0.82
SRE-free 20.7 vs
17.1 mo
Denosumab approved
TROPIC
N = 755
Cabazitaxel/prednisone vs
mitoxantrone/prednisone
0.70
OS 15.1 vs
12.7 mo
Cabazitaxel approved postdocetaxel
COU-AA-301
N = 1195
Abiraterone/prednisone vs
Placebo/prednisone
0.65
OS 14.8 vs
10.9 mo
Abi/pred approved postdocetaxel
ALSYMPCA
N = 922
Radium-223/BSC vs placebo/BSC
0.70
OS 14.0 vs
11.2 mo
Pending approval
AFFIRM
N=1199
Enzalutamide vs Placebo
0.63
OS 18.4 vs
13.6 mo
Enzalutamide approved postdocetaxel
COU-AA-302
N = 1088
Abiraterone/prednisone vs
Placebo/prednisone
0.43
16.5 mos vs
8.3 mo
Strong trend for OS