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Treatment of Advanced Prostate Cancer: Treatment of Advanced Prostate Cancer: The Changing LandscapeThe Changing Landscape
Wm. Kevin Kelly, DOProfessor, Medical Oncology and Urology
Director, Division of Solid Tumor OncologyThomas 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 anti-androgens
– Abiraterone, Enzalutamide (MDV-3100)
• Cytotoxics – Cabazitaxel
• Immunotherapies– Sipuleucel-T
• Bone\micro-environment directed therapies– Alpharadin
– “Picking the right treatment for the right patients at the right time”
Prostate Cancer: Growth Rate and Progression
Life Expectancy
Can
cer
Pro
gre
ssio
n
Onset ofCancer
EarlyDetection
LocalizedDisease
MetastaticDisease
Prostate Cancer Death
NaturalDeath
Castration resistant:deaths from disease
Diagnoses
Rising PSA
3Clinical
Metastases:Castrate1st Line
DocetaxelStandard
2Clinical
Metastases:Castrate
Pre-
ClinicallyLocalizedDisease
1Rising PSA:
Castrate
ClinicalMetastases:Non-Castrate
4Clinical
Metastases:Castrate2nd Line
No Standard
With detectable metastases:deaths from cancer exceed
that from other causes
28,660186,320
Non-CastrateAndrogen depletion /
blockade (bicalutamide)
Prostate Cancer Clinical States: A Framework for ClinicalPractice, Drug Development, and Biomarker Qualification
Mediansurvival Hazard
(mos) ratio P-value
Combined: 18.2 0.83 0.03D 3 wkly: 18.9 0.76 0.009D wkly: 17.3 0.91 0.3Mitoxantrone 16.4 – –
Months
Pro
bab
ilit
y o
f S
urv
ivin
g
0 6 12 18 24 300.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Docetaxel 3 wkly
Docetaxel wkly
Mitoxantrone
Eisenberger M, et al. ASCO Annual Meeting Proceedings. June 2004. Abstract 4.
Docetaxel – CRPCOverall Survival—TAX 327
What to do when first line What to do when first line Docetaxel treatment fails?Docetaxel treatment fails?
VS.
Three years ago the choices were limited
Palliative Chemotherapy Phase I study
Beach
Understanding the Biology of CRPCDriver Pathways of Dependency of PC
Tomlins, S. A. Eur Urol 2009Taylor, B et al, Cancer Cell 2010
Kong D. Cancer Sci 2008Jenkins, R. B. Cancer Res 1997
Khor, L. Y. Clin Cancer Res 2007
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
Primary Mets
Intratumoral Androgen Levels Are Increased Due ToOverexpression of The Androgen Synthetic Enzymes
Steroid content
Gerald et al, Amer J Pathol 164:217, 2004
LIVERPositive control
Non-castrate metastatic
Castrate metastatic
Montgomery et al. Cancer Res 68:4447, 2008
Squaline Monoxygenase
Prostate Cancer: “Adapting” to castrate environment
ALTERN.SPLICING
ABERRANTMODIFICATION•GF, cytokines
•Src
Sumo
AC
P
COFACTORPERTURBATION
•CoAct gain•CoR loss/dismissal
CoACT
INTRACRINEANDROGENSYNTHESIS
T
MUTATION•gain of function
AR
selectivepressure
Hormone Therapy
adaptation
RECURRENT TUMOR DEVELOPMENTCRPC
RESTORED AR ACTIVITY(rising PSA)
>30% CRPC
ARDEREGULATION•amplification
•overexpression
Penning & Knudsen2010
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
H O
H O
H O
H O
O H O H
O O O
O O O
O O
O O
O
O
O
O O
O H O H O H
H
H O
O H
O H
Pregnenolone Proges terone Corticos terone
17α-Hydroxypregnenolone 17αa-Hydroxyproges terone Cortis ol
Dehydroepiandroserone Andros tenedione Tes tos terone 5α-Dihydrotes tos terone
P45017a
(17α-hydroxylase)
P45017a
(C17,20-lyas e)
21-hydroxylase11bb-hydroxylase
tes tos terone5α-reductase
H O
P450SCC
Choles terol
Aldosterone
Abiraterone
Abiraterone
Low-dose steroid replacement minimizes mineralocorticoid-related toxicity
Confidential. For Internal Use Only. Do not distribute.
60
Testosterone (by LC-MS/MS)
01
1
2
3
4
5
6
ng
/dL
10 20Start of Treatment
At Progression
70
Days
Lower Limit of Sensitivity
DHEA
Start of Treatment
28 56 At ProgressionDays
0
2.5
5.0
7.5
10.0
12.5
Nm
ol/
L
0
2
1
0.07
28 56 At ProgressionDaysStart of
Treatment
Androstenedione
nm
ol/
L
Estradiol
10 20 30 40 50 60Days Post Treatment
2.5
5.0
7.5
10.0
12.5
0
ρm
ol/
L
Abiraterone Suppresses Steroids Downstream of C17,20-lyase: Proof-of-Concept Phase I Trial
Confidential. For Internal Use Only. Do not distribute.
Phase II Trials of Abiraterone Acetate in Castration Resistant Prostate Cancer
Phase II Trials of Abiraterone Acetate in Castration Resistant Prostate Cancer
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)
Patient population NPSA decline
≥ 50%
Tumor response
(RECIST)
ECOG PS Improvement(at least one
level)
CRPC: Chemotherapy naïve1 33 24 (73%)
PR: 9 (27%)SD: 19 (58%)
8 (61.5%)
CRPC: Prior docetaxel2
47 24 (51%)PR: 6 (13%)
SD: 25 (53%)11 (35%)
CRPC: Prior docetaxel3
No prior ketoconazolePrior ketoconazole
3127
16 (52%)8 (30%)
(n = 18)PR: 3 (17%)
SD: 11 (61%)16 (48%)
COU-AA-301 Study Design
• 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)
Abiraterone 1000 mg dailyPrednisone 5 mg BID
n=797
Primary end point
• OS (25% improvement; HR 0.8)
Secondary endpoints (ITT)
• TTPP
• PFS
• PSA response
Efficacy endpoints (ITT)
Placebo dailyPrednisone 5 mg BID
n=398
RANDOMIZED
2:1
• 1195 patients with progressive mCRPC
• Failed 1 or 2 chemotherapy regimens, one of which contained docetaxel
Patients
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
HR=0.646 (0.54-0.77) P <0.0001
Placebo: 10.9 months (95% CI: 10.2, 12.0)
0 100 200 300 400 500 600 700
0
20
40
60
80
100
Ove
rall
Su
rviv
al,
%
Days from Randomization
Abiraterone: 14.8 months (95% CI: 14.1, 15.4)
1 Prior Chemo OS: 15.4 months abiraterone vs 11.5 months placebo
Abiraterone 797 728 631 475 204 25 0
Placebo 398 352 296 180 69 8 1
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
Baseline BPI <4 659 0.64 0.50-0.82
4 536 0.68 0.53-0.85
No. of prior chemo regimens 1 833 0.63 0.51-0.78
2 362 0.74 0.55-0.99
Type of progression 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
Region North America 652 0.64 0.51-0.80
Other 543 0.69 0.54-0.90
0.5 0.75 1 1.5Favors
AbirateroneFavors
PlaceboAbbreviations: HR=hazard ratio; ALK-P=alkaline phosphatase.
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
Drug-related deaths 0 0
deBono N Engl J Med. 2011 May 26;364(21):1995-2005
Overall Study Design of COU-AA-302
• 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
AA 1000 mg dailyPrednisone 5 mg BID
(Actual n = 546)
AA 1000 mg dailyPrednisone 5 mg BID
(Actual n = 546)
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
Efficacy end points
Placebo dailyPrednisone 5 mg BID
(Actual n = 542)
Placebo dailyPrednisone 5 mg BID
(Actual n = 542)
RANDOMIZED
1:1
RANDOMIZED
1:1
• Progressive chemo-naïve mCRPC patients(Planned N = 1088)
• Asymptomatic or mildly symptomatic
Patients
Ryan et al. ASCO 2012
Statistically Significant Improvement in rPFS Primary End Point
NR, not reached; PL, placebo.Data cutoff 12/20/2010.
100
80
60
40
20
0
0
Pro
gre
ssio
n-F
ree
(%)
3 6 9 15 1812
546542
489400
340204
16490
123
00
AAPL
4630
Time to Progression or Death (Months)
AA + PPL + P
AA + P (median, mos): NR
PL + P (median, mos): 8.3
HR (95% CI): 0.43 (0.35-0.52)
P value: < 0.0001
Ryan et al. ASCO 2012
Strong Trend in OS Primary End Point
546542
538534
482465
452437
2725
00
524509
503493
02
120106
258237
412387
100
80
60
40
20
0
0
Su
rviv
al (
%)
3 12 15 27
Time to Death (Months)
33
AA + PPL + P
6 9 30242118
AAPL
AA + P (median, mos): NR
PL + P (median, mos): 27.2
HR (95% CI): 0.75 (0.61-0.93)
P value: 0.0097
Updated GU ASCO 2013: Rathkopf et al. Abstract # 5-r PFS 16.5 vs. 8.3 mo. HR 0.53 (0.45-0.62) p = <0.0001- OS 35.3 vs. 30.1 mo. HR 0.79 (0.66-0.96) 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
Atrial fibrillation 4 1.3 5 0.9
ALT increased 12 5.4 5 0.8
AST increased 11 3.0 5 0.9
Most ALT and AST increases occurred during the first 3 months of treatment
Ryan et al. ASCO 2012
Subsequent Therapy Was Commonand Still a Survival Trend Observed
AA + P(n = 546)
n (%)
Placebo + P(n = 542)
n (%)
No. with selected subsequent therapy for mCRPC 242 (44.3) 327 (60.3)
Docetaxel 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)
*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
X Previous ketoconazole therapy
Agus DB, et al. ASCO 2011. Abstract 4531.
275250225200175150125100
25
-25
-75
7550
0
-50
-100-125P
SA
Ch
an
ge
at
12
Wk
s (
%)
x x xx
X x x x xx
x xx x
X x xx x x x x x
300 mg BID (n = 23)600 mg BID + prednisone (n = 26)
400 mg BID + prednisone (n = 24)600 mg QDAM (n = 24)
Treatment
Enzalutamide (MDV3100)
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
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
Enzalutamide1
3
2
T
AR
T
Cell nucleus
Inhibits Binding of Androgens to AR
Inhibits Nuclear Translocation of AR
Inhibits AssociationOf AR with DNA
AR
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.
Cell cytoplasm
Tran et al. Science 2009;324:787–90.
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 castration-resistant prostate cancer: a phase 1-2 study
Pre-chemotherapyN=65
Post-chemotherapyN=75
Grade 3-4 adverse events in >2 patients N (%)
Adverse eventAll doses(n = 140)
≤ 240mg/day (n = 87)
Fatigue 16 (11%) 5 (17%)
Anemia 4 (3%) 3 (3%)
Arthralgia 3(2%) 2(2%)
Seizure 3 (2%) 0Scher et al. Lancet 375:1437-1446, 2010
AFFIRM: Phase 3 Trial of Enzalutamide vs Placebo in Post-Chemotherapy Castration-
Resistant Prostate Cancer (CRPC)
RANDOMIZED
2:1
RANDOMIZED
2:1
Primary
Endpoint:Overall Survival
Enzalutamide 160 mg daily
n = 800
Enzalutamide 160 mg daily
n = 800
Placebon = 399Placebon = 399
Patient Population:
1199 patients with progressive CRPC
* Failed docetaxel chemotherapy
*Glucocorticoids were not required but allowed
ASCO June 2012Tran et al. Science 2009;324:787–90.
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 Grade ≥ 3 Events
Enzalutamide
(n = 800)
Placebo(n = 399)
Enzalutamide
(n = 800)
Placebo(n = 399)
Seizure 0.6% 0.0% 0.6% 0.0%
De Bono et al. ASCO 2012
rPFS
PSA
Association of PSA progression and rPFS
de Bono JS et al. N Engl J Med 2011;364:1995-2005De Bono et al. ASCO 2012
AFFIRM COU-AA-301
Agent Function PhaseAbiraterone Acetate CYP 17 α-hydroxylase\12,20-lyase
inhibitorFDA approved
TAK-700 CYP 17,20 lyase inhibitor -Phase III
Enzalutamide (MDV3100) Anti-androgen\androgen receptor signaling inhibitor
-Completed Phase III-Ongoing Phase III in non-castrate disease
ARN-509 Anti-androgen -Phase III
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
Novel Agents Targeting the Androgen Pathway
Cabazitaxel
• Microtubule stabilizer
• Developed in docetaxel-resistant prostate cancer cell lines
• a favorable pharmacokinetic and safety profile
• decreased propensity for P-glycoprotein (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
RA
ND
OM
IZE
Cabazitaxel 25 mg/m2 Q 21 dPrednisone 10 mg daily
N=755
MitoxantronePrednisone 10 mg daily
146 Sites / 26 Countries
Abbreviation: PD=progressive disease.Source: deBono et al. Lancet. 2010;376:1147-1154.
TROPIC Primary Endpoint – OS (ITT Analysis)
MP 377 300 188 67 11 1 CBZP 378 321 231 90 28 4
Numberat Risk
80
60
40
20
0
100
0 months 6 months 12 months 18 months 24 months 30 months
15.112.7Median OS (months)
0.59–0.8395% CI
<.0001P Value
0.70Hazard Ratio
CBZPMP
Abbreviation: ITT=intent-to-treat.Source: deBono et al. Lancet. 2010;376:1147-1154.
Pro
po
rtio
n o
f O
S (
%)
Most Frequent Grade ≥3 Treatment-Emergent AEs*
MP (n=371) CBZP (n=371)
All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%)
Any AE 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.
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
Patient’s white blood cells harvested
Short-term culture with protein “cassette”
Shipping
Cells infused back into patient (IV)
GM-CSFProstatic acid
phosphatase
Active Cellular Immunotherapy(Sipuleucel-T)
Overall Survival Study D9902B
Study D9902A
StudyD9901
Sip-T Placebo Sip-T Placebo Sip-T Placebo
Median, Months
(95% CI)
25.8
(22.8, 27.7)
21.7
17.7, 23.8)
19
(13.6, 31.9)
15.7
(12.8, 25.4)
25.9
(20.0, 32.4)
21.4
(12.3, 25.8)
Hazard Ratio
(95% CI)
0.775
(0614,0.979)
0.786
(0.484, 1.278)
0.568
(0.388, 0.884)
P 0.032 0.010 0.331
Sipuleucel-T in Prostate Cancer
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
Liu H et al. Cancer Res 1997; 57: 3629Liu H et al. Cancer Res 1998; 58: 4055
Capromab binding site
J591binding site
90% decline
177Lu-J591 Rx: Excellent Targeting & PSA Response
6 months
99mTc-MDP bone scan 177Lu-J591 mAb PSADT=3.9 mo
Ant Post Ant Post
Log scale
Arithmetic scale
30/32 (94%) with accurate targeting of known sites of disease
Tagawa et al, ASCO 2008
Defining the Future:Ongoing Immumotherapy Trials
Study Phase StudyPopulation
Treatment Outcome
PROTECTP-11
III Non-metastatic ADPC 3 mo. ADT + Sip-T vs. control
PSADT,Distant Failure,OS
NeoACTP07-1
II Localized PC Sip-T x 3 prior to RPPost-op Boost vs. no Boost
Immune response, Safety
ProACTP07-2
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 177Lu-J591
PFS, OS, PSA, RECIST
BMS CA 184043Ipi\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
Ra
Ca
Alpha Beta
Relative particle mass 7000 1
Initial energy (MeV) 3-8 0.01-2.5
Range in tissue (µm) 40-90 50-5000
LET (KeV/µm) 60-230 0.015-0.4
Charge +2 -1
Ion pairs/µm 2000-7000 5-20
DNA hits to kill cell 1-5 100-1000
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
Range of alpha-particleRange of alpha-particle
Radium-223Radium-223
Encouraging Phase II results
TREATMENT
6 injections at 4-week intervals
Radium-223 (50 kBq/kg) + Best standard of care
Radium-223 (50 kBq/kg) + Best standard of care
Placebo (saline) + Best standard of care
Placebo (saline) + Best standard of care
RANDOMISED
2:1
N = 922
PATIENTS
• Confirmed symptomatic
CRPC
• ≥ 2 bone metastases
• No known visceral
metastases
• Post-docetaxel or unfit for docetaxel
• Confirmed symptomatic
CRPC
• ≥ 2 bone metastases
• No known visceral
metastases
• Post-docetaxel or unfit for docetaxel
ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design
Clinicaltrials.gov identifier: NCT00699751.
• Total ALP: < 220 U/L vs ≥ 220 U/L
• Bisphosphonate use: Yes vs No
• Prior docetaxel: Yes vs No
• Total ALP: < 220 U/L vs ≥ 220 U/L
• Bisphosphonate use: Yes vs No
• Prior docetaxel: Yes vs No
STRATIFICATION
Planned follow-up is 3 yearsPlanned follow-up is 3 years
Month 0 3 6 9 12 15 18 21 24 27
Radium- 223 541 450 330 213 120 72 30 15 3 0
Placebo 268 218 147 89 49 28 15 7 3 0
ALSYMPCA Overall Survival
00
1010
2020
3030
4040
5050
6060
7070
8080
9090
100100
% %Radium-223, n = 541
Median OS: 14.0 monthsRadium-223, n = 541
Median OS: 14.0 months
Placebo, n = 268Median OS: 11.2 months
Placebo, n = 268Median OS: 11.2 months
HR 0.695; 95% CI, 0.552-0.875
P = 0.00185HR 0.695; 95% CI, 0.552-0.875
P = 0.00185
EORTC 2011
Radium-223n (%)
Placebon (%)
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.*In patients who had elevated total ALP at baseline.
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
ALSYMPCA Secondary Endpoints: ALP and PSA
EORTC 2011
ALSYMPCA Adverse EventsAll Grades Grades 3 or 4
Radium-223(n = 509)
n (%)
Placebo(n = 253)
n (%)
Radium-223(n = 509)
n (%)
Placebo(n = 253)
n (%)
Haematologic
Anaemia 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)
Non-Haematologic
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)
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
*At progression, patients on placebo could cross-over to cabozantinib (n = 14).
Lead-in StageCabozantinib
100 mg/day PO(n = 171)
Patients with mCRPC and measurable
disease; rising PSA only, not eligible
SD(n = 31)
12 wks
Cabozantinib100 mg/day PO
(n = 14)
Placebo daily(n = 17)
Until PD*
Randomization
PR or CR
(n = 79)
Open-Label ExtensionCabozantinib
100 mg/day PO
PD(n = 61)
Discontinue cabozantinib
Hussain M, et al. ASCO 2011. Abstract 4516.
Cabozantinib vs Placebo in mCRPC: Efficacy and Safety
• 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.
-12 0 10 20 30 40 50 60
PFS per mRECIST, Postrandomization (Wks)
12-WkLead-in Stage
Pro
po
rtio
n
Pro
gre
ss
ion
Fre
e
1.00
0.75
0.50
0.25
Cabozantinib (n = 14)Placebo (n = 17)
(HR 0.13; log-rank P = .0007)
Median PFS, Wks21 6
Phase III Trials for CRPC (First line chemotherapy trials)
Sponsor Treatment
*Novacea Docetaxel ± DN101
*SWOG Docetaxel ± atrasentan
*CALGB Docetaxel ± bevacizumab
*Sanofi-Aventis Docetaxel ± aflibercept
NCI Docetaxel or KAVE
Doxorubicin ± Strontium-89
*Cell Genesys Docetaxel vs. GVAX
*Cell Genesys Docetaxel ± GVAX
*Zeneca Docetaxel ± zibotentan
*Bristol Docetaxel ± dasatinib
OncGeneX Docetaxel ± Custirsen*Closed to accrual*Closed to accrualNo improvement of Survival
OS Benefit in Recent CRPC TrialsTrial/
Agent/ Date
Approved
Mechanism ComparatorSurvival(months)
Hazard Ratio
P-value
AFFIRMEnzalutamid
e2012
Androgen Receptor Signaling Inhibitor
Placebo 18.4 vs. 13.6 0.631 <0.0001
COU-AA-301 Abiraterone
+ prednisone
2011
CYP17 Inhibitor
Placebo +prednisone
14.8 vs. 10.9 0.646 <0.0001
TROPIC Cabazitaxel
+ prednisone
2010
CytotoxicMitoxantrone +
prednisone15.1 vs. 12.7 0.70 <0.0001
Alpharadin*2012
Alpha-particle emitting
radionuclidePlacebo 14.9 vs. 11.3 0.69 0.0018
* Only 60% of these patients were post-docetaxel patients
Would suggest the post-chemotherapy population remains
heterogonous
Would suggest the post-chemotherapy population remains
heterogonous
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?
Multivariate Model: Higher Baseline Androgens Associate With Improved OS:
• Treatment effect: Robust• Laboratory parameters: All significant (LDH, Hgb, ALP, PSA)*Including 1 androgen at a time (dichotomized) and other lab parameters (dichotomized).
HR p Value
Testosterone 0.667 < 0.0001
HR p Value
Androstenedione 0.679 < 0.0001
HR p Value
DHEA 0.691 < 0.0001
Ryan et al Proc AACR 2012
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
• 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.
Efstathiou E et al. JCO 2012;30:637-643
Effects of Abiraterone Acetate on Androgen Signaling in Castrate-Resistant Prostate Cancer in Bone
• Serum Androgen Levels
Molecular characterization of CTCs in CRPC(N= 89 patients treated with Abiraterone)
Attard, G. et al. Cancer Res 2009;69:2912-2918
1. CTC collected by Immunicon system
2. 57% had CTC ≥ 4 (40% chemo naïve; 82% Docetaxel treated)
3. ERG rearrangement was associated with magnitude of PSA decline on abiraterone
4. Concordance in ERG gene status of CRPC tumor biopsy and CTC’s
5. Heterogeneity in AR copy number and PTEN loss noted
The RB loss signature should be developed as a metric to direct therapeutic intervention for CRPC
Direct toward therapies that hyperactivate RB function
RB+ gene signature
e.g. CDK4 inhibitors
Capitalize on loss of cell cycle checkpoints
RB- gene signature
e.g. a subset of chemotherapeutics that induce DNA damage
•Feb 2011:Gene Chip to readout for RB
function & other key prostate-specific markers generated &
validated
Sharma et al, J. Clin Investigation
RB+/RB-tumors
Cabazitaxel + abiraterone acetateRegistration
A phase II multicenter trial combining Cabazitaxel and Abiraterone Acetate in treatment of metastatic
Castration Resistant Prostate Cancer (Knudsen\Kelly)
Lower quartile Interquartile range Upper quartile
RB
tar
get
gene
s
RB Prostate Signature
Androgen Profiles•Testosterone•Androstenedione•DHEA
Conducted in PCCTC
The Changing Landscape in Prostate Cancer
EnzalutamideAbirateroneCabazitaxelAlpharadinSipuleucel-T
AlpharadinSipuleucel-TZolendronic AcidDenosumabSamariumDocetaxelMitoxantrone
BicalutamideFlutamideNilutamide
LhRH agonistsLhRH antagonists
BicalutamideFlutamideNilutamide
LhRH agonistsLhRH antagonists
Therapies with a Clinical Benefit
Need for biomarker driven trials to direct patient treatment
17α hydrolase/17, 20 lyase inhibitor Abiraterone, TAK 700Anti-angiogenic/immunomodulatory CC-4047,Lenalidomide, ABR-215050, cediranib, AS1404Anti-CTLA4\PD-1 antibody Ipilimumab, MLN2704Anti-CCL2 CNTO 888Anti-FGFR3 TKI 258Anti-Il-6 antibody CNTO 95Anti-insulin-like GFR antibody IMC-A12Anti-integrin anti-body CNTO 95Anti-PSMA immunoconjugate MLN2704, 177 Lu-J591Anti-prostate stem cell antibody AGS-PSCAAnti-VEGF Bevacizumab, AlfiberceptCytotoxic agent ABT-751, abraxane, E7389, SB-715992, carbazitaxel
Irofulven, Paclitaxel poliglumex, TPI 287, E7389Clusterin inhibitor OGX-11EGFR antibodies\TKI Pertuzumab, Cetuximab, Erlotinib, Gefitnib, Faranesyl protein transferase inhibitor R115777GMP phospodiesterase inhibitor ExisulindHSP-90 inhibitor 17-AAG, IPI-504HDACi LBH589, Vorinostat, Belinostat, SB939HGF inhibitor AMG 102Hypoxia activated pro-drug TH 302IGF inhibotors Citutumumab, figitumumab, octreotide, pasireotideIntegrin receptor antagonist CilengitideIl-11 inhibitor BMTP-11JAK inhibitor INCB-18424M-TOR inhibitor Temsirolimus Multi-targeted TKI Sunitinib, Sorafenib, CEP 701, vatalinib, DMXAAMMP-9 inhibitor PCK 3145Pro-apoptotic agent AT-101Proteosome Inhibitor BortezomibRANKL inhibitor DenosumabSRC kinase inhibitor KX2-391Signal Transduction inhibitor PCK-3145Survivin suppressant YM155
Novel Agents in CRPC
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
GU-Investigator Initiated Trails at KCC
Genitourinary Oncology TeamMedical 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