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Prostate Cancer: New
Agents and Emerging
Clinical Algorithms
Thursday, October 11, 2012
7:30 PM – 8:30 PM ET
Neil Love, MD
Research To Practice
Miami, Florida
Christopher J Logothetis, MD
Chairman/Professor
Genitourinary Medical Oncology
The University of Texas MD Anderson Cancer Center
Houston, Texas
A Oliver Sartor, MD
Medical Director
Tulane Cancer Center
Laborde Professor of Cancer Research
Professor of Medicine and Urology
Tulane Medical School
New Orleans, Louisiana
Agenda — Emerging Systemic Treatments
for Prostate Cancer
• Optimal Sequencing of Endocrine Therapy
– Case from Dr Sartor: 75-year-old retired attorney
– Continuous vs intermittent ADT
– COU-AA-301, COU-AA-302: Abiraterone
– AFFIRM: Enzalutamide
– Early data with TAK-700 (Orteronel)
• Bone-Targeted Treatment
– ALSYMPCA: Radium-223
• Tolerability of Next-Generation Hormonal Agents
– Faculty cases
• Other New Agents of Interest
– Cabozantinib, dasatinib
Current Controversies, Recent
Developments and Emerging Strategies
in the Management of Prostate Cancer
A Clinical Investigator Think Tank
Faculty
Tomasz M Beer, MD
Robert Dreicer, MD, MS
Mario A Eisenberger, MD
William K Oh, MD
Daniel P Petrylak, MD
A Oliver Sartor, MD
Susan F Slovin, MD, PhD
Matthew R Smith, MD, PhD
Moderator
Neil Love, MD
Faculty Case: Dr Sartor
• A 75-year-old retired attorney with an active lifestyle
• Underwent radical prostatectomy 5 years prior
– Recurrence followed by salvage radiation therapy
• PSA-only recurrence:
– PSADT = 8 months
– PSA 4.6 ng/mL
• Patient experiencing “PSA anxiety”
A 75-year-old underwent radical prostatectomy 5
years ago  recurrence  salvage radiation  PSA
recurrence. Workup shows no metastases. PSADT =
8 months, PSA currently 4.6 ng/mL.
What systemic treatment, if any, would you likely
recommend?
Observation only
18%
Continuous androgen-deprivation
therapy (ADT)
33%
Intermittent ADT
Other
48%
0%
0%
10%
20%
30%
40%
50%
60%
Current Controversies, Recent Developments and
Emerging Strategies in the Management of Prostate
Cancer — A Clinical Investigator Think Tank
September 7, 2012
75-year-old with PSA-only disease
• Robert Dreicer, MD, MS: “There’s no right answer; I
would not have initiated therapy.”
• Mario A Eisenberger, MD: “No, I don’t think we would
start treatment. We would wait”
• Susan F Slovin, MD, PhD: “I would not initiate therapy.”
A 55-year-old underwent radical prostatectomy 5
years ago  recurrence  salvage radiation  PSA
recurrence. Workup shows no metastases. PSADT =
8 months, PSA currently 4.6 ng/mL.
What systemic treatment, if any, would you likely
recommend?
Observation
only
19%
Continuous
ADT
36%
Intermittent
ADT
39%
Other
6%
0%
10%
20%
30%
40%
50%
Intermittent (IAD) versus Continuous
Androgen Deprivation (CAD) in
Hormone Sensitive Metastatic
Prostate Cancer (HSM1PC) Patients
(pts): Results of S9346 (INT-0162), an
International Phase III Trial
Hussain M et al.
Proc ASCO 2012;Abstract 4.
Study Design
STEP 1
Induction Registration
Newly diagnosed metastatic prostate cancer & a PSA ≥5 ng/mL
Induction AD = Goserelin + Bicalutamide X 7 months
STEP 2
Randomly Assign
If PSA ≤4 ng/mL on months 6 & 7 (PSA
normalization criteria)
Continuous AD
Intermittent AD
Discontinue AD, monthly PSAs.
Resume AD based on pre-specified criteria
Hussain M et al. Proc ASCO 2012;Abstract 4.
Overall Survival (OS): Intermittent Therapy Is
Inferior Compared to Continuous Therapy
Continuous therapy
(n = 765)
Intermittent therapy
(n = 770)
5.8 years
5.1 years
Median overall survival
1.09
(0.95-1.24)
Hazard ratio (95% CI)*
7-year survival
42%
38%
* OS for intermittent therapy was deemed inferior based on the prespecified statistical
design requirement that the 95% CI for the hazard ratio should include 1.2.
Hussain M et al. Proc ASCO 2012;Abstract 4.
The 75-year-old retired attorney with PSA-only
relapse receives intermittent ADT but 2 years later
is found to have multiple bone metastases on
routine follow-up. Patient is asymptomatic.
PSA = 30, PS = 0.
What systemic treatment would you likely
recommend?
28%
Abiraterone
Enzalutamide (MDV3100)
7%
Sipuleucel-T
7%
45%
Docetaxel
Cabazitaxel 0%
Radium-223 (on a clinical trial)
Ketoconazole
3%
Other
3%
0%
7%
10%
20%
30%
40%
50%
The 75-year-old retired attorney with PSA-only
relapse receives intermittent ADT but 2 years later
is found to have 3 small liver metastases and is
experiencing pain from several sites of bone
metastasis along with anorexia and fatigue.
What systemic treatment would you likely
recommend?
10%
Abiraterone
Enzalutamide (MDV3100)
2%
Sipuleucel-T 0%
Docetaxel
81%
Cabazitaxel 0%
Radium-223 (on a clinical trial) 0%
Ketoconazole 0%
7%
Other
0%
20%
40%
60%
80%
100%
What percentage of your patients with late-line
metastatic prostate cancer receiving
abiraterone have discernible corticosteroidassociated side effects?
Less than 5%
30%
6%-10%
22%
11%-15%
15%
16%-30%
22%
31%-50%
11%
More than 50% 0%
0%
10%
20%
30%
40%
The mechanism of action of enzalutamide
(MDV3100) is identical to that of bicalutamide,
but enzalutamide is much more potent.
Agree
31%
Disagree
31%
I don’t know
38%
0%
10%
20%
30%
40%
Enzalutamide Mechanism of Action
• Oral drug rationally
designed to target AR
signaling, impacting
multiple steps in AR
signaling pathway
• No demonstrated agonist
effects in preclinical
models
Inhibits binding of
androgens to AR
Inhibits nuclear
translocation of AR
Inhibits association
of AR with DNA
Tran et al. Science 2009;324:787-90.
Enzalutamide Inhibits Multiple Steps in the AR
Signaling Pathway
Testosterone/DHT
Enzalutamide
Mukherji D et al. Expert Opin Investig Drugs 2012;21:227-33. Carson C et al. Urology 2003;61:2-7.
Abiraterone Mechanism of Action
Abiraterone inhibits 17α-hydroxylase (crossed out in red)
Attard G et al. J Clin Oncol 2008;26:4563-71.
Current Controversies, Recent Developments and Emerging
Strategies in the Management of Prostate Cancer — A Clinical
Investigator Think Tank
September 7, 2012
Sequence of enzalutamide and abiraterone in metastatic
disease
•
Tomasz M Beer, MD: “Given no data, go with enzalutamide first.”
•
Robert Dreicer, MD, MS: “With all the caveats, enzalutamide.”
•
Mario A Eisenberger, MD: “Enzalutamide. It’s easier to use. It’s less toxic.
No need for steroids.”
•
William K Oh, MD: “Probably enzalutamide…less toxicity”
•
Daniel P Petrylak, MD: “Since we’re trying to sequence these drugs, if you
believe that corticosteroids may have an abrogating effect on sipuleucel-T, I
would tend to go with enzalutamide first.”
•
Susan F Slovin, MD, PhD: “Enzalutamide, with one caveat…in patients
where I want to go to a completely different category of drugs I would use
abiraterone”
•
Matthew R Smith, MD, PhD: “Prefer to use abiraterone first for now in the
prechemotherapy setting, since I have longer experience with it. It’s a very
transient answer, and we await the results of the PREVAIL trial.”
Interim Analysis (IA) Results of COUAA-302, a Randomized, Phase III Study
of Abiraterone Acetate (AA) in
Chemotherapy-Naïve Patients (pts)
with Metastatic Castration-Resistant
Prostate Cancer (mCRPC)
Ryan CJ et al.
Proc ASCO 2012;Abstract LBA4518.
Overall Study Design of COU-AA-302
Efficacy endpoints
Patients
•Progressive chemonaïve mCRPC patients
(Planned N = 1,088)
•Asymptomatic or mildly
symptomatic
1:1
AA 1,000 mg daily
Prednisone 5 mg BID
(Actual n = 546)
R
Placebo daily
Prednisone 5 mg BID
(Actual n = 542)
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 CJ et al. Proc ASCO 2012;Abstract LBA4518.
AA + P (median, mos):
NR
AA + P (median, mos):
NR
PL + P (median, mos):
8.3
PL + P (median, mos):
27.2
HR
P value:
0.43
< 0.0001
HR:
P value:
0.75
0.0097
100
100
80
80
Survival (%)
Progression-Free (%)
Statistically Significant Improvement in rPFS Not OS
60
40
20
40
20
AA + P
PL + P
0
0
60
AA + P
PL + P
0
3
6
9
12
15
18
Time to Progression or Death (Months)
Data cutoff 12/20/2010
NR = not reached
PL = placebo
0
3
6
9
12 15 18 21 24 27 30 33
Time to Death (Months)
Data cutoff 12/20/2011
Prespecified significant p-value by O'BrienFleming Boundary for overall survival = 0.0008
With permission from Ryan CJ et al. Proc ASCO 2012;Abstract LBA4518.
Side Effects of Abiraterone
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 CJ et al. Proc ASCO 2012;Abstract LBA4518.
Increased Survival with
Enzalutamide in Prostate Cancer
After Chemotherapy
Scher HI et al.
N Engl J Med 2012;367:1187-97.
AFFIRM: Interim Analysis of Enzalutamide versus
Placebo in Patients with CRPC
Enzalutamide
(n = 800)
Placebo
(n = 399)
Hazard
ratio
p-value
Overall
survival
18.4 mo
13.6 mo
0.63
< 0.001
Progressionfree survival*
8.3 mo
2.9 mo
0.40
< 0.001
Time to PSA
progression
8.3 mo
3.0 mo
0.25
< 0.001
54%
2%
—
< 0.001
PSA response
rate
* According to radiographic evidence
Scher HI et al. N Engl J Med 2012;367:1187-97.
AFFIRM: Frequent Adverse Events More Common
with Enzalutamide
Enzalutamide
(n = 800)
Adverse event
Any grade Grade ≥3
Placebo
(n = 399)
Any grade
Grade ≥3
Fatigue
34%
6%
29%
7%
Diarrhea
21%
1%
18%
< 1%
Hot flash
20%
0%
10%
0%
Musculoskeletal
pain
14%
1%
10%
< 1%
Headache
12%
< 1%
6%
0%
Seizures were reported in 5 patients (0.6%) receiving enzalutamide.
Scher HI et al. N Engl J Med 2012;367:1187-97.
Safety and Activity of the
Investigational Agent Orteronel
without Prednisone in Men with
Nonmetastatic Castration-Resistant
Prostate Cancer and Rising
Prostate-Specific Antigen: Updated
Results of a Phase II Study
George DJ et al.
Proc ASCO 2012;Abstract 4549.
Orteronel (TAK-700) in Nonmetastatic CRPC
• 39 patients with non-mCRCP and rising PSA received
orteronel 300 mg BID
• Drug-related Grade ≥3 AEs: 36%
– Dyspnea: 8%
– Hypertension: 13%
– Fatigue, hypokalemia, pneumonitis: 5% each
• At 3 months,
– PSA ≤0.2 ng/mL: 16%
– PSA 50: 76%
– PSA 90: 32%
• At 6 months,
– PSA 50: 45%
– PSA 90: 21%
• Median time to PSA progression: 14.8 months
George DJ et al. Proc ASCO 2012;Abstract 4549.
Ongoing Phase III Studies of Orteronel
Study ID
No. of
patients
Randomization
Setting
NCT01193244
1,454
Orteronel/prednisone
Placebo/prednisone
Chemo-naïve mCRPC
NCT01193257
1,083
Orteronel/prednisone
Placebo/prednisone
mCRCP progressing
on/after docetaxel
900
LHRH + oral anti-androgen/RT
LHRH + oral anti-androgen/RT
+ orteronel BID x 2 years
High-risk PC
NCT01546987
www.clinicaltrials.gov, September 2012
A Phase III, Randomized, Double-Blind,
Multicenter Trial Comparing the
Investigational Agent Orteronel (TAK700) plus Prednisone (P) with Placebo
plus P in Patients with Metastatic
Castration-Resistant Prostate Cancer
(mCRPC) That Has Progressed During
or Following Docetaxel-Based Therapy
Dreicer R et al.
Proc ASCO 2012;Abstract TPS4693.
Radium Targets Osteoblastic Bone Metastases
by Acting as a Calcium Mimetic
• Radium-223 acts as a calcium mimetic
• Naturally self-targets to bone metastases
Cheetham PJ et al. Oncology 2012;26(4):330-7.
Lethality of Alpha-Particles Is a Consequence
of DNA Double-Strand Breaks
• Beta and gamma radiation → single-strand DNA
breaks, more repairable
• Alpha radiation → double-strand DNA breaks, which
are lethal and more difficult to repair
Bruland OS et al. Clin Cancer Res 2006;12:6250s-7s.
Radium-223 Targets Bone Metastases
• Alpha-particles induce double-strand DNA breaks in
adjacent tumor cells
• Short penetration of alpha emitters (2-10 cell diameters) =
highly localized tumor cell killing and minimal damage to
surrounding normal tissue
Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103.
Updated Analysis of the Phase III, DoubleBlind, Randomized, Multinational Study of
Radium-223 Chloride in CastrationResistant Prostate Cancer (CRPC)
Patients with Bone Metastases
(ALSYMPCA)
Parker C et al.
Proc ASCO 2012;Abstract LBA4512.
ALSYMPCA (Radium-223 Dichloride in
Symptomatic Prostate Cancer) Phase III
Study Design
TREATMENT
• Confirmed
PATIENTS
symptomatic
CRPC
• ≥ 2 bone
metastases
• No known
visceral
metastases
6 injections at
4-week intervals
STRATIFICATION
Radium-223 (50 kBq/kg)
+ best standard of care
• Total ALP:
< 220 vs ≥ 220 U/L
• Bisphosphonate use:
Yes vs No
• Prior docetaxel:
Yes vs No
• Post-docetaxel
or unfit for
docetaxel
Planned follow-up is 3 years
www.clinicaltrials.gov, September 2012
R
2:1
Placebo (saline)
+ best standard of care
N = 921
Primary endpoint: OS
Secondary: Time to first SRE,
safety, etc.
ALSYMPCA Updated Analysis: Overall Survival
Median OS
Radium-223
(n = 614)
Placebo
(n = 307)
14.9 mo
11.3 mo
Hazard ratio
p-value
Parker C et al. Proc ASCO 2012;Abstract LBA4512.
0.695
0.00007
ALSYMPCA Updated Analysis: Time to First SRE*
Time to first SRE
Radium-223
(n = 614)
Placebo
(n = 307)
12.2 mo
6.7 mo
Hazard ratio
p-value
* Provisional data
Parker C et al. Proc ASCO 2012;Abstract LBA4512.
0.64
<0.0001
Radium-223 Chloride Impact on
Skeletal-Related Events and ECOG
Performance Status in Patients with
Castration-Resistant Prostate Cancer
with Bone Metastases: Interim Results
of a Phase III Trial (ALSYMPCA)
Sartor AO et al.
Proc ASCO 2012;Abstract 4551.
Faculty Case: Dr Sartor
• An 85-year-old man
• Metastatic CRPC unsuitable for docetaxel due to frailty
– Increasing pain
– Prior treatments: LHRH/nilutamide, then
abiraterone/prednisone, denosumab, low-dose
dexamethasone
• Expanded access protocol: Radium-223
– 4 doses with diminished pain and no side effects
– PSA rising but more slowly
Cabozantinib has resulted in bone scan
improvements and pain relief in chemotherapypretreated metastatic CRPC.
43%
Agree
5%
Disagree
51%
I don’t know
0%
10%
20%
30%
40%
50%
60%
Cabozantinib (XL184) in ChemotherapyPretreated Metastatic Castration
Resistant Prostate Cancer (mCRPC):
Results from a Phase II Nonrandomized
Expansion Cohort (NRE)
Smith MR et al.
Proc ASCO 2012;Abstract 4513.
Cabozantinib: Dual Inhibitor of MET and VEGFR
• MET and its ligand HGF
drive tumor cell invasion and
metastasis
• MET and VEGFR2 synergize to
promote angiogenesis
• Bone metastases associated with
high levels of MET expression
– HGF and VEGF direct crosstalk
between tumor cells, osteoblasts and
osteoclasts
In Prostate Cancer:
• Preclinically, androgen deprivation increases MET
expression
• MET increases with progression and metastases
in bone and lymph nodes
With permission from Hussain M et al. Proc ASCO 2011;Abstract 4516.
Bone Scan Response to Cabozantinib by
Independent Radiology Review
Computer-assisted evaluation of BSLA
Bone scan evaluable (n = 93)a
n (%)
Bone scan response
Complete (100% reduction of BSLA)
Partial (≥30% reduction of BSLA)
62 (67)
4 (4)
58 (62)
Stable
15 (16)
Progressive disease
Median duration of response, months (range)
7 (8)
5.4 (5.0 – 6.9)
BSLA = bone scan lesion area
a Bone metastases at baseline and ≥1 post-baseline scan available for 84 patients
Smith MR et al. Proc ASCO 2012;Abstract 4513.
Potential Effects of Dasatinib in Prostate Cancer
Potential effects
Invasion and
tumor spread
Src-dependent
bone resorption
Invasive growth of
primary tumors and
metastases
Potential role in
early and advanced
disease
Dasatinib
Malignant
bone disease
Chemomodulation
Pivotal role in
survival, apoptosis,
growth and
resistance pathways
Saad F. Medscape Oncology 2012.
Dasatinib Combined with Docetaxel for
Castration-Resistant Prostate Cancer:
Results from a Phase 1-2 Study
Araujo JC et al.
Cancer 2012;118(1):63-71.
Dasatinib 100 mg QD plus Docetaxel
Best response by RECIST (N = 30)
Partial response
60%
Stable disease (≥18 wk)
17%
Overall disease control rate
77%
Araujo JC et al. Cancer 2012;118(1):63-71.
READY: Phase III Study of Docetaxel ± Dasatinib
Metastatic CRPC
(N = 1,500)
Docetaxel +
prednisone +
placebo
R
•
Primary endpoint: OS
•
Secondary endpoints: Change in uNTX,
time to first SRE, change in pain intensity,
time to PSA progression, objective tumor
response rate, PFS, safety/tolerability
www.clinicaltrials.gov, September 2012
Docetaxel +
prednisone +
dasatinib 100 mg PO QD
Dasatinib 100 mg QD plus Docetaxel
Best response by RECIST (N = 30)
Partial response
60%
Stable disease (≥18 wk)
17%
Overall disease control rate
77%
Araujo JC et al. Cancer 2012;118(1):63-71.
Potential Predictive Biomarkers in CRPC
Biomarker
Context of use in CRPC
Androgen precursor levels
(DHEA, etc)
Abiraterone sensitivity
AR splice variants
Enzalutamide sensitivity
PTEN loss or PI3K pathway activation PI3 kinase inhibitor sensitivity
Microtubule mutations
Taxane sensitivity
High bone turnover biomarkers
(TRAP, urine NTx, BAP, etc)
Bone-targeted agent benefit
(denosumab, zoledronic acid, radium223)
Ras/Raf mutations
B-raf inhibitor sensitivity (sorafenib,
vemurafenib)
DNA repair defects
PARP inhibition sensitivity
Myc amplification
Cytotoxic chemo, cell cycle inhibitors
C-MET activity
Cabozantinib sensitivity
Pain intensity
Value of immediate immunotherapy
(sipuleucel-T)
Armstrong AJ. ASCO 2012 Education Session. Armstrong AJ et al. Eur Urol 2012;61(3):549-59.