Transcript Challenges in the Treatment of Breast Cancer: Overcoming

Clinical Updates
Controversies in the Treatment of
Castration Resistant Prostate Cancer
Daniel P. Petrylak, MD
Associate Professor of Medicine
Columbia University Medical Center
Prostate Cancer Statistics
(2008)
• Newly diagnosed cases in the US
– 220,900
• Deaths due to prostate cancer
– 28,900
• Second leading cause of death in men
– Accounts for 10% of male cancer-related deaths
• Incidence is increasing due to earlier detection and screening
• Estimate 2 million American men alive with CaP
– Of the patients diagnosed, 97% survive >5 years
American Cancer Society. Key statistics about prostate cancer 2003.
Jemal A, et al. CA Cancer J Clin. 2002;52:23-47.
Prostate Cancer (Invasive)
Incidence and Mortality Rates by Race
United States:1988–1996*
300
250
200
Incidence Black
Incidence White
Mortality Black
Mortality white
150
100
50
0
73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96
Year
National Cancer Institute. SEER Cancer Statistics Review. 1973-1994
Therapeutic Options by Stage
for Prostate Cancer
T1a
• WW
•P
• XRT
T4
• HT,
possibly
w/ XRT
T1b–1c
T2
•P
• XRT
• HT – with
or w/o P
or XRT
•P
• XRT
• HT – with
or w/o P
or XRT
D1.5
D1,D2
• XRT
•P
• HT
• Combination
WW = watchful waiting
P = prostatectomy
• HT
XRT = radiation
HT = hormone therapy
T3b
T3a
• XRT w/
HT
• P for
some
patients
• XRT w/
HT
D3
• CT w/ or
w/o HT
CT = chemotherapy
Effect of Testosterone on Prostate Cancer
Pioneered by Charles Huggins
60
Units per 100 mL Serum
Stilbestrol, 1 mg daily
40
Acid Phosphatase
20
Alkaline Phosphatase
0
40
50
60
70
80
Time (Days)
Huggins C, Hodges CV. Cancer Res. 1941;1:293-279.
Hormonal Influences on Prostate Cancer
Hypothalamus
LHRH
Testes
Pituitary
Leydig
Cells
FSH
LH
Stromal
Cells
Other
Target
Tissues
GnRH
Recept
or
FSH
Testosterone
DHT
Receptor
Prostate
Combined Androgen Blockade
Most Recent Survival Data
100
Androgen suppression only
Androgen suppression + antiandrogen
Proportion Alive (%)
80
8,000 prostate cancer patients in 27 trials
of antiandrogen (nilutamide, flutamide, or
cyproterone acetate)
60
40
25.4%
20
23.6%
Treatment better by 0.7% (SE 1.1)
Logrank 2 P>0.1
Absolute difference
1.8% (SE 1.3)
0
0
5
6.2%
5.5%
10
Time Since Randomization (Years)
Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355:1491-1498
Natural History of
Metastatic Prostate Cancer
Castration
Chemo Rx
Tumor
Volume
and
Activity
Secondary
Hormonal Rx
Time
Case 1
• A 47 year old male develops urinary frequency. His
internist detects a prostate nodule on digital rectal
exam. PSA = 7.4
• He is referred to a urologist, who performs a biopsy,
and detects a Gleason 7 adenocarcinoma
• After considerable discussion, he undergoes a radical
prostatectomy.
• His final pathology demonstrates a T3aN1 Gleason 7
adenocarcinoma
Case 1 (cont.)
• He reviews the options with his urologist.
• He undergoes combined androgen blockade (CAB). He
had a baseline bone mineral density which is normal.
• After 2 years of androgen blockade, his bone mineral
density is consistent with osteoporosis.
Case 1 (cont.)
• Which treatment option would you consider at this
time?
 Starting calcium and vitamin D
 Bisphosphonate therapy
 Investigational treatment
Case 1 (cont.)
• Which treatment option would you consider at this time?
 Starting Calcium and Vitamin D
 Bisphosphonate therapy
 Investigational treatment
Recommended approach:
 Zoledrinic acid or an oral bisphosphonate
 Calcium and vitamin D
Types of Progression in AIPC
• PSA progression only
– Rising PSA often precedes + scan by 6 mo
• Symptomatic progression
• Bone metastases (80%)
– Positive bone scan with or without rising PSA
• Soft tissue only (≈20%)
– Lymph nodes, lung, liver, adrenal, dura sites
• Soft tissue plus bone metastases
Treatment Options
• Secondary hormonal therapy
• Chemotherapy
• Investigational treatments
– Targeted therapy
– Immune therapy
Biological Evidence for a Continued
Hormone ‘Driver’ in CRPC
• High intratumoral androgens despite castration
• Castration resistance:
– AR amplification/mutations in CRPC increase AR activity
– ↑ AR mRNA expression alone → resistance in isogenic lines
• Preclinical and clinical evidence of intracrine synthesis
• Identification of oncogenic translocations driven by
androgens (TMPRSS2-ETS fusion)
Case 1 (cont.)
• After 3 more years of CAB, patient’s PSA begins to rise
from 0.2 to 0.8 to 1.0 over a 6 month period.
• Bone scan and CT scan of the abdomen and pelvis are
without metastases.
Case 1 (cont.)
• Which treatment option would you consider at this
time?
 Discontinue Casodex, monitor for antiandrogen withdrawal
 Start Second line hormonal therapy with Nizoral and
hydrocortisone
 Investigational treatment
Case 1 (cont.)
• Which treatment option would you consider at this
time?
 Discontinue Casodex, monitor for antiandrogen withdrawal
 Start Second line hormonal therapy with Nizoral and
hydrocortisone
 Investigational treatment
Recommended approach:
 Discontinue Casodex, monitor for antiandrogen withdraw and
initiate second-line treatment with Nizoral and hydrocortisone.
Prostate Cancer
Chemotherapy Trials
• 22 single-agent trials between 1988 and 1991
• CR + PR=8.8%, 95% CI=6.4–9.0%
Yagoda and Petrylak Cancer 1993
Mitoxantrone + Corticosteroids
Mitoxantrone
Canadian
CALGB
12 mg/m2 Q3 weeks
14 mg/m2 Q3 weeks
Hydrocortisone
Steroid
Prednisone 10 mg/day
N
161
243
Objective
Palliation
Survival
Symptomatic
disease?
Required
Not required
Crossover?
Allowed
Not allowed
Median age
68 years
72 years
40 mg/day
Tannock et al. J Clin Oncol 1996;14:1756-1764; Kantoff et al. J Clin Oncol 1999;17:2506-2513.
Mechanism of Action
Inhibition of Polymerization:

colchicine

vinca alkaloids
Estramustine + Docetaxel
Preliminary Studies HICC
Study
N
Open
Completed
Phase I
34
2/96
2/97
Phase II
37
4/97
1/00
Docetaxel HRPC Trials
Mitoxantrone 12 mg/m2
Prednisone 10 mg q day
Q 21 days up to 10 cycles
N = 1,006
Randomize
TAX 3271
Docetaxel 30 mg/m2/wk
Prednisone 10 mg q day
5 on; 1 off x 6 cycles
Docetaxel 75 mg/m2
Prednisone 10 mg q day Q 21 days up
to 10 cycles
N = 770
* Warfarin and aspirin
Randomize
SWOG 99162
Mitoxantrone 12 mg/m2
Prednisone 5 mg bid Q 21 days
Docetaxel 60 mg/m2 d 2
Estramustine 280 mg d1-5*
Dexamethasone 20 mg tid d 1 & 2
1. Tannock et al. N Engl J Med 2004:351;1502-1512.
2. Petrylak et al. N Engl J Med 2004;351:1513-1520.
Docetaxel HRPC Trials
Patient Characteristics
TAX 3271
SWOG 99162
Docetaxel
3-weekly
Docetaxel
weekly
M+P
DE
Q 3 wk
M+P
N
335
334
337
386
384
Pain ≥ 2
45%
46%
46%
36%
36%
≤ 70
≤ 70
≤ 70
2/3
2/3
12%
13%
14%
10%
12%
Median Age
68
69
68
70
70
Bone mets
90%
91%
92%
84%
88%
PS
1. Tannock et al. N Engl J Med 2004:351;1502-1512.
2. Petrylak et al. N Engl J Med 2004;351:1513-1520.
Overall Survival
100%
D+E
M+P
80%
# at
Risk
338
336
# of
Deaths
217
235
Median
in Months
18
16
HR: 0.80 (95% CI 0.67, 0.97), P = 0.01
60%
40%
20%
0%
0
12
Months
24
36
48
Petrylak et al. NEJM 2004
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
18.2
18.9
17.3
16.4
0.83
0.76
0.91
–
P-value
0.03
0.009
0.3
–
0.0
0
6
12
18
24
30
Months
Tannock et al. N Engl J Med 2004:351;1502-1512.
Intermittent Chemotherapy
ASCENT Study
Intermittent Chemotherapy
ASCENT Study
Case 1 (cont.)
• However, his PSA rises to 5 and 4 weeks later, his PSA
rises to 9
• His Nizoral and hydrocortisone are stopped
• CT scan of the abdomen and pelvis demonstrates new
retroperitoneal adenopathy
• Bone scan demonstrates 4 new lesions in the ribs and
spine
• He has lumbar-sacral spine pain in the area of a
metastases
Case 1 (cont.)
• Which treatment option would you consider at this
time?
 Add zoledronic acid 4 mg IVSS q 3 weeks
 Start docetaxel based chemotherapy
 Try a 3rd line hormonal manipulation with nilutamide
 Clinical trial with docetaxel/atrasentan
Case 1 (cont.)
• Which treatment option would you consider at this time?
 Add zoledronic acid 4 mg IVSS q 3 weeks
 Start docetaxel based chemotherapy
 Try a 3rd line hormonal manipulation with nilutamide
 Clinical trial with docetaxel/atrasentan
Recommended approach:
 Add zoledronic acid
 Initiate docetaxel-based chemotherapy
 Clinical trial with docetaxel/atrasentan
What is the Role of PSA
in the Management of
Metastatic Prostate Cancer?
Minimum Time Intervals
SWOG 99-16 Surrogacy Analysis
50% Dec
PTE (95% CI)
3 months
1.0 (.45,1.0)
2 months
.64 (.26,1.0)
1 month
.15 (.00,.69)
30% Dec
PTE (95% CI)
3 months
1.0 (.73,1.0)
2 months
1.0 (.62,1.0)
1 month
.50 (.18,1.0)
Petrylak, et al. JNCI 98: 516-521,2006
PSA-P as a Predictor of Overall Survival
Time Varying Analysis
PSA-P Definition
S9346 (HSPC)
S9916 (HRPC)
HR (95% CI)
P
HR (95% CI)
P
Rising trend
1.97 (1.67, 2.32)
<.0001
1.21 (0.98, 1.48)
.07
50% and 5 ng/mL
2.39 (2.05, 2.80
<.0001
1.22 (1.02, 1.45)
.03
25% and 5 ng/mL
(PSAWG ’99)
2.44 (2.09, 2.85)
<.0001
1.41 (1.17, 1.69)
.0003
25% and 2 ng/mL
(PCWG ’08)
2.49 (2.13, 2.91)
<.0001
1.38 (1.14, 1.67)
.001
Response-based
(PSAWG ’99)
2.39 (2.05, 2.80)
<.0001
1.37 (1.15, 1.65)
.0006
All results from multivariate Cox regression
Criterion 1c
Survival by Treatment and Surrogate
100%
D + E, no 50% dec
D + E, 50% dec
M + P, no 50% dec
M + P, 50% dec
80%
At Risk
99
162
192
76
60%
Median
Deaths in Months
71
15
91
21
143
14
39
21
P < .0001
40%
20%
0%
0
12
24
Months After Registration
36
48
Armstrong AJ, et al. J Clin Oncol. 2007;25(25)3965-70. Erratum in :
Clin Cancer Res. 2009 Feb 15;15(4):1506
Armstrong AJ, et al. J Clin Oncol. 2007;25(25)3965-70. Erratum in : Clin Cancer
Res. 2009 Feb 15;15(4):1506
PSA
Progression Definitions
1.
Any increase (rising trend)
2.
Increase by ≥ 50% & ≥ 5 ng/mL
3.
Increase by ≥ 25% & ≥ 5 ng/mL (PSAWG’99)
4.
Increase by ≥ 25% & ≥ 2 ng/mL (PCWG ‘08)
5.
Increase by ≥ 25% and ≥ 5 ng/mL OR Increase by ≥ 50% and ≥ 5
ng/mL (based on “PSA response of 50% decrease” -- PSAWG ’99)
For all definitions, PSA-P must be confirmed ≥ 7 days later
Pain Response as a Surrogate
• Pain response identified in 29% of 466 evaluable
subjects
• Pain response defined as:
– 2-point reduction in present pain inventory score (PPI) without
an increase in analgesic score (AS)
– ≥ 50% reduction in AS without an increase in PPI
Median survival, months
(95% CI)
Pain response
No pain response
(n=135)
(n=331)
18.6 (16.4-20.3)
12.5 (11.3-14.3)
HR = 0.60 (95% CI: 0.48-0.75) for overall survival
PTE = 0.64 (95% CI: 0.22-1.0)
Armstrong AJ, et al. J Clin Oncol. 2007;25(25)3965-70. Erratum in :
Clin Cancer Res. 2009 Feb 15;15(4):1506
Circulating Tumor Cells as Predictive
Markers in Prostate Cancer
<5 vs. ≥ 5 Ctc 2-5 Weeks After Start of Treatment
Predicts Survival
N=210
<5 CTCs
n=124 (59%)
9.5 Months
Logrank p < 0.0001
20.6 Months
>5 CTCs
n=86 (41%)
de Bono JS, et al. Clin Cancer Res. 2008; 14(19):6302-6309
Changes In Ctc At 2-5 Weeks
From Baseline Is Also Predictive
N=205
20.6 Months
<5
<5CTCs
n=84 (41%)
8.4
Months
14.4
Months
<5
>5CTCs
n=5 (2%)
19.6 Months
>5
<5CTCs
n=39 (19%)
>5
>5 CTCs
n=77 (38%)
de Bono JS, et al. Clin Cancer Res. 2008; 14(19):6302-6309
Future Directions of Circulating
Tumor Cells
• Correlate with pretreatment patient characteristics to
determine whether this is the best prognostic marker
• Potential use in defining pre and post treatment
markers and mechanisms of resistance
• Does the circulating tumor cell correlate with the entire
phenotype of the patient?
Clinical Development of New Classes of
Agents in Prostate Cancer
Pituitary
ACTH
Adrenal Cortex
Cholesterol
Cholesterol Side
Ketoconazole
Chain Cleavage
Pregnenolone
Progesterone
3-BHSD-I
DOC
21-hydroxylase
Corticosterone
11 -hydroxylase
Ketoconazole
18OHCorticosterone
Aldosterone
18-hydroxylase
18-oxidase
Abiraterone
17 -hydroxylase
Mineralocorticoids
17OHpregnenolone
17OH-progesterone
11-DOC
Cortisol
Glucocorticoids
3-BHSD-I
Peripheral Tissues
C17-20 lyase
Abiraterone
DHEA
Androstenedione
Testosterone
DHT
3-BHSD-I
Androgens
17-keto-reductase
5 -reductase
Abiraterone
Hormone Decline
Abiraterone
Response
Response
Parameter
Untreated
Prior Docetaxel
PSA >50%
27/44 (61%)
14/28 (50%)
>75%
22/44 (50%)
8/28 (32%)
>90%
11/44 (25%)
5/28 (18%)
TTP PSA
252 days
167 days
RECIST
12/21 (60%)
4/18 (22%)
MDV3100
• Small molecule AR antagonist with novel mechanism of
action that blocks nuclear translocation of AR, DNA
binding, an no agonist activity when AR is over expressed
• Identified from a cell-based screen that mimics castrationresistant tumors with over expressed AR
• Active in casodex-resistant prostate cancer models
• Currently under investigation in a Phase 1-2 trial in
patients with CRPC.
What is the Best
Combination to Pursue?
• Endothelins
• Angiogenesis
Atrasentan
• A potent, selective ETA receptor antagonist
• Orally bioavailable
• Once daily dosing
t ½ = 25 hours
• 1800 x more selective
for ETA than ETB
– ETA binding constant
= 34 pM
Opgenorth et al, Pharm Exp Ther 1996: 276
Verhaar et al, Br. J Clin Pharm 2000: 562
Endothelin-1 and the Vicious Cycle of
Osteoblastic Bone Metastases
Adapted from Guise TA, et al. Cancer. 2003 Feb 1;97(3 Suppl):779-84. Copyright © 2003 American
Cancer Society. This material is used by permission of John Wiley & Sons, Inc.
Kopetz ES, et al. Invest New Drugs. 2002 May;20(2):173-82.
Study M00-211
Atrasentan 10 mg (n = 408)
Open-label atrasentan
extension
Screening
Placebo (n = 401)
Randomization
Disease progression
or study close
• 809 patients with metastatic HRPC
• Major entry criteria
–
Confirmed radiographic evidence of metastases
•
Independent radiologic review of all baseline scans
–
Confirmed medically or surgically castrate for ≥ 3 months
–
Rising PSA or PSA ≥ 20 ng/mL
–
No PCa-related pain requiring opiates
–
Chemotherapy-naïve
–
No prior or ongoing bisphosphonate therapy
Time to Disease Progression
Study M00-211 – Patients With Bone Metastases
P = .016
Probability of not progressing
1.0
HR = 0.813 (95% CI = 0.685 – 0.965)
0.8
0.6
Atrasentan 10 mg (n = 355)
0.4
Placebo (n = 335)
0.2
0.0
0
90
180
270
Time from randomization (days)
360
Time to 50% Worsening in PCS Pain Score
Study M00-211 – Patients With Bone Metastases
P = .003
HR = 0.644 (95% CI = 0.478 – 0.868)
Probability of not worsening by 50%
1.0
0.8
0.6
0.4
Atrasentan 10 mg
Placebo
0.2
0.0
0
90
180
270
Time from randomization (days)
360
Clinical Benefit of Atrasentan
Consistent Benefit for Patients With Bone Metastases
Favors atrasentan
M00-211
Time to disease progression
0.2 0.4
0.6
0.8
Hazard ratio (95% CI)
1.0
Clinical Benefit of Atrasentan
Consistent Benefit for Patients With Bone Metastases
Across Multiple Measures and Studies
Favors atrasentan
M00-211
Time to disease progression
Radiographic
Clinical
0.2 0.4
0.6
0.8
1.0
Hazard ratio (95% CI)
Clinical Benefit of Atrasentan
Consistent Benefit for Patients With Bone Metastases
Across Multiple Measures and Studies
Favors atrasentan
M00-211
Time to disease progression
Radiographic
Clinical
BAP progression
PSA progression
0.2 0.4
0.6
0.8
Hazard ratio (95% CI)
1.0
Clinical Benefit of Atrasentan
Consistent Benefit for Patients With Bone Metastases
Across Multiple Measures and Studies
Favors atrasentan
M00-211
Time to disease progression
Radiographic
Clinical
BAP progression
PSA progression
50% decline in FACT-P pain score (>56 days)
Opioid initiation (85 days)
Adverse event of bone pain (40 days)
0.2
0.4 0.6
0.8 1.0
Hazard ratio (95% CI)
Phase I
Combination Studies with Docetaxel
• Phase I studies by Moore, et al. and Petrylak, et al.
have established the safety of administering full doses
of docetaxel and atrasentan
• Synergistic toxicities were not observed
Moore, et al. Proc ASCO 2006
Petrylak, et al. Proc ASCO 2006
Phase III Study of Docetaxel + Placebo vs Docetaxel +
Atrasentan in Patients with Hormone-Refractory
Prostate Cancer (S0421)
Stratification:
•
•
•
•
Type of progression
PS:0-1 vs 2-3
Prior RP
Total ALK-PO4
< 5 vs. ≥ 5 XULN
• Bisphosphonate
R
A
N
D
O
M
I
Z
E
• Docetaxel 75 mg/m2 Q3 wks
• Prednisone 10 mg
• Placebo
• Docetaxel 75 mg/m2 Q3 wks
• Prednisone 10mg
• Atrasentan 10 mg
ZD4054 in Prostate Cancer
• Specific endothelin A antagonist, orally administered
• 312 patients with androgen independent prostate
cancer, randomized against placebo
• Median survivals were 23.5, 24.5, and 17.3 months for
patients treated with 15 mg ZD4054, 10 mg ZD4054 ,
or placebo, respectively
James et al Proc ECCO 2007
Evidence for Angiogenesis as
A Target for Prostate Cancer
• Microvessel density correlates with prognosis in radical
prostatetectomy specimens
• Elevated levels of VEGF correlate with prognosis in
CRPCa
• bFGF expressed in epithelial and stromal cells
Potential Strategies for Angiogenesisbased Cancer Therapies
Scappaticci, F. A. J Clin Oncol; 20:3906-3927 2002
Copyright © American Society of Clinical Oncology
CALGB 9040
Randomized Double Blinded Placebo controlled Phase III Trial Comparing
Docetaxel + Prednisone with or without Bevacizumab in Men with HRPC
Arm A
•
•
•
•
Metastatic PC
T <50 ng/ml
No prior chemo
Adequate hem, renal
& liver function
Stratification
• Halabi
• nomogram
N = 1,020 patients
CALGB, ECOG, NCIC
RANDOMIZE
Eligibility
Dexamethasone
Docetaxel
Prednisone
Placebo*
8 mg po x 3 doses
75 mg/m2 on d1 q21d
10 mg po daily
IV on day 1 q 21 days
Arm B
Dexamethasone
Docetaxel
Prednisone
Bevacizumab*
8 mg po x 3 doses
75 mg/m2 on d1 q 21d
10 mg po daily
15 mg/kg IV on day 1q 21d
VENICE Study Design
Multinational, Multicenter, Double Blind, Randomized Study
mAIPC
Stratification factor:
ECOG PS (0,1 vs 2)
R
A
N
D
O
M
I
Z
E
1:1
Docetaxel plus Pred q3w 600 pts
+ Aflibercept 6 mg/kg IV, over
1hr, day 1, q 3 weeks
Disease
Progression
Death
Docetaxel plus Pred q3w 600
pts
+ Placebo day 1, q 3 weeks
Safety data monitored by and DMC (Q 6 months)
Treatment planned until PD, consent withdrawn, or unacceptable toxicity
Follow-up until death
68
VENICE
Study Endpoints
• Primary:
– Overall survival (OS):
•
To detect a 20% increase in survival in AVE0005 group with 90%
power (assuming a median OS in control group of 19 months)
– 873 death events required
– 1200 patients required (600 in each arm)
– Interim Analysis for early efficacy demonstration
• Main Secondary:
– Efficacy:
•
PSA response
•
Pain response
•
Time to occurrence of SRE
•
Progression free survival
– Safety (NCI-CTC version 3.0)
– PK and Immunogenicity, in selected centers
69
IMiDs®
Novel Thalidomide Analogs
• Thalidomide
• Lenalidomide (CC-5013)
• CC-4047
Single-Agent Thalidomide in AIPC
• Durable PSA responses in several trials1,2
–  50% PSA rate ranged from 18% – 40%
• Well tolerated
– Drug-related adverse events included constipation, dizziness,
edema, fatigue, neuropathy
1. Figg et al. Clin Cancer Res. 2001;7:1888
2. Drake et al. Br J Cancer. 2003;88:822
Thalidomide Combination With
Chemotherapy in AIPC
• Thalidomide/docetaxel1,2
–  50% PSA rate ranged from 51%–66% in
D+T arm vs 32%–37% in D arm alone
– Acceptable safety profile
• Thalidomide/paclitaxel/estramustine in chemorefractory AIPC3
–  50% PSA rate = 55%;  80% PSA rate = 21%
– Acceptable safety profile
– Promising regimen for chemorefractory patients with AIPC
1. Dahut et al. Proc Am Soc Clin Oncol. 2002 [abstract 730]
2. Salomichokami et al. Proc Am Soc Clin Oncol. 2003 [abstract 1725]
3. Daliani et al. Eur J Cancer. 2003;1(suppl):S261
Fig 1. Kaplan-meier Graph Showing
Progression-free Survival of Docetaxel and
Docetaxel/Thalidomide Groups
Dahut, W. L. et al. J Clin Oncol; 22:2532-2539 2004
Copyright © American Society of Clinical Oncology
Fig 2. Kaplan-meier Graph Showing
Overall Survival Of Docetaxel And
Docetaxel/Thalidomide Groups
Dahut, W. L. et al. J Clin Oncol; 22:2532-2539 2004
Copyright © American Society of Clinical Oncology
Phase I/II Study of
Lenalidomide/Docetaxel in Hormone
Refractory Prostate Cancer
Planned Dose Escalation
Cohort
Docetaxel
(mg/m2)
Lenalidomide
(mg)
1
60
10
2
75
10
3
75
15
4
75
20
5
75
25
6
75
30
Petrylak DP, et al. J Clin Oncol. 2009;27:15s(suppl;abstract 5156)
Percent PSA Response From Baseline
(Number of treatment cycles completed)
100
75
% PSA Reduction
50
25
15 14 16
14
13
12
12
11
11
9
9
9
9
8 6 6
7 6
6 5
5
4
4 6 4
2 2
0
# Cycles completed
-25
-50
-75
-100
Petrylak DP, et al. J Clin Oncol. 2009;27:15s(suppl;abstract 5156)
Lenolidamide/Docetaxel
Future Plans
• International registration trial of docetaxel/lenolidamide
vs docetaxel
Second-line Chemotherapy
• Many agents are currently being evaluated in the
taxane failure environment
• No FDA approved agent
• Mitoxantrone has defaulted as the standard of care
• Epothilones
• Satraplatin
– Phase III study
Case 1 (cont.)
• His PSA declines to 0.1 after 8 cycles of docetaxel
• His pain improves, however, after 2 more cycles, his
PSA rises to 10 and then to 20
• His pain worsens, requiring narcotic analgesics
• He has a repeat bone scan which demonstrates new
lesions in the thoracic spine
• MRI of the thoracic spine demonstrated bone
metastases at T12 but no epidural lesions
Case 1 (cont.)
• Which treatment option would you consider at this
time?
 Systemic chemotherapy with mitoxatrone
 Isotope therapy with samarium
 Palliative care only with radiation therapy to the thoracic spine
Case 1 (cont.)
• Which treatment option would you consider at this time?
 Systemic chemotherapy with mitoxatrone
 Isotope therapy with samarium
 Palliative care only with radiation therapy to the thoracic spine
Recommended approach:
 All selections are appropriate. Additionally, one could consider
enrolling the patient in a systemic therapy protocol
SPARC
Study Schema
Arm A:
2:1
Randomization
No cross-over to satraplatin
Satraplatin 80 mg/m2 d1-5 q 35d
Antiemetic 1 mg BID d1-5 q 35d
Prednisone 5 mg BID
Arm B:
Placebo 80 mg/m2 d1-5 q 35d
Placebo* 1 mg BID d1-5 q 35d
Prednisone 5 mg BID
* Placebo antiemetic
All patients treated until progression, intolerable toxicity or death
Progression Free Survival
ITT Population (per IRC)
100
33% Improvement in PFS
Proportion Event Free (%)
90
80
S
P
70
11.1
9.7
60
Satraplatin
+ Prednisone
50
Median (wks) HR: 0.67 (95% CI:
0.57 - 0.77)
Log-Rank P = 0.0000003
40
30
Placebo
+ Prednisone
20
10
0
10
20
30
Satraplatin 635
363
229
Placebo
140
63
0
40
50
Weeks
60
70
80
90
143
90
63
43
24
18
12
37
24
11
5
5
1
0
No. at Risk
315
Progression Free Survival
ITT with Prior Docetaxel (per IRC)
100
33% Improvement in PFS
Proportion Event Free (%)
90
80
70
60
S
P
10.1
9.1
Median (wks)
50
Satraplatin
+ Prednisone
40
HR: 0.67 (95% CI: 0.54 - 0.83)
Log-Rank P = 0.0006
30
20
Placebo
+ Prednisone
10
0
10
20
30
40
50
Weeks
60
70
80
90
Satraplatin 327
167
107
69
39
28
19
13
9
5
Placebo
61
28
16
8
4
1
1
0
0
0
No. at Risk
160
Time to Pain Progression
(per IRC)
36% Reduction in Time to Pain Progression
100
90
Satraplatin
+ Prednisone
Probability, %
80
S
P
66.1
22.3
Median (wks)
70
HR: 0.64 (95% CI: 0.51 - 0.79)
60
Log-Rank P = 0.0002
50
Placebo
+ Prednisone
40
30
20
10
0
0
10
20
30
No. at risk
40
50
60
70
80
90
Time, weeks
Satraplatin 635
360
241
144
88
61
36
15
10
6
315
130
67
36
21
10
5
4
1
0
Placebo
Other Pre-specified Endpoints
Response Rates
Patients, %
Endpoint
Satraplatin
Placebo
Pain
24.2
13.8
(n=85/351)
(n=25/181)
Tumor Response
(RECIST)
PSA
6.5
0.6
(n=23/352)
(n=1/177)
25.4
12.4
(n=121/476)
(n=28/225)
P value
0.005
0.001
< 0.001
Median duration of pain response was 39.1 weeks as compared to 24.1 weeks
SPARC Overall Survival
ITT Population, Unstratified Analysis
Satraplatin + Prednisone
Placebo + Prednisone
100
100
Proportion Event Free (%)
90
90
80
80
Satraplatin
70
70
61.3
61.4
Median (wks)
Unstratified HR: 0.97 (95% CI:
0.83, 1.13)
Log-Rank P value = 0.7011
60
60
50
50
40
40
Placebo
30
30
20
20
10
10
0
0
10
10
20
20
At Risk
Satraplatin 635
Placebo
315
30
30
40
40
528
262
50
50
60
60
398
194
70
70
80
80
90
90
100
100 110
110 120
120 130
130 140
140 150
150 160
160 170
170 180
180 190
Weeks
288 208
150 105
103
53
50
21
20
10
6
1
3
0
Ongoing/Planned Second Line Studies
• SWOG mitoxantrone/prednisone vs
mitoxantrone/prednisone/ixabepilone
• Sunintinib/prednisone vs prednisone
• Mitoxantrone/IMC A12 vs mitoxantrone/IMC 3G3
Conclusions
• Standard of care for CRPCA is docetaxel/prednisone
• Novel phase IIII studies are combining docetaxel with
novel targeted agents
• The role of second line chemotherapy is currently being
defined
• New biological approaches are being evaluated in the
second line setting