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Trends, Issues & Treatment in Late-Stage Prostate Cancer
Oliver Sartor, M.D.
LaBorde Professor for Cancer Research
Medical Director, Tulane Cancer Center
Tulane Medical School
New Orleans, LA
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Charles B. Huggins
“Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.”
Nobel Lecture
December 13, 1966
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“Castrate-Refractory” Prostate Cancer
• Progressive prostate cancer despite surgical or medical castration
• Serum Testosterone (<50 ng/dL)
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“Castrate-Refractory” Prostate Cancer: The Face of Change
• Many changes have occurred in our understanding of this disease– Pathophysiology
• The evolution from “hormone-refractory” and “androgen-independent”, to “castrate-refractory”
– Therapeutic options• Current Standards
• Multiple new paradigms on the rise
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Pathophysiology: The Continued Importance of the Androgen Receptor
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Androgen Receptor Gene Over-Expression in “Castrate-Refractory”
Prostate Cancer
Linja et al., Can Res 61:3550 2001
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Tissue Androgen Levels in Benign Prostate vs. Castrated Cancer Tissue
Mohler et al., Clin Cancer Res 10:440, 2004
Shaded=Benign Clear=Castrate
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Over-Expression of Enzymes in the Androgen Synthesis Pathway in Metastatic Castrate-
Refractory Prostate Cancer Cells Stanbrough et al. Cancer Res. 66:2815, 2006
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Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic
Exons Signify CRPCHu et al. Cancer Research 69:16-22, 2009
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Conclusions
• Androgen receptor signaling remains a key factor in prostate cancer growth despite castrate serum levels of testosterone
• The prostate cancer switches from a traditional endocrine paradigm to an autocrine/paracrine paradigm BUT some of the apparent mechanisms of AR activation are ligand-independent
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Therapeutic Options for CRPC Today• Secondary Hormonal Manipulations
– Antiandrogen Withdrawal, Antiandrogen Administration, Adrenal Suppressives (ketoconazole), Corticosteroids (prednisone, dexamethasone, etc.), Estrogens (DES, etc.)
• External Beam Radiation Therapy• Intravenous Bone-seeking Radioisotopes
– Samarium-153 EDTMP, Strontium-89 (FDA approvals)• Bisphosphonates
– Zoledronate (FDA approval)• Chemotherapy
– Mitoxantrone, docetaxel, estramustine, cabazitaxel (FDA approvals)
• Immune Therapies– Sipuleucel T (FDA approved)
• Experimental Therapies (Clinical Trials)
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Despite Many New Promising Agents, Docetaxel was, For Many Years, the only FDA Approved Chemotherapy shown to have a Survival Benefit in
CRPC
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Ra
nd
om
ize
Mitoxantrone 12 mg/m2
Prednisone 10 mg q dayQ 21 days up to 10 cycles
Docetaxel 75 mg/m2
Prednisone 10 mg q dayQ 21 days up to 10 cycles
Docetaxel 30 mg/m2/wkPrednisone 10 mg q day5 on; 1 off x 6 cycles
N=1006
TAX 327
SWOG 9916
Ra
nd
om
ize
Mitoxantrone 12 mg/m2
Prednisone 5 mg bidQ 21 days
Docetaxel 60 mg/m2 d 2Estramustine 280 mg d1-5*Dexamethasone 20 mg, tid d 1 & 2
N=770
*Warfarin and aspirin
Phase III Docetaxel Studies in HRPC Demonstrating Survival Benefit
Tannock et al. N Engl J Med 2004:351;1502-1512; Petrylak et al. N Engl J Med 2004;351:1513-1520.
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0%
20%
40%
60%
80%
100%
0 12 24 36 48Months
D+EM+P
# at Risk
338 336
# of Deaths
217235
Medianin Months
17.515.6
HR: 0.80 (95% CI 0.67, 0.97), p = 0.01
Overall SurvivalPetrylak et al. N Engl J Med 2004;351:1513-1520
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Overall Survival: Tax 327 Tannock et al. N Engl J Med 2004:351;1502-1512
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 36
0.0
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
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New Agents in CRPC Clinical Trials (#1)
• Vaccines and immune stimulants
– PROSTVAC-VF-Tricom Vaccine (phase III in planning)
– Anti-CTLA4 (Ipilimumab phase III underway post-docetaxel)
– GMCSF• Angiogenesis inhibitors
– Lenalinomide (Revlimid phase III well underway)
– Bevacizumab (Avastin phase III negative 3/12/10)
– VEGF TRAP (Aflibercept phase III accrual completed)
• Novel Anti-Tubular Agents
– Cabazitaxel (phase III announced positive 12/09 and FDA approved June 17, 2010!)
– Ixabepalone (phase III in combination with mitoxantrone in planning post-docetaxel)
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New Agents in CRPC Clinical Trials (#2)
• Newer Androgen-Signaling Targeted Therapies
– Abiraterone , Cougar phase III post-docetaxel accrual complete in 4/09 and pre-docetaxel accrual completed 5/10)
– Takeda and Tokai androgen synthesis now in trials
– AR blockade (MDV3100, Sawyers new compound)
• MDV3100 phase III underway
• Newer Signal Transduction Inhibitors
– PI3 Kinase (Exelexis XL147, Novartis BEZ235, Genentech GDC-0941, Semafore SF 1126)
– p60src and other kinases (dasatinib phase III well underway)
– Multi-kinase inhibitor (sunitinib phase III well underway)
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New Agents in CRPC Clinical Trials (#3)
• Bone targeted agents
– Isotopes: radium-223 (alpharadin phase III well underway)
– Isotopes: strontium-89 (phase III underway with taxotere)
– RANK ligand: denusomab phase III accrual complete for metastases prevention vs placebo and also vs zoledronic acid for SREs (announced as positive 2/10)
• Endothelin antagonists
- Atrasentan (failed monotherapy phase III but in docetaxel combination phase III completed accrual 5/10)
- ZD4054 (Three phase III trials, one with docetaxel and 2 without (M0 and M+): All but M0 completed accrual
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New Agents in CRPC Clinical Trials (#4)
• Stem cell targeted agents– Anti-Prostate stem cell antigen (PSCA), – Sonic hedgehog (IPI-926, others)
• Prostate specific surface targets– Anti-PSMA (J591, 7E11, MLN2704, others)– New generation of various aptamers and targeted
nanoparticles
• Chemotherapeutic resistance and apoptotic regulators– Anti-Clusterin (OGX-011 or custirsen) phase IIIs in
planning for both chemo-naïve and post-docetaxel– AT-101 (gossypol) phase III in planning
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Selected Phase III Trials That Have Completed Accrual in Prostate Cancer
• Docetaxel/bevacizumab vs docetaxel in chemo-naïve mCRPC (CALGB)– Announced negative March 12, 2009
• XRP6258 (cabazitaxel) vs mitoxatrone post-docetaxel in mCRPC (Sanofi-Aventis)– Announced positive 12/09, presented 3/10 at ASCO GU, FDA 6/10
• Abiraterone vs prednisone post-docetaxel in mCRPC (Cougar)– Anticipated late 2010
• Denusomab vs placebo in metastases prevention in non-metastatic CRPC – Fall/Winter 2010 anticipated
• Denosumab vs zoledronate for SRE prevention in mCRPC– Announced positive 2/9/10 for SRE, presented ASCO 6/10
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Selected Novel Therapeutics and Concepts in for CRPC
• New hormonal therapies– Abiraterone and MDV3100
• A new chemotherapy
– Cabazitaxel
• A new immunotherapy
– Sipuleucel-T
• A brief mention, “Stromal Targeted” therapies
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Abiraterone: Potent Inhibitor of CYP17: (17-20 Lyase and 17-Alpha Hydroxylase)
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Maximal PSA Declines in Abiraterone Post-Docetaxel
Reid et al. JCO 28:1489, 2010
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MDV3100: A New Anti-AndrogenTran et al: Science 324:787-790, 2009
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MDV3100 PSA Changes in Phase I TrialScher et al. ASCO GU, 2009, #151
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PSA Declines with MDV3100 Pre- and Post-Docetaxel
Scher et al. Lancet 375:1437, 2010
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Reminder
• AR targeted therapy effects PSA disproportionately to tumor volume– PSA gene has an androgen response element in
the promoter
• Effects on survival with the new AR targeted therapies are yet to be reported
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Cabazitaxel:A New Tubulin-Targeting Agent
• New semi-synthetic taxane
– Selected to overcome the emergence of taxane resistance¹,²
• Preclinical data¹,²
– As potent as docetaxel against sensitive cell lines and tumor models
– Active against tumor cells/models resistant to currently available taxanes
• Clinical data
– Antitumor activity in mCRPC including docetaxel-resistant disease³
1. Attard G, Greystoke A, Kaye S, De Bono J. Pathol Biol (Paris). 2006;54(2):72-84. 2. Pivot X, Koralewski P, Hidalgo JL, et al. Ann Oncol. 2008;19(9):1547-1552. 3. Mita AC, Denis LJ, Rowinsky EK, de bono JS et al. Clin Can Res. 2009; Jan
15;15(2):723-30.
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Primary endpoint = Overall Survival, Secondary endpoint = PFS, response rate and safety, interim (futility) PFS based analysis after 225 events
TROPIC: Phase 3 Study: 146 Sites, 26 Countries
Sartor et a. GU ASCO 2010
Randomization (1:1)Stratified for Measurability of Disease and ECOG PS
Randomization (1:1)Stratified for Measurability of Disease and ECOG PS
cabazitaxel 25 mg/m² q3w + Prednisone*
cabazitaxel 25 mg/m² q3w + Prednisone*
mitoxantrone 12 mg/m² q3w + Prednisone*
mitoxantrone 12 mg/m² q3w + Prednisone*
755 patients, Maximum treatment duration 10 cycles, planned 511 events to detect 25% reduction in hazard ratio, 90% power, 2 sided 5% alpha level
* Or prednisolone – 10 mg given orally daily
Hormone Resistant Metastatic Prostate Cancer Patients Previously Treated With A Taxotere Containing Regimen
Hormone Resistant Metastatic Prostate Cancer Patients Previously Treated With A Taxotere Containing Regimen
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Eligibility Criteria
• mCRPC patients with documented disease progression
– If measureable: RECIST progression
– If non-measurable : Documented rising PSA levels (at least2 consecutive rises in PSA over a reference value taken at least 1 week apart ) or appearance of new lesion
• Previous treatment with at least 225 mg/m2 docetaxel-containing regimen (protocol amended)
• No previous treatment with mitoxantrone
• ECOG-PS: 0–2
• Normal organ function (CBC and serum chemistries)
• No grade 2 or worse neuropathies
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MP (n=377) CBZP (n=378)
Age (years)
Median [range] 67 [47–89] 68 [46–92]≥65 (%) 57.0 64.9
ECOG PS (%)
0, 1 91.2 92.62 8.8 7.4
PSA* (ng/mL)
Median [range] 127.5 [2–11220] 143.9 [2–7842]Measurability of disease (%)
Measurable 54.1 53.2Non-measurable 45.9 46.8
Disease site (%)
Bone 87.0 80.2Lymph node 44.8 45.0Visceral 24.9 24.9
Summary of Patient Characteristics
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Pre-Protocol Treatments MP (n=377) CBZP (n=378)
Chemotherapy (%)
1 regimen 71.1 68.82 regimens 21.0 24.9≥3 regimens 8.0 6.3
Docetaxel-containing regimens administered (% patients)
1 regimen 86.7 83.62 regimens 11.4 14.0≥3 regimens 1.9 2.4
Total prior docetaxel dose (mg/m²)
Median 529.2 576.6Months from last docetaxel dose to progression
Median 0.70 0.80
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Pre-Protocol Treatments
MP (n=377) CBZP (n=378)
Total prior docetaxel dose
Median (mg/m²) 529.2 576.6
Median cycles 7 7
% of patients per docetaxel dose
<225 mg/m² 8.0 7.7
≥225 to 450 mg/m² 29.7 24.9
≥450 to 675 mg/m² 27.9 29.6
≥675 to 900 mg/m² 15.1 19.6
≥900 mg/m² 18.0 17.5
Unknown 1.3 0.8
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Primary Endpoint: Overall Survival (ITT Analysis)
MP 377 300 188 67 11 1
CBZP 378 321 231 90 28 4Number
at risk
Proportionof OS (%)
80
60
40
20
0
100
0 months 6 months 12 months 18 months 24 months 30 months
Median OS
0.59–0.8395% CI
<.0001P-value
0.70Hazard Ratio
CBZPMP
12 .7 15.1
Sartor et al. GU ASCO, 2010
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35
Subgroup Overall Survival Analysis
Factor Hazard Ratio (95% CI)
All patients 0.69 (0.57 – 0.84)
ECOG status: 0,1 0.68 (0.57 – 0.82)
ECOG status: 2 0.81 (0.48 – 1.38)
Measurable disease: No 0.72 (0.55 – 0.93)
Measurable disease: Yes 0.68 (0.54 – 0.85)
No of prior chemo: 1 0.71 (0.54 – 0.93)
No of prior chemo: >=2 0.68 (0.54 – 0.86)
Age: < 65 0.81 (0.61 – 1.08)
Age: >=65 0.62 (0.50 – 0.78)
Country: Europe 0.68 (0.53 – 0.86)
Country: North America 0.59 (0.43 – 0.82)
Country: Other country 1.00 (0.65 – 1.54)
Pain: no 0.57 (0.43 – 0.77)
Pain: Yes 0.76 (0.59 – 0.98)
Rising PSA: No 0.87 (0.59 – 1.29)
Rising PSA: Yes 0.65 (0.53 – 0.82)
Hazard Ratio0 1 2
Favors CBZ
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Subgroup Overall Survival AnalysisCategory Factor Hazard Ratio (95% CI)
ITT population All Patients 0.69 (0.57 – 0.84)
Last taxotere to random < 6 months 0.78 (0.62 – 0.97)
Last taxotere to random >=6 months 0.66 (0.46 – 0.96)
Total taxotere dose < 225 mg/m2 0.96 (0.46 – 2.03)
Total taxotere dose >= 225 to 450 mg/m2 0.61 (0.43 - 0.88)
Total taxotere dose >= 450 to 675 mg/m2 0.80 (0.56 – 1.16)
Total taxotere dose >= 675 to 900 mg/m2 0.73 – (0.46 – 1.13)
Total taxotere dose >= 900 mg/m2 0.49 (0.31 – 0.79)
Progression During last taxotere treatment
0.67 (0.47 – 0.96)
Progression Within first 3 monthssince last taxotere dose
0.69 (0.52 – 0.91)
Progression Between 4th & 6th month since last taxotere dose
0.82 (0.48 – 1.40)
Progression More than 6 months since 0.73 (0.35 – 1.53)
Hazard Ratio0 1 2 3
Favors CBZ
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Progression-Free Survival
Pro
por
tion
of
PF
S (
%)
377378
5592
1218
61
41
100
80
60
40
20
0Time (months)0 6 12 18 213 9 15
117168
3055
96
25% reduction in risk of progression
MP CBZP
Median PFS (months) 1.4 2.8
Hazard ratio 0.75
95% CI 0.65–0.87
P-value 0.0002
Numberat Risk
MP CBZP
CensoredMPCBZP
Combined medianfollow-up: 13.7 months
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Secondary Endpoints:Response Rate and Time to Progression
MP (n=377) CBZP (n=378) Hazard ratio (95% CI) P-value
Tumor assessment
Response rate* (%) 4.4 14.4 – .0005
Median TTP (months) 5.4 8.8 0.61 (0.49–0.76) <.0001
PSA assessment
Response rate* (%) 17.8 39.2 – .0002
Median TTP (months) 3.1 6.4 0.75 (0.63–0.90) .001
Pain assessment
Response rate* (%) 7.8 9.2 – .6286
Median TTP (months) NR 11.1 0.91 (0.69–1.19) .5192
*Determined only for subjects with at baseline measurable disease, PSA ≥20 ng/ml, or pain, respectively. NR=Not reached.
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Exposure: Median 6 cycles CBZ vs 4 cycles MTZ
Mitozantrone + P(N=1736)
Cabazitaxel + P(N=2251)
Actual dose level (mg/m2) Full dose level (%) Reduced by 20% More than 20% reduction Unknown actual dose
MTX1648 (94.9) 77 (4.4) 9 (0.5) 2 (0.1)
CBZ2030 (90.2)
193 (8.6) 27 (1.2)
1 (<0.1)
Number of cycles delayed Delay 4 to 6 days Delay 7 to 9 days Delay > 9 days
28 (1.6)82 (4.7)28 (1.6)
42 (1.9)115 (5.1) 51 (2.3)
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40
MP (n=371) CBZP (n=371)
All grades (%)
Grade ≥3 (%)
All grades (%)
Grade ≥3 (%)
Any adverse event 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
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
Most Frequent Treatment-EmergentAdverse Events*
*Sorted by ≥2% incidence rate for grade ≥3 events in the cabazitaxel arm.
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Hematological Results
MP (n=371) CBZP (n=371)All grades
(%)Grade ≥3
(%)All grades
(%)Grade ≥3
(%)
Hematology
Anemia 81.4 4.9 97.3 10.5
Leukopenia 92.5 42.3 95.7 68.2
Neutropenia* 87.6 58.0 93.5 81.7
Thrombocytopenia 43.1 1.6 47.4 4.0
*Prophylactic use of G-CSF was permitted except for cycle 1 of treatment at the discretion of the investigator.
58% grade ≥3 neutropenia in MP arm of the TROPIC study compares to 22% reported for the TAX 327 (first-line) study
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Fatal Events—Update (cut-off date 3/10/10)
MP (n=371) CBZP (n=371)
Total deaths during study 304 (81.9%) 270 (72.8%)
Due to progression 264 (71.2%) 218 (58.8%)
Due to AE 7 (1.9%) 18 (4.9%)
Due to AE (N America, n=235) 1 (0.8%) 1 (0.9%)
Due to AE (Europe, n=402) 6 (3.0%) 10 (4.9%)
Due to other reasons 15 (4.0%) 12 (3.2%)
Cause unknown (> 3 mo following last dose)
11 (3.0%) 20 (5.4%)
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FDA Package Insert on Growth Factors
• Primary prophylaxis with G-CSF should be considered for pts >65 years, poor performance status, prior febrile neutropenia, poor nutritional status, or other serious co-morbidities
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Cabazitaxel Conclusion
• An effective drug fulfilling an unmet need with a safety profile that demands meticulous attention to detail in particular with careful management of neutropenia and diarrhea
• It should be reserved for patients with metastatic CRPC with progressive disease post-docetaxel and a good performance status and organ function
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Immune Based Therapies
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GM-CSF Induces the Greatest Anti-Tumor Immunity in Cytokine Transduced Tumor Cells
Dranoff et al, PNAS 90:3539, 1993
100
0
20
40
60
80
% T
um
or
Fre
e A
nim
als
IL- 7
GM
-CS
FIL
-3
IL-6
IL-4
SC
FG
-CS
FIL
-2 +
IL-
1
IL-2
TN
F-
IFN
-
MIF
B7-
1
M-C
SF
CD
2
IL-1
0
ICA
M-1
IL-5
MIP
-1
MIP
-1
IL-1
RA
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Antigen Delivery Fusion Protein Used to Stimulate Antigen Presenting Cells
(APCs) in Preparation of Sipuleucel-T
Prostatic Acid Phosphatase (PAP)
Granulocyte MacrophaseColony Stimulating Factor
(GM-CSF)
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Vaccination with Antigen (GM-CSF/PAP) Loaded Antigen Presenting Cells (APCs)
Leukapheresis
Isolation of APC
Antigen-loadedAPCs
PAP-GM-CSF“Antigen”
Patient
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Randomized Phase III Trial with Sipuleucel-T (IMPACT or D9902B)
Primary endpoint: Overall SurvivalSecondary endpoint: Time to Objective Disease Progression
Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512)
Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512)
Placebo Q 2 weeks x 3
Placebo Q 2 weeks x 3
Sipuleucel-T Q 2 weeks x 3
Sipuleucel-T Q 2 weeks x 3
P R O G R E S S I O N
P R O G R E S S I O N
2:1
SURVIVAL
SURVIVAL
Treated at Physician discretion and/or Salvage Protocol
Treated at Physician discretion and/or Salvage Protocol
Treated at Physician discretion
Treated at Physician discretion
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Sipuleucel T: IMPACT Phase III Trial Overall Survival
0 6 12 18 24 30 36 42 48 54 60 660
25
50
75
100
Perc
ent
Surv
ival
Survival (Months)
P = 0.032 (Cox model)HR = 0.775 [95% CI: 0.614, 0.979]Median Survival Benefit = 4.1 Mos.
Provenge (n = 341) Median Survival: 25.8 Mos.
Placebo (n = 171)Median Survival: 21.7 Mos.
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Stromal Targeted Therapy
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Castrate-Refractory Prostate Cancer Is a Heterogeneous Group of Diseases: Lessons
from a Rapid Autopsy Program
Shah RB, et al. Cancer Res. 2004;64:9209-9216.
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Cancer Stem Cell Model
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Heterogeneity and Stem Cells:The Dual Challenge of Advanced
Prostate Cancer
• How do we target cancers that are heterogeneous in both genotype and phenotype in the same patient?– Targeting a stable stroma?
• How do we kill a stem cell in patients with widespread cancer?– The critical question in oncology today!
• Destruction of “ecologic” niches that support cancer growth?????
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Lessons from the Ivory Bill Woodpecker: Habitat Destruction is the Key to Extinction
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Stromal Targeted Therapy: New Concept in Cancer Therapeutics
• Anti-angiogenesis inhibitors– Bevacizumab, sunitinib, thalidomide, lenalidomide
• Bone + tumor targeting with endothelin antagonism– Atrasentan and ZD4054
• Bone + tumor targeting with anti-p60src– Dasatinib
• Bone stromal targeted radiopharmaceuticals– Strontium-89, Samarium-153 EDTMP, Radium-223
• Osteoclast inhibition– Zolendronic acid and denosumab– No effects seen in CRPC to date
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Where do we go from here?
• It takes 4 drugs to cure Hodgkin’s disease, one of our most curable malignancies– Clearly multiple drugs will be necessary to cure
mCRPC and that is our greatest challenge today
• Multi-targeted therapy to multiple micro-environmental sites and the tumor too?
• If we ever figure out how to kill metastatic stem cells, then the game changes
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Trends, Issues & Treatment in Late-Stage Prostate Cancer
Oliver Sartor, M.D.
LaBorde Professor for Cancer Research
Medical Director, Tulane Cancer Center
Tulane Medical School
New Orleans, LA