Post on 05-Feb-2016
description
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
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
“Castrate-Refractory” Prostate Cancer
• Progressive prostate cancer despite surgical or medical castration
• Serum Testosterone (<50 ng/dL)
“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
Pathophysiology: The Continued Importance of the Androgen Receptor
Androgen Receptor Gene Over-Expression in “Castrate-Refractory”
Prostate Cancer
Linja et al., Can Res 61:3550 2001
Tissue Androgen Levels in Benign Prostate vs. Castrated Cancer Tissue
Mohler et al., Clin Cancer Res 10:440, 2004
Shaded=Benign Clear=Castrate
Over-Expression of Enzymes in the Androgen Synthesis Pathway in Metastatic Castrate-
Refractory Prostate Cancer Cells Stanbrough et al. Cancer Res. 66:2815, 2006
Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic
Exons Signify CRPCHu et al. Cancer Research 69:16-22, 2009
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
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)
Despite Many New Promising Agents, Docetaxel was, For Many Years, the only FDA Approved Chemotherapy shown to have a Survival Benefit in
CRPC
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.
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
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
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)
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)
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
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
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
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
Abiraterone: Potent Inhibitor of CYP17: (17-20 Lyase and 17-Alpha Hydroxylase)
Maximal PSA Declines in Abiraterone Post-Docetaxel
Reid et al. JCO 28:1489, 2010
MDV3100: A New Anti-AndrogenTran et al: Science 324:787-790, 2009
MDV3100 PSA Changes in Phase I TrialScher et al. ASCO GU, 2009, #151
PSA Declines with MDV3100 Pre- and Post-Docetaxel
Scher et al. Lancet 375:1437, 2010
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
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.
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
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
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
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
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
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
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
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
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
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.
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)
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.
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
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%)
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
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
Immune Based Therapies
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
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)
Vaccination with Antigen (GM-CSF/PAP) Loaded Antigen Presenting Cells (APCs)
Leukapheresis
Isolation of APC
Antigen-loadedAPCs
PAP-GM-CSF“Antigen”
Patient
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
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.
Stromal Targeted Therapy
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.
Cancer Stem Cell Model
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?????
Lessons from the Ivory Bill Woodpecker: Habitat Destruction is the Key to Extinction
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
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
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