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Trends, Issues

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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 – PowerPoint PPT presentation

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Title: Trends, Issues


1
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

2
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
3
Castrate-Refractory Prostate Cancer
  • Progressive prostate cancer despite surgical or
    medical castration
  • Serum Testosterone (lt50 ng/dL)

4
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

5
Pathophysiology The Continued Importance of
the Androgen Receptor
6
Androgen Receptor Gene Over-Expression in
Castrate-Refractory Prostate Cancer
Linja et al., Can Res 613550 2001
7
Tissue Androgen Levels in Benign Prostate vs.
Castrated Cancer Tissue
ShadedBenign ClearCastrate
Mohler et al., Clin Cancer Res 10440, 2004
8
Over-Expression of Enzymes in the Androgen
Synthesis Pathway in Metastatic
Castrate-Refractory Prostate Cancer Cells
Stanbrough et al. Cancer Res. 662815, 2006
9
Ligand-Independent Androgen Receptor Variants
Derived from Splicing of Cryptic Exons Signify
CRPCHu et al. Cancer Research 6916-22, 2009
10
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

11
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)

12
Despite Many New Promising Agents, Docetaxel was,
For Many Years, the only FDA Approved
Chemotherapy shown to have a Survival Benefit in
CRPC
13
Phase III Docetaxel Studies in HRPC Demonstrating
Survival Benefit
Mitoxantrone 12 mg/m2 Prednisone 10 mg q day Q 21
days up to 10 cycles
TAX 327
Randomize
Docetaxel 30 mg/m2/wk Prednisone 10 mg q day 5
on 1 off x 6 cycles
N1006
Docetaxel 75 mg/m2 Prednisone 10 mg q day Q 21
days up to 10 cycles
SWOG 9916
Mitoxantrone 12 mg/m2 Prednisone 5 mg bid Q 21
days
Randomize
N770
Docetaxel 60 mg/m2 d 2 Estramustine 280 mg
d1-5 Dexamethasone 20 mg, tid d 1 2
Warfarin and aspirin
Tannock et al. N Engl J Med 20043511502-1512
Petrylak et al. N Engl J Med 20043511513-1520.
14
Overall Survival Petrylak et al. N Engl J Med
20043511513-1520
at Risk
of Deaths
Median
in Months
DE
338
217
17.5
MP
336
235
15.6
HR 0.80 (95 CI 0.67, 0.97), p 0.01
15
Overall Survival Tax 327 Tannock et al. N Engl
J Med 20043511502-1512
1.0
Docetaxel 3 wkly
0. 9
Docetaxel wkly
0.8
Mitoxantrone
0.7
0.6
Probability of Surviving
0.5
Median survival Hazard
(mos) ratio P-value Combined 18.2 0.83 0.03
D 3 wkly 18.9 0.76 0.009 D wkly
17.3 0.91 0.3 Mitoxantrone 16.4
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
36
Months
16
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)

17
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)

18
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

19
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

20
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

21
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

22
Abiraterone Potent Inhibitor of CYP17 (17-20
Lyase and 17-Alpha Hydroxylase)
23
Maximal PSA Declines in Abiraterone
Post-DocetaxelReid et al. JCO 281489, 2010
24
MDV3100 A New Anti-AndrogenTran et al Science
324787-790, 2009
25
MDV3100 PSA Changes in Phase I TrialScher et al.
ASCO GU, 2009, 151
26
PSA Declines with MDV3100 Pre- and
Post-DocetaxelScher et al. Lancet 3751437, 2010
27
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

28
CabazitaxelA 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). 200654(2)72-84. 2. Pivot
X, Koralewski P, Hidalgo JL, et al. Ann Oncol.
200819(9)1547-1552. 3. Mita AC, Denis LJ,
Rowinsky EK, de bono JS et al. Clin Can Res.
2009 Jan 1515(2)723-30.
29
TROPIC Phase 3 Study 146 Sites, 26
CountriesSartor et a. GU ASCO 2010
Hormone Resistant Metastatic Prostate Cancer
Patients Previously Treated With A Taxotere
Containing Regimen
Randomization (11) Stratified for Measurability
of Disease and ECOG PS
cabazitaxel 25 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
Primary endpoint Overall Survival, Secondary
endpoint PFS, response rate and safety, interim
(futility) PFS based analysis after 225 events
Or prednisolone 10 mg given orally daily
30
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 02
  • Normal organ function (CBC and serum chemistries)
  • No grade 2 or worse neuropathies

31
Summary of Patient Characteristics
MP (n377) CBZP (n378)

Age (years)
Median range 67 4789 68 4692
65 () 57.0 64.9
ECOG PS ()
0, 1 91.2 92.6
2 8.8 7.4
PSA (ng/mL)
Median range 127.5 211220 143.9 27842
Measurability of disease ()
Measurable 54.1 53.2
Non-measurable 45.9 46.8
Disease site ()
Bone 87.0 80.2
Lymph node 44.8 45.0
Visceral 24.9 24.9
32
Pre-Protocol Treatments
MP (n377) CBZP (n378)

Chemotherapy ()
1 regimen 71.1 68.8
2 regimens 21.0 24.9
3 regimens 8.0 6.3
Docetaxel-containing regimens administered ( patients)
1 regimen 86.7 83.6
2 regimens 11.4 14.0
3 regimens 1.9 2.4
Total prior docetaxel dose (mg/m²)
Median 529.2 576.6
Months from last docetaxel dose to progression Months from last docetaxel dose to progression
Median 0.70 0.80
33
Pre-Protocol Treatments
MP (n377) CBZP (n378)

Total prior docetaxel dose
Median (mg/m²) 529.2 576.6
Median cycles 7 7
of patients per docetaxel dose
lt225 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
34
Primary Endpoint Overall Survival (ITT Analysis)
Proportionof OS ()
12 .7 15.1
MP 377 300 188 67 11 1
CBZP 378 321 231 90 28 4
Numberat risk
Sartor et al. GU ASCO, 2010
35
Subgroup Overall Survival Analysis
Favors CBZ
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 gt2 0.68 (0.54 0.86)
Age lt 65 0.81 (0.61 1.08)
Age gt65 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)
36
Subgroup Overall Survival Analysis
Category Factor Hazard Ratio (95 CI)
ITT population All Patients 0.69 (0.57 0.84)
Last taxotere to random lt 6 months 0.78 (0.62 0.97)
Last taxotere to random gt6 months 0.66 (0.46 0.96)
Total taxotere dose lt 225 mg/m2 0.96 (0.46 2.03)
Total taxotere dose gt 225 to 450 mg/m2 0.61 (0.43 - 0.88)
Total taxotere dose gt 450 to 675 mg/m2 0.80 (0.56 1.16)
Total taxotere dose gt 675 to 900 mg/m2 0.73 (0.46 1.13)
Total taxotere dose gt 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)
Favors CBZ
37
Progression-Free Survival
MP CBZP
Median PFS (months) 1.4 2.8
Hazard ratio 0.75 0.75
95 CI 0.650.87 0.650.87
P-value 0.0002 0.0002
25 reduction in risk of progression
Proportion of PFS ()
377 378
55 92
12 18
6 1
4 1
117 168
30 55
9 6
38
Secondary EndpointsResponse Rate and Time to
Progression
MP (n377) CBZP (n378) Hazard ratio (95 CI) P-value

Tumor assessment
Response rate () 4.4 14.4 .0005
Median TTP (months) 5.4 8.8 0.61 (0.490.76) lt.0001
PSA assessment
Response rate () 17.8 39.2 .0002
Median TTP (months) 3.1 6.4 0.75 (0.630.90) .001
Pain assessment
Response rate () 7.8 9.2 .6286
Median TTP (months) NR 11.1 0.91 (0.691.19) .5192
Determined only for subjects with at baseline
measurable disease, PSA 20 ng/ml, or pain,
respectively. NRNot reached.
39
Exposure Median 6 cycles CBZ vs 4 cycles MTZ
Mitozantrone P(N1736) Cabazitaxel P(N2251)
Actual dose level (mg/m2) Full dose level () Reduced by 20 More than 20 reduction Unknown actual dose MTX 1648 (94.9) 77 (4.4) 9 (0.5) 2 (0.1) CBZ 2030 (90.2) 193 (8.6) 27 (1.2) 1 (lt0.1)
Number of cycles delayed Delay 4 to 6 days Delay 7 to 9 days Delay gt 9 days 28 (1.6) 82 (4.7) 28 (1.6) 42 (1.9) 115 (5.1) 51 (2.3)
40
Most Frequent Treatment-EmergentAdverse Events
MP (n371) MP (n371) CBZP (n371) CBZP (n371)
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
Sorted by 2 incidence rate for grade 3 events
in the cabazitaxel arm.
41
Hematological Results
MP (n371) MP (n371) CBZP (n371) CBZP (n371)
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
42
Fatal EventsUpdate (cut-off date 3/10/10)
MP (n371) CBZP (n371)

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, n235) 1 (0.8) 1 (0.9)
Due to AE (Europe, n402) 6 (3.0) 10 (4.9)
Due to other reasons 15 (4.0) 12 (3.2)
Cause unknown (gt 3 mo following last dose) 11 (3.0) 20 (5.4)
43
FDA Package Insert on Growth Factors
  • Primary prophylaxis with G-CSF should be
    considered for pts gt65 years, poor performance
    status, prior febrile neutropenia, poor
    nutritional status, or other serious
    co-morbidities

44
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

45
Immune Based Therapies
46
GM-CSF Induces the Greatest Anti-Tumor Immunity
in Cytokine Transduced Tumor Cells Dranoff et
al, PNAS 903539, 1993
100
80
60

Tumor Free Animals
40
20
0
47
Antigen Delivery Fusion Protein Used to
Stimulate Antigen Presenting Cells (APCs) in
Preparation of Sipuleucel-T
Prostatic Acid Phosphatase (PAP)
Granulocyte Macrophase Colony Stimulating
Factor (GM-CSF)
48
Vaccination with Antigen (GM-CSF/PAP) Loaded
Antigen Presenting Cells (APCs)
49
Randomized Phase III Trial with Sipuleucel-T
(IMPACT or D9902B)
Primary endpoint Overall Survival Secondary
endpoint Time to Objective Disease Progression

50
Sipuleucel T IMPACT Phase III Trial Overall
Survival
P 0.032 (Cox model) HR 0.775 95 CI 0.614,
0.979 Median Survival Benefit 4.1 Mos.
51
Stromal Targeted Therapy
52
Castrate-Refractory Prostate Cancer Is a
Heterogeneous Group of Diseases Lessons from a
Rapid Autopsy Program
Shah RB, et al. Cancer Res. 2004649209-9216.
53
Cancer Stem Cell Model
54
Heterogeneity and Stem CellsThe 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?????

55
Lessons from the Ivory Bill Woodpecker Habitat
Destruction is the Key to Extinction
56
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

57
Where do we go from here?
  • It takes 4 drugs to cure Hodgkins 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

58
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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