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Castration-Resistant Metastatic Prostate Cancer: Novel Therapeutics

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Castration-Resistant Metastatic Prostate Cancer: Novel Therapeutics Robert Dreicer, M.D., M.S., FACP Chairman Department of Solid Tumor Oncology – PowerPoint PPT presentation

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Title: Castration-Resistant Metastatic Prostate Cancer: Novel Therapeutics


1
Castration-Resistant Metastatic Prostate Cancer
Novel Therapeutics
  • Robert Dreicer, M.D., M.S., FACP
  • Chairman Department of Solid Tumor Oncology
  • Taussig Cancer Institute
  • Cleveland Clinic Professor of Medicine
  • Cleveland Clinic Lerner College of Medicine

2
Clinical States In Prostate Cancer
Metastatic Disease (De novo)
Organ Confined
Metastases Castrate Asymptomatic
Metastases Castrate Symptomatic
Metastases Castrate Post Docetaxel
Rising PSA Hormone Naive
Locally Advanced Disease
Rising PSA Castrate
3
Second Line Hormonal Therapy Next Generation
  • Lyase inhibitors Abiraterone, TAK 700
  • Inhibits the CYP 17 (17a-hydroxylase and
    C17,20-lyase) dual enzyme complex, which is
    principally responsible for androgen synthesis
  • Anti-androgens MDV 3100
  • Novel small-molecule AR antagonist
  • Binds the AR with greater relative affinity than
    the clinically used antiandrogen bicalutamide
  • Reduces the efficiency of its nuclear
    translocation and impairs both DNA binding to
    androgen response elements and recruitment of
    coactivators

4
Abiraterone Activity/Toxicity
  • Phase I/II multiple studies in castration-resistan
    t metastatic disease, prior ketoconazole and
    pre/post docetaxel
  • Broad anti-tumor activity across these patient
    subsets
  • Oral agent, administered with prednisone
  • Hypertension, fatigue, hypokalemia, glucose
    intolerance (secondary to prednisone)

Ryan CJ et al. J Clin Oncol 281481, 2010- Danila
DC, et al. J Clin Oncol 281496, 2010- Reid AH et
al, J Clin Oncol 281489, 2010
5
Abiraterone, TAK 700 Clinical Development
  • Given evidence of activity, abiraterone rapidly
    taken into phase III program Trials completed
  • Phase III trial metastatic CRPC post docetaxel
  • 21 randomization abiraterone/prednisone vs
    prednisone
  • Primary endpoint OS
  • Phase III trial metastatic CRPC no prior
    chemotherapy
  • Abiraterone/prednisone vs prednisone
  • Primary endpoint PFS
  • TAK 700 two phase III trials pending activation

Ryan CJ et al. J Clin Oncol 281481, 2010
6
MDV 3100 Activity/Toxicity
  • Phase I/II multiple studies in castration-resistan
    t metastatic disease, prior ketoconazole and
    pre/post docetaxel
  • Broad anti-tumor activity across these patient
    subsets
  • Oral agent
  • Fatigue, mild nausea, anorexia

7
MDV 3100 Clinical Development
  • Given evidence of activity, MDV3100 rapidly taken
    into phase III program
  • Phase III trial metastatic CRPC post docetaxel
  • MDV3100 (160 mg daily vs placebo)
  • Primary endpoint OS, SE PFS, toxicity
  • Randomized Phase II trial metastatic CRPC no
    prior chemotherapy (planned)
  • MDV3100 vs placebo
  • Primary endpoint PFS

8
Endothelin A Antagonists
  • The endothelins are a class of peptides expressed
    in a variety of human tissues, which control
    vasoconstriction, mitogenesis, nociception, and
    bone matrix formation
  • There is compelling evidence supporting the role
    of endothelin receptors in the proliferation of
    prostate cancer and development of bone
    metastases
  • Atrasentan and zibotentan are specific endothelin
    receptor A antagonists in late stage development
    in advanced prostate cancer

James ND, et al. Eur Urol 551112, 2009
Carducci MA, et al, Cancer 1101959, 2007
9
Atrasentan, Zibotentan Clinical Development
  • SWOG 421 Phase III trial of docetaxel/prednisone/p
    lacebo vs docetaxel/prednisone/atrasentan front
    line chemotherapy for metastatic CRPC
  • Zibotentan vs placebo in CRPC without metastatic
    disease
  • Zibotentan vs placebo in metastatic CRPC
    (pain-free or mild pain)
  • Docetaxel / prednisone /- Zibotentan in patients
    with symptomatic metastatic CRPC

10
Phase III Trial Comparing Docetaxel Prednisone
With or Without Bevacizumab (CALGB 90401)
Metastatic CRPC No prior chemotherapy PS 0-2
DPDocetaxel 75 mg/m2 Q 3wk Placebo Q
3wk Prednisone 10 mg daily
Metastatic CRPC No prior chemotherapy PS 0-2
DP BDocetaxel 75 mg/m2 Q 3wk Bevacizumab 15
mg/kg Q 3wk Prednisone 10 mg daily
11
Results
Endpoint DPB(N524) DP(N526) HazardRatio p value
Median OS (months) 22.6 21.5 0.91 0.181
Median PFS (months) 9.9 7.5 0.77 lt 0.0001
50 decline in PSA 69.5 57.9 N/A 0.0002
Objective response 53.2 42.1 N/A 0.0113
Grade 3 or higher treatment-related AE 74.8 55.3 N/A lt0.001
Treatment-related deaths 4.4 1.1 N/A 0.0014
AE, adverse event OS, overall survival PFS,
progression-free survival
Stratified log-rank p value.
Kelly WK et al. Proc ASCO 2010Abstract LBA4511
12
Dasatinib
  • Dasatinib is an oral tyrosine kinase inhibitor
    with potent activity against SRC and SRC family
    kinases, BCR-ABL, platelet-derived growth factor
    receptor, and c-KIT
  • In experimental models, inhibition of SRC has
    both antitumor effects, directly on prostate
    cancer cells (proliferation and metastasis), and
    decreases bone turnover
  • Activity in phase II study lead to phase III
    development

Yu E, et al. Clin Cancer Res 2009 157421
13
Dasatinib Clinical Development
  • Randomized Double-Blind Phase III Trial Comparing
    Docetaxel Combined With Dasatinib (100 mg/day) to
    Docetaxel Combined With Placebo in
    Castration-Resistant Prostate Cancer
  • Primary endpoint OS, SE Rate of change in
    urinary N-telopeptide values, time to first SRE,
    safety and tolerability

14
Anti CTLA-4 therapy Ipilimumab
  • Ipilimumab is a humanized anti-CTLA-4 antibody
  • Intriguing evidence of activity in combination
    with ADT, GM-CSF
  • Episodes of autoimmunity, termed immunerelated
    serious adverse events have been reported
    including life threatening panhypopituitarism and
    colitis

Tollefson MK, et al. 2010 Genitourinary Cancers
Symposium abst 168 Small EJ, et al. Clin Ca Res
2007 131810
15
Ipilimumab Clinical Development
  • Randomized phase II trial of Ipilimumab
    with/without GM-CSF in metastatic CRPC-planned
  • Phase III in post docetaxel patients ipilimumab
    vs placebo ongoing
  • Phase III trial in asymptomatic metastatic CRPC
    prior to chemotherapy ipilimumab vs placebo
    ongoing
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