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 Taussig Cancer Institute Cleveland Clinic Professor of Medicine Cleveland Clinic Lerner College of Medicine. Clinical States In Prostate Cancer.

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Castration resistant metastatic prostate cancer novel therapeutics

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


Clinical states in prostate cancer
Clinical States In Prostate Cancer Therapeutics

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

Modified from Scher HI and Heller G. Urology 2000;55:323–7


Second line hormonal therapy next generation
Second Line Hormonal Therapy: Next Generation Therapeutics

  • Lyase inhibitors: Abiraterone, TAK 700

    • Inhibits the CYP 17 (17α-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


Abiraterone activity toxicity
Abiraterone: Activity/Toxicity Therapeutics

  • Phase I/II multiple studies in castration-resistant 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 28:1481, 2010- Danila DC, et al. J Clin Oncol 28:1496, 2010- Reid AH et al, J Clin Oncol 28:1489, 2010


Abiraterone tak 700 clinical development
Abiraterone, TAK 700: Clinical Development Therapeutics

  • Given evidence of activity, abiraterone rapidly taken into phase III program: Trials completed

  • Phase III trial metastatic CRPC post docetaxel

    • 2:1 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 28:1481, 2010


Mdv 3100 activity toxicity
MDV 3100: Activity/Toxicity Therapeutics

  • Phase I/II multiple studies in castration-resistant metastatic disease, prior ketoconazole and pre/post docetaxel

  • Broad anti-tumor activity across these patient subsets

  • Oral agent

  • Fatigue, mild nausea, anorexia

Scher HI, et al. Lancet. 2010;375:1437-46


Mdv 3100 clinical development
MDV 3100: Clinical Development Therapeutics

  • 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


Endothelin a antagonists
Endothelin A Antagonists Therapeutics

  • 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 55:1112, 2009 Carducci MA, et al, Cancer 110:1959, 2007


Atrasentan zibotentan clinical development
Atrasentan, Zibotentan: Clinical Development Therapeutics

  • SWOG 421 Phase III trial of docetaxel/prednisone/placebo 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


Phase iii trial comparing docetaxel prednisone with or without bevacizumab calgb 90401
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


Results
Results Without Bevacizumab (CALGB 90401)

AE, adverse event; OS, overall survival; PFS, progression-free survival

* Stratified log-rank p value.

Kelly WK et al. Proc ASCO 2010;Abstract LBA4511


Dasatinib
Dasatinib Without Bevacizumab (CALGB 90401)

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 157:421


Dasatinib clinical development
Dasatinib: Clinical Development Without Bevacizumab (CALGB 90401)

  • 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


Anti ctla 4 therapy ipilimumab
Anti CTLA-4 therapy: Ipilimumab Without Bevacizumab (CALGB 90401)

  • 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 13:1810


Ipilimumab clinical development
Ipilimumab: Clinical Development Without Bevacizumab (CALGB 90401)

  • 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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