Castration-Resistant Metastatic Prostate Cancer: Novel Therapeutics
Robert Dreicer, M.D., M.S., FACPChairman Department of Solid Tumor OncologyTaussig Cancer InstituteCleveland Clinic Professor of Medicine Cleveland Clinic Lerner College of Medicine
Modified from Scher HI and Heller G. Urology 2000;55:323–7
LocallyAdvancedDisease
Rising PSAHormone
Naive
Rising PSACastrate
MetastasesCastrate
Asymptomatic
MetastasesCastrate
Symptomatic
OrganConfined
Metastatic Disease
(De novo)
Clinical States In Prostate Cancer
MetastasesCastrate
Post Docetaxel
Second Line Hormonal Therapy: Next Generation
• 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
• 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
• 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
Scher HI, et al. Lancet. 2010;375:1437-46
MDV 3100: Activity/Toxicity
• 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
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
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 55:1112, 2009 Carducci MA, et al, Cancer 110:1959, 2007
Atrasentan, Zibotentan: Clinical Development
• 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)
Metastatic CRPC
No prior chemotherapy
PS 0-2
DP + BDocetaxel 75 mg/m2 Q 3wk
Bevacizumab 15 mg/kg Q 3wkPrednisone 10 mg daily
DPDocetaxel 75 mg/m2 Q 3wk
Placebo Q 3wkPrednisone 10 mg daily
Metastatic CRPCNo prior
chemotherapyPS 0-2
Results
Kelly WK et al. Proc ASCO 2010;Abstract LBA4511
EndpointDP+B
(N=524)DP
(N=526)HazardRatio p value
Median OS (months) 22.6 21.5 0.91 0.181*
Median PFS (months) 9.9 7.5 0.77 < 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 <0.001
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.
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 157:421
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
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 13:1810
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