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Naomi B Haas, MDAssociate Professor of Medicine
Abramson Cancer Center
April 24, 2013
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Modulation of androgen and testosterone
New therapies for castrate resistantprostate cancer
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Intratumoral testosterone Androgen receptor (AR) mutations and splice
variants
Ligand modulation (things that influence theAR)
Targets in advance disease
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Castrate-treated with androgen deprivationtherapy
Non-castrate- not previously treated withandrogen deprivation therapy
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Rising PSA after surgery or radiation or both New metastatic disease and rising PSA :non-
castrate (not previously treated withandrogen deprivation therapy)
Metastatic castrate prostate cancer
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Orchiectomy LHRH (GHRH) (Luteinizing hormone releasing
hormone) agonists
Anti-androgens
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Anti-androgen LHRH
Pills Implants and shots
LHRH antagonist- degarelix
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Tiredness Metabolic syndrome- weight gain, high blood
pressure and high blood sugar Osteopenia-decreased bone density Secondary risks for heart attack, blood clot or
stroke Mood changes Loss of sex drive (libido) Hot flashes
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Prednisone 10 mg by mouth two times a daycan decrease PSA by more than 50% inapproximately 1/3 of patients with hormone-refractory progressive prostate cancer (Sartor Oet al, The Journal of Urology Vol161, Issue 1, January 1999,Page 360
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Scholz M et al. J Urol. 2005 Jun;173(6):1947-52.
Median and mean time to PSA progression was 6.7 and 14.5 months.
Median and mean survival time was 38.0 and 42.4 months, respectively.
Response time and survival were highly correlated (r = 0.799). A total of
34 (44%) men had a greater than 75% decrease in PSA. The median
survival times in men with more vs less than a 75% decrease were 60 vs24 months, respectively.
78 patients
0 1 to 3, >3 lesions bone scan
25, 35, and 18 patients
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Lyase inhibitors- get rid of intratumoral testosterone and
residual sources of testosterone/androgens
Abiraterone acetate and prednisone Tax 700
Toc 1 (dual lyase and AR inhibitor)
AR inhibitors- address mutations in the receptor, splice variants
MDV3100Aragon agent
Other AR ModulatorsHSP 90 inhibitorsHDAC inhibitors
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Prednisone Ketoconazole
Abiraterone
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AA (Zytiga) 1000mg qd + pred 5mg twice daily14 of 35 pts had decrease in PSA of >50%
Phase III trial completed post chemotherapy showed overallsurvival improvement of almost 5 months in a study of1000+ patients, leading to FDA approval
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Dizziness
Fatigue
Low or high blood pressure
Fluid retention
Elevation of liver enzymes Low potassium
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AR modulation
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Decline docetaxel
or are not suitable
for docetaxel
1:1 randomization
MDV3100
Something else
? patients
Coming soon
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Failed 1 or 2 prior
chemotherapies
(docetaxel)
2:1 randomization
MDV3100
Placebo
1170 patients
Improvement in overall survival of more than 5 months
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Asymptomatic
Castrate
metastatic disease
2:1 randomization
MDV3100
Placebo
850 patients
Closed to accrual in the US
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ARN-509 versus MDV3100
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ARN-509 versus MDV3100
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PK week Continuous Daily Dosing
Wk 1 2 3 4 5 9 13
Cycle 1 2 3
ARN-509
Single
Dose
Tumor
Evaluation
Q 12 wksDisease
Progression
DLT period for dose escalation
PSA
and CTC
Q 4 wks
ARN-509 dose escalation cohorts (n=3-6/cohort):
30, 60, 90, 120, 180, 240, 300, 390 and 480 mg
ARN-509 once daily until progression
PK D1-6
OptionalFDHT-PET
at
Baseline,
4 and 12
wks
Phase 1 Study Design
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-100
-75
-50
-25
0
25
50
75
100
%
PSAChangefromB
aseline
14 out of 29 patients (48.3%)
experienced 50% reduction in PSA at 12 weeks
30 mg
60 mg
90 mg
120 mg
180 mg
240 mg
300 mg
390 mg
480 mg
Dose
PSA Response Rates
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Baseline
4 Weeks
F-DHT-PET: Pharmacodynamic
MarkerOF AR INHIBITION IN RESPONSE TO ARN-509
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Metastatic
Post-Abiraterone
CRPCpatients
MetastaticTreatment-Nave
Non-Metastatic (M0)
(n = 93)
Primary Endpoint:12-week PSA response
Ongoing Phase 2 Trial
ASCO GU 2013
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Provenge Prostvac
CARs
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randomized (2:1) to receive 3 doses ofsipuleucel-T (n = 341) or placebo (n = 171)intravenously at 2-week intervals
median survival of 25.8 and 21.7 months
survival probability at 36 months of 32.1%and 23.0% in the sipuleucel-T and placeboarms
Kantoff GU ASCO 2010
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Harness antigens expressed uniquely by acancer (for example Prostate specificmembrane antigen, prostate specific stemcell antigen, F77, c-met ) and link to T cells
to turn on immunity against the antigen ongoing trials in leukemia, pancreatic cancer
Can be given IV or into the tumor
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Targets c-met and VEGFR2 both importanttargets in prostate cancer
c-met is overexpressed in bone metastasesas a later event in men on androgen
deprivation therapy
VEGF expressed in aggressive prostatecancer
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RDT trial in patients previously treated withdocetaxel showed 86% had response in bonescan; 65% had improvement in pain
Expanded prostate trial 64% (51/80 pts
evaluable) had a PR on bone scans, 24 pts(30%) SD at 100mg daily
other cohort treated at 39 mg daily resultspending
Two new phase III trials of XL184 coming
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Original Normalized CAD Annotated
Screening
Week 6
XL 1129-2408
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Original CAD AnnotatedNormalized
Screening
Week 6
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Original CAD AnnotatedNormalized
Screening
Week 6
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XL 1521-2565
Original Normalized
Screening
Week 6
CAD Annotated
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Adjuvant/
Neoadjuvant
Rising PSA Only Rising PSA
and
metastatic
disease
noncastrate)
Progression
after ADT
castrate)
Progression after
Docetaxel
TKIs +ADT ADT ADT Provenge Cabazetaxel
Docetaxel ECOG 2809 ketoconazole mitoxantrone andprednisone
abiraterone abiraterone
docetaxel enzalutamide
StrivePrevail
XL184?Radium chloride
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Biopsy with molecular profile Treatment with chemotherapy or targeted
agents or more hormonal therapy dependingon your molecular profile
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Hormone Sensit ive v. Hormone Refracto ry Prostate Cancer
Hormone Sensitive
Hormone Refractory
Biology
Clinical Trials
Open or Planned at
UPENN
1. High risk RT+ ADT+/- docetaxel
trial
2. everolimus + salvage XRT
3. Phase I Docetaxel/ cmet
inhibitor trial
4. CAR-T cells in advanced disease5. TKI258 plus INC280
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Combines VEGFR+ FGF inhibitor with a C-metinhibitor.
Phase I/II planned
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