prostate cancer: what’s new? treatment options for advanced castrate resistant disease
DESCRIPTION
Prostate Cancer: What’s New? Treatment Options For Advanced Castrate Resistant Disease. Naomi B Haas, MD Associate Professor of Medicine Abramson Cancer Center. April 24, 2013. Objectives: to discuss the new modulation of androgen and the androgen receptor for prostate cancer. - PowerPoint PPT PresentationTRANSCRIPT
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Naomi B Haas, MDAssociate Professor of Medicine
Abramson Cancer CenterApril 24, 2013
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Modulation of androgen and testosterone New therapies for castrate resistant
prostate cancer
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Intratumoral testosterone Androgen receptor (AR) mutations and
splice variants Ligand modulation (things that influence the
AR) Targets in advance disease
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Castrate-treated with androgen deprivation therapy
Non-castrate- not previously treated with androgen 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 with androgen 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 day can decrease PSA by more than 50% in approximately 1/3 of patients with hormone-refractory progressive prostate cancer (Sartor O et 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 vs 24 months, respectively.
78 patients 0 1 to 3, >3 lesions bone scan25, 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 variantsMDV3100Aragon 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 daily 14 of 35 pts had decrease in PSA of >50%Phase III trial completed post chemotherapy showed
overall survival improvement of almost 5 months in a study of 1000+ 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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AsymptomaticCastrate 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-509Single Dose
Tumor EvaluationQ 12 wks
Disease Progression
DLT period for dose escalation
PSA and CTCQ 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
Optional FDHT-PET
at Baseline, 4 and 12
wks
Phase 1 Study Design
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14 out of 29 patients (48.3%) experienced ≥ 50% reduction in PSA at 12 weeks
30 mg 60 mg 90 mg120 mg180 mg240 mg300 mg390 mg480 mg
Dose
PSA Response Rates
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Baseline
4 Weeks
F-DHT-PET: Pharmacodynamic Marker
OF AR INHIBITION IN RESPONSE TO ARN-509
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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 of sipuleucel-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 placebo arms
Kantoff GU ASCO 2010
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Harness antigens expressed uniquely by a cancer (for example Prostate specific membrane antigen, prostate specific stem cell 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 important targets in prostate cancer
c-met is overexpressed in bone metastases as a later event in men on androgen deprivation therapy
VEGF expressed in aggressive prostate cancer
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RDT trial in patients previously treated with docetaxel showed 86% had response in bone scan; 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 results pending
Two new phase III trials of XL184 coming
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Original Normalized CAD Annotated
Screening
Week 6
XL 1129-2408XL 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 1521-2565XL 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 CabazetaxelDocetaxel ECOG 2809 ketoconazole mitoxantrone and
prednisone
abiraterone abiraterone
docetaxel enzalutamideStrivePrevail
XL184?Radium chloride
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Biopsy with molecular profile Treatment with chemotherapy or targeted
agents or more hormonal therapy depending on your molecular profile
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Hormone Sensitive v. Hormone Refractory Prostate Cancer
Hormone Sensitive
Hormone Refractory
Biology
Clinical TrialsOpen or Planned at
UPENN
1. High risk RT+ ADT+/- docetaxel trial
2. everolimus + salvage XRT3. Phase I Docetaxel/ cmet
inhibitor trial4. CAR-T cells in advanced disease5. TKI258 plus INC280
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Combines VEGFR+ FGF inhibitor with a C-met inhibitor.
Phase I/II planned