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Prostate Cancer: What

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Naomi B Haas, MD Associate Professor of Medicine Abramson Cancer Center April 24, 2013 RDT trial in patients previously treated with docetaxel showed 86% had response ... – PowerPoint PPT presentation

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Title: Prostate Cancer: What


1
Prostate Cancer Whats New?Treatment Options
For Advanced Castrate Resistant Disease
  • Naomi B Haas, MD
  • Associate Professor of Medicine
  • Abramson Cancer Center

April 24, 2013
2
Objectives to discuss the new modulation of
androgen and the androgen receptor for prostate
cancer
  • Modulation of androgen and testosterone
  • New therapies for castrate resistant prostate
    cancer

3
Overcoming resistance mechanisms in prostate
cancer
  • Intratumoral testosterone
  • Androgen receptor (AR) mutations and splice
    variants
  • Ligand modulation (things that influence the AR)
  • Targets in advance disease

4
Semantics
  • Castrate-treated with androgen deprivation
    therapy
  • Non-castrate- not previously treated with
    androgen deprivation therapy

5
Conventional categories
  • 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

6
Androgen deprivation Therapy
  • Orchiectomy
  • LHRH (GHRH) (Luteinizing hormone releasing
    hormone) agonists
  • Anti-androgens

7
ADT
  • Anti-androgen LHRH
  • Pills
    Implants and shots

LHRH antagonist- degarelix
8
Side Effects
  • 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

9
Other Hormonal Manipulations
  • 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

10
Other options ketoconazole prednisone or
hydrocortisone
Scholz M et al. J Urol. 2005 Jun173(6)1947-52.
78 patients 0 1 to 3, gt3 lesions bone scan 25,
35, and 18 patients
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.
11
NEW Hormonal Manipulations!
  • 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
  • MDV3100
  • Aragon agent
  • Other AR Modulators
  • HSP 90 inhibitors
  • HDAC inhibitors

12
Other hormonal manipulations
  • Prednisone
  • Ketoconazole
  • Abiraterone

13
Abiraterone acetate and prednisone in patients
(Pts) with progressive metastatic castration
resistant prostate cancer (CRPC) after failure of
docetaxel-based chemotherapy.JClin Oncol 26
2008 (May 20 suppl abstr 5019)
  • AA (Zytiga) 1000mg qd pred 5mg twice daily
  • 14 of 35 pts had decrease in PSA of gt50
  • Phase III trial completed post chemotherapy
    showed overall survival improvement of almost 5
    months in a study of 1000 patients, leading to
    FDA approval

14
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15
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16
Abiraterone side effects
  • Dizziness
  • Fatigue
  • Low or high blood pressure
  • Fluid retention
  • Elevation of liver enzymes
  • Low potassium

17
MDV3100/ Enzalutamide / Xtandi
AR modulation
18
MDV 3100 Phase II trial
MDV3100
11 randomization
Decline docetaxel or are not suitable for
docetaxel
Something else
? patients
Coming soon
19
MDV 3100 Phase III AFFIRM trial
MDV3100
21 randomization
Failed 1 or 2 prior chemotherapies (docetaxel)
Placebo
1170 patients
Improvement in overall survival of more than 5
months
20
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21
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22
MDV 3100 Phase III PREVAIL trial
MDV3100
21 randomization
Asymptomatic Castrate metastatic disease
Placebo
850 patients
Closed to accrual in the US
23
ARN-509 versus MDV3100
24
ARN-509 versus MDV3100
25
Phase 1 Study Design
Optional FDHT-PET at Baseline, 4 and 12 wks
Tumor Evaluation Q 12 wks
PSA and CTC Q 4 wks
ARN-509 Single Dose
Disease Progression
ARN-509 once daily until progression
PK week Continuous Daily Dosing
PK D1-6
Wk 1 2 3 4 5 9
13
Cycle 1 2
3
DLT period for dose escalation
  • ARN-509 dose escalation cohorts (n3-6/cohort)
  • 30, 60, 90, 120, 180, 240,
    300, 390 and 480 mg

26
PSA Response Rates
Dose
14 out of 29 patients (48.3) experienced 50
reduction in PSA at 12 weeks
27
F-DHT-PET Pharmacodynamic Marker OF AR
INHIBITION IN RESPONSE TO ARN-509
Baseline 4 Weeks
28
Ongoing Phase 2 Trial
ASCO GU 2013
29
Immunotherapies
  • Provenge
  • Prostvac
  • CARs

30
IMPACT trial of sipuleucel-T for metastatic
castration-resistant prostate cancer
  • randomized (21) 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

31
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32
CARs (Chimeric Antigen and T cell Receptor)(Carl
June)
  • 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

33
XL184 (Cabozantanib)
  • 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

34
XL184 (Cabozantanib)
  • 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

35
XL 184 Cases
36
XL 1129-2408
Screening
Week 6
Original
Normalized
CAD Annotated
37
XL 1129-2426
Screening
Week 6
Original
CAD Annotated
Normalized
38
XL 1522-2459
Screening
Week 6
Original
CAD Annotated
Normalized
39
XL 1521-2565
Screening
Week 6
Original
Normalized
CAD Annotated
40
The Landscape
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 and prednisone
abiraterone abiraterone
docetaxel enzalutamide
Strive Prevail XL184? Radium chloride

41
The future
  • Biopsy with molecular profile
  • Treatment with chemotherapy or targeted agents or
    more hormonal therapy depending on your molecular
    profile

42
Hormone Sensitive v. Hormone Refractory Prostate
Cancer
Clinical Trials Open or Planned at UPENN
Biology
1. High risk RT ADT/- docetaxel
trial 2. everolimus salvage XRT 3. Phase I
Docetaxel/ cmet inhibitor trial 4. CAR-T cells
in advanced disease 5. TKI258 plus INC280
43
TKI258 INC280
  • Combines VEGFR FGF inhibitor with a C-met
    inhibitor.
  • Phase I/II planned
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