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New Clinical Trials in Prostate Cancer

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New Clinical Trials in. Prostate Cancer. William K. Oh, M.D. Clinical Director, Lank Center for Genitourinary Oncology. Dana-Farber Cancer Institute ... – PowerPoint PPT presentation

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Title: New Clinical Trials in Prostate Cancer


1
New Clinical Trials in Prostate Cancer
  • William K. Oh, M.D.
  • Clinical Director, Lank Center for Genitourinary
    Oncology
  • Dana-Farber Cancer Institute
  • Associate Professor, Harvard Medical School

2
U.S. Cancer Statistics Prostate Cancer 2007
  • Leading cause of cancer in men (218,890 cases,
    29)
  • Second leading cause of cancer death in men,
    after lung (27,050 deaths, 9)
  • Cancer-specific survival estimates
  • 5 years 100
  • 10 years 93
  • 15 years 77

American Cancer Society 2007
3
Clinical States of Prostate Cancer
10-15 yrs
Hormone Therapy
Pre-Hormone Therapy
  • Source figure based on Scher HI, Morris MJ,
    Kelly WK, Schwartz LH, Heller G. Prostate cancer
    clinical trial end points RECISTing a step
    backwards. Clin Cancer Res. 2005115223-5232.

4
Clinical States of Prostate Cancer
Hormone Therapy
Pre-Hormone Therapy
  • Source figure based on Scher HI, Morris MJ,
    Kelly WK, Schwartz LH, Heller G. Prostate cancer
    clinical trial end points RECISTing a step
    backwards. Clin Cancer Res. 2005115223-5232.

5
High Risk Prostate Cancer
  • High risk of failure with surgery or radiation
  • Bulky cancers on prostate exam (T3, T4)
  • PSA 20 ng/ml
  • Gleason score 8-10
  • Nomograms also risk stratify
  • www.nomograms.org

6
CHEMOTHERAPY?
Surgery or Radiation Therapy
CHEMOTHERAPY?
Hormonal therapy
Chemotherapy
7
Hormones/Radiation /- Chemotherapy (OPEN)
R A N D O M I Z E
Radiation therapy Hormone therapy x 6 mo
High Risk Prostate Cancer
Taxotere (docetaxel) chemotherapy Radiation
therapy Hormone therapy x 6 mo
n 350 PI Dr. DAmico
Primary Endpoint Survival
8
Preoperative Chemotherapy? Radical Prostatectomy
  • 6 months of Taxotere before surgery
  • Monthly PSA, DRE assessments
  • Prostate MRI at 0, 2, and 6 months
  • Primary endpoint Complete eradication of cancer
    from surgical specimen

Febbo Clin Cancer Res 2005
9
(No Transcript)
10
Treatment Response
  • PSA decline 50
  • 11/19 patients (58)
  • Tumor shrinkage 25 on MRI
  • 13/19 (68)
  • Complete eradication of cancer
  • 0/16 (0)

11
Feasibility
  • Major side effect mild-mod fatigue
  • No nausea, numbness, infection
  • No surgical complications
  • After 2 years (avg) since surgery, median PSA
  • 3 patients started hormones

12
Chemo-treated Tumors Have Unique Molecular
Signatures
13
Preoperative Taxotere Avastin in High Risk
Cancer (OPEN)
Taxotere x 18 wks Avastin x 15 wks
High Risk Prostate Cancer
Surgery (RP)
Prostate MRI response ?
n 42 PI Dr. Oh
14
Summary High Risk Cancer
  • Multi-modality therapy is the key to improved
    outcome
  • Better systemic agents and combinations
  • Improved understanding of biology
  • Chemoresistance
  • New targets

15
Clinical States of Prostate Cancer
Hormone Therapy
Pre-Hormone Therapy
  • Source figure based on Scher HI, Morris MJ,
    Kelly WK, Schwartz LH, Heller G. Prostate cancer
    clinical trial end points RECISTing a step
    backwards. Clin Cancer Res. 2005115223-5232.

16
Failure of Local Therapy
  • Most men treated for localized prostate cancer
    are cured
  • About 1/3 recur, initially as a rising PSA alone
    (biochemical failure)
  • Little is known about optimal management of
    rising PSA patients

17
Natural History of Rising PSA
  • Patrick Walsh (_at_Johns Hopkins)
  • 15 relapsed after surgery
  • No hormones until () bone scan

RP
7.5 yrs
6.5 yrs
2 yrs
First Rise in PSA
Bone scan ()
Death
Eisenberger Proc ASCO 2003
18
Rapid PSA Doubling Time More Aggressive Cancer
PSADT
Percent Dead of Prostate Cancer
DAmico JNCI 2003
19
Investigational Therapies for Rising PSA
  • Lifestyle or diet
  • Pomegranate juice
  • Novel targeted therapies
  • Rosiglitazone (Avandia)
  • Celecoxib (Celebrex)
  • Thalidomide/Revlimid
  • Statins
  • Vaccines
  • TRICOM-Prostvac

20
Brief Hormones /- Avastin for Rising PSA (OPEN
SOON)
R A N D O M I Z E
Hormone therapy x 6 mo
Rising PSA No mets Any PSADT
Hormone therapy x 6 mo Avastin x 6 mo
n 100 PI Dr. Taplin
Endpoint PSA 0.2 ng/ml
21
Chemohormonal Therapy in Rapid PSADT patients
(OPEN)
Taxotere x 3 mo Avastin x 6 mo Hormones x 18 mo
PSADT PSA0 _at_ Month 28
n 40 PI Dr. Taplin
22
Conclusions Rising PSA State
  • Biochemical failure is heterogeneous
  • All patients should not be treated alike
  • PSADT should guide therapeutic decisions
  • Observation or diet in slow PSADT patients
  • Hormones alone once PSA 10 ng/ml?
  • Chemohormonal therapy in rapid PSADT patients?

23
Clinical States of Prostate Cancer
Hormone Therapy
Pre-Hormone Therapy
  • Source figure based on Scher HI, Morris MJ,
    Kelly WK, Schwartz LH, Heller G. Prostate cancer
    clinical trial end points RECISTing a step
    backwards. Clin Cancer Res. 2005115223-5232.

24
Hormone-Refractory Prostate Cancer (HRPC)
HRPCCRPCAIPC
25
Primary Hormonal Therapy
Secondary Hormonal Therapy
Chemotherapy
26
Secondary Hormonal Therapy for HRPC
27
  • Testosterone
  • Testicles 90
  • Adrenal glands 10
  • Prostate cancer cells ?

28
Can we block testosterone better?
  • MDV 3100 a better antiandrogen?
  • Abiraterone a better adrenal blocker?
  • Casodex RAD001 blocking two pathways of cancer
    growth instead of one

29
MDV 3100 A Novel Antiandrogen (OPEN SOON)
  • Blocks androgen receptor (AR) from moving into
    the nucleus and activating growth genes
  • Phase I/II trial HRPC pre and post chemotherapy
  • 7 dose levels tested (24 men each)
  • Responses at all dose levels
  • Well tolerated so far

PI Dr. Taplin
30
Abiraterone (Abi)
  • Blocks testosterone from adrenal gland
  • Phase I/II trials completed
  • PSA responses in 60 of patients
  • Median time to progression 9 mo
  • Responses seen even after ketoconazole,
    chemotherapy

31
Abiraterone suppresses steroids
6
Testosterone
2
Androstenedione
5
4
ng/dl
nmol/l
Lower limit of sensitivity
3
1
No rise at progression
No rise at progression
2
1
0.07
0
0
60
10
20
70
28
56
At progression
At progression
1
Start of treatment
Start of treatment
Days
Days
12.5
12.5
DHEA
Estradiol
10.0
10.0
7.5
7.5
nmol/l
?mol/l
No rise at progression
5.0
5.0
2.5
2.5
0
0
28
56
At progression
10
20
30
40
50
60
Start of treatment
Days
Days post treatment
32
Phase III Study Abiraterone vs Placebo (OPEN
SOON)
R A N D O M I Z E
1x
Placebo
HRPC, Prior Chemo Required
Abiraterone (daily pill)
2x
n 1158 PI Dr. Taplin
Endpoint Survival
33
Phase II Trial of Casodex RAD001 (OPEN)
  • mTOR pathway stimulates cancer growth
  • RAD001 blocks mTOR, oral therapy
  • Casodex may synergize with RAD001
  • HRPC patients
  • one prior chemotherapy ok
  • up to 2 years of prior Casodex ok
  • PSA 2.0.
  • 38 patients to enroll

PI Dr. Taplin
34
Clinical States of Prostate Cancer
Hormone Therapy
Pre-Hormone Therapy
  • Source figure based on Scher HI, Morris MJ,
    Kelly WK, Schwartz LH, Heller G. Prostate cancer
    clinical trial end points RECISTing a step
    backwards. Clin Cancer Res. 2005115223-5232.

35
Taxotere Chemotherapy for HRPC
Taxotere every 3 weeks Prednisone
R A N D O M I Z E
Metastatic HRPC Patients
Taxotere weekly Prednisone
Mitoxantrone Prednisone
Treatment duration in all 3 arms 30 weeks
36
(No Transcript)
37
Angiogenesis is Necessary for Tumor Growth
ANGIOGENESISINHIBITORS Thalidomide Avastin
38
Survival Taxotere /- Thalidomide
Dahut JCO 2004
39
Taxotere Avastin in HRPC
  • PSA response 77
  • Measurable response 44
  • Median time to progression 10.3 mo

40
Completed Phase III Trial of Taxotere /- Avastin
in HRPC
R A N D O M I Z E
Taxotere/Prednisone Placebo
SURV I VAL
HRPC
Taxotere/Prednisone Avastin
n 1020
41
If Taxotere Avastin is Better for HRPC, Then
  • Ongoing trials discussed earlier
  • Preoperative in high risk patients
  • Rising PSA, with rapid PSADT

42
Clinical States of Prostate Cancer
Hormone Therapy
Pre-Hormone Therapy
  • Source figure based on Scher HI, Morris MJ,
    Kelly WK, Schwartz LH, Heller G. Prostate cancer
    clinical trial end points RECISTing a step
    backwards. Clin Cancer Res. 2005115223-5232.

43
Therapeutic Options After Taxotere
  • Traditional options
  • Chemotherapy (Novantrone, carboplatin)
  • Radiopharmaceutical (Quadramet, radium)
  • Active areas of clinical investigation
  • Chemotherapy (Ixempra, XRP 6258)
  • Vaccines (Provenge, GVAX, PSMA ADC)
  • Targeted therapy (IPI-504, Sutent)

44
Heat Shock Protein-90 Inhibitor IPI-504 (OPEN)
  • HSP90 is an important chaperone protein that
    helps other proteins to fold
  • Client proteins include androgen receptor (AR)?
    degrades AR
  • Twice weekly IV infusions
  • Phase II study open nationally

PI Dr. Oh
45
PSMA ADC (Open Soon)
  • Antibody directed towards PSMA
  • Prostate-specific membrane antigen
  • Antibody attached to a toxin called auristatin
    (ADC)
  • After attaching to cancer cell, the toxic payload
    is delivered

PI Dr. Kantoff
46
Conclusions
  • Many novel strategies to improve outcome with
    prostate cancer
  • Early use of chemotherapy in combination with
    surgery and radiation
  • New chemo combinations with angiogenesis
    inhibitors
  • More effective hormone blockade
  • New targeted therapies

47
Clinical Staff GU Oncology
  • Dr. Philip Kantoff
  • Dr. William Oh
  • Dr. Mary-Ellen Taplin
  • Dr. Julia Hayes
  • Dr. Bill Hahn
  • Dr. Mark Pomerantz
  • Dr. Robert Ross
  • Dr. Jonathan Rosenberg
  • Laurie Appleby, NP
  • Sandra Kelly, NP

Jennifer Lowell, RN Stephanie Morrissey, RN Judy
Prisby, RN Geoff Buckle David Flanagan Kori
Hesse Peggy Inman Jin Kim Matt Lawlor Gina
Scibelli
48
Contact for Clinical Trials
  • David Flanagan
  • Project Manager
  • 617-632-3466
  • David_flanagan_at_dfci.harvard.edu
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