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
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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.

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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

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CHEMOTHERAPY?
Surgery or Radiation Therapy
CHEMOTHERAPY?
Hormonal therapy
Chemotherapy
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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
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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
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Treatment Response

• PSA decline 50
• 11/19 patients (58)
• Tumor shrinkage 25 on MRI
• 13/19 (68)
• Complete eradication of cancer
• 0/16 (0)

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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

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Chemo-treated Tumors Have Unique Molecular
Signatures
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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
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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

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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.

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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

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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
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Rapid PSA Doubling Time More Aggressive Cancer
PSADT
Percent Dead of Prostate Cancer
DAmico JNCI 2003
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Investigational Therapies for Rising PSA

• Lifestyle or diet
• Pomegranate juice
• Novel targeted therapies
• Rosiglitazone (Avandia)
• Celecoxib (Celebrex)
• Thalidomide/Revlimid
• Statins
• Vaccines
• TRICOM-Prostvac

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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
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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
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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?

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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.

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

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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

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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
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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

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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
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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
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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
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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
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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.

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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
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Angiogenesis is Necessary for Tumor Growth
ANGIOGENESISINHIBITORS Thalidomide Avastin
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Survival Taxotere /- Thalidomide
Dahut JCO 2004
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Taxotere Avastin in HRPC

• PSA response 77
• Measurable response 44
• Median time to progression 10.3 mo

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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
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If Taxotere Avastin is Better for HRPC, Then

• Ongoing trials discussed earlier
• Preoperative in high risk patients
• Rising PSA, with rapid PSADT

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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.

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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)

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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
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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
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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

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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
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Contact for Clinical Trials

• David Flanagan
• Project Manager
• 617-632-3466
• David_flanagan_at_dfci.harvard.edu