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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 Associate Professor, Harvard Medical School. U.S. Cancer Statistics: Prostate Cancer 2007. Leading cause of cancer in men (218,890 cases, 29%)

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New clinical trials in prostate cancer l.jpg

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


U s cancer statistics prostate cancer 2007 l.jpg
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


Clinical states of prostate cancer l.jpg
Clinical States of Prostate Cancer

10-15 yrs +

Source: figure based on Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232.

Pre-Hormone Therapy

Hormone Therapy


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Clinical States of Prostate Cancer

Source: figure based on Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232.

Pre-Hormone Therapy

Hormone Therapy


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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. D’Amico

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 <0.1 ng/ml (n=13)

    • 3 patients started hormones



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Preoperative Taxotere + Avastin in High Risk Cancer (OPEN)

High Risk

Prostate

Cancer

Taxotere x 18 wks

Avastin x 15 wks

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

Source: figure based on Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232.

Pre-Hormone Therapy

Hormone Therapy


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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 (@Johns Hopkins)

  • ~15% relapsed after surgery

  • No hormones until (+) bone scan

RP

2 yrs

7.5 yrs

6.5 yrs

First Rise in PSA

Bone scan

(+)

Death

Eisenberger Proc ASCO 2003


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Rapid PSA Doubling Time = More Aggressive Cancer

PSADT

<2 mo.

<3

Percent Dead of Prostate Cancer

<4

<6

<12

D’Amico 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)

PSADT < 8 mo

No mets

No chemo

Taxotere x 3 mo

Avastin x 6 mo

Hormones x 18 mo

% PSA=0

@

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

Source: figure based on Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232.

Pre-Hormone Therapy

Hormone Therapy



Slide25 l.jpg

Primary Hormonal Therapy

Secondary Hormonal Therapy

Chemotherapy



Slide27 l.jpg

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

2

Testosterone

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

10

20

60

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

ρmol/l

nmol/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

Source: figure based on Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232.

Pre-Hormone Therapy

Hormone Therapy


Slide35 l.jpg

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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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

Source: figure based on Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232.

Pre-Hormone Therapy

Hormone Therapy


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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

Jennifer Lowell, RN

Stephanie Morrissey, RN

Judy Prisby, RN

Geoff Buckle

David Flanagan

Kori Hesse

Peggy Inman

Jin Kim

Matt Lawlor

Gina Scibelli

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


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Contact for Clinical Trials

  • David Flanagan

    • Project Manager

    • 617-632-3466

    • David_flanagan@dfci.harvard.edu