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“Fighting Cancer: It’s All We Do.” ™. Therapies in Androgen Resistant Prostate cancer and non metastatic prostate cancer. Ulka Vaishampayan M.D. Chair, GU Multidisciplinary team Associate Professor Of Medicine Detroit Medical Center

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Therapies in androgen resistant prostate cancer and non metastatic prostate cancer

Therapies in Androgen Resistant Prostate cancer and non metastatic prostate cancer

Ulka Vaishampayan M.D.

Chair, GU Multidisciplinary team

Associate Professor Of Medicine

Detroit Medical Center

Wayne State University/ Karmanos Cancer Institute, Detroit MI.


Tax 327 trial results 1006 pts
TAX 327 Trial Results-1006 Pts metastatic prostate cancer

Eisenberger et al. ASCO 2004, abstr#4


Tax 327 docetaxel prednisone vs mitoxantrone prednisone in aipc
TAX 327: Docetaxel/Prednisone vs. Mitoxantrone/Prednisone in AIPC

De Wit et al. Presented at the Annual Meeting of the American Society for Clinical Oncology, 2004. Plenary Session [abstract 4]

Eisenberger MA et al. J Clin Oncol. 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 suppl), 2004:4 [Kathy to style refs]


Novel agents under investigation in androgen independent metastatic prostate cancer

Novel Agents Under Investigation in Androgen-Independent Metastatic Prostate Cancer

Chemobiologic combinations

Vaccines

Novel hormone agents: abiraterone, Kinex, TAK-700

Androgen receptor blockers- MDV-3100

Integrin inhibitors: EMD525797


Docetaxel based combinations disappointing
Docetaxel based combinations: Metastatic Prostate CancerDisappointing!!

  • Docetaxel and calcitriol (Vit D)- Showed increased death rate with the combination.

  • Docetaxel and Avastin:No benefit with combination

  • Docetaxel and G Vax (vaccine made from prostate cancer cells) Trial completed, again increased risk of death with combination as compared to docetaxel alone.

  • So far no therapy has proven benefit when added to docetaxel alone.


Provenge dendritic cell therapy small e et al jco 2008
Provenge/Dendritic cell therapy Metastatic Prostate Cancer[Small E. et al.JCO 2008]

  • Peripheral stem cells collected and pulsed with prostatic acid phosphatase antigen and GMCSF

  • Antigen loaded, dendritic cells enriched preparation infused to patients

  • Patients with asymptomatic CRPC randomized to Provenge versus placebo in a 2:1 ratio

  • Administration was IV infusion every 2 weeks for 3 doses


Fighting cancer it s all we do

Sipuleucel-T Immunotherapy for Advanced Prostate Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

Penson et al.

IMPACT Study Investigators

Presented at

American Urological Association Annual Meeting

April 28, 2009

IMPACT STUDY


Randomized phase 3 impact trial immunotherapy prostate adenocarcinoma treatment
Randomized Phase 3 IMPACT Trial Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial(IMmunotherapy Prostate AdenoCarcinoma Treatment)

P R O G R E S S I O N

S

U

R

V

I

V

A

L

Treated at Physician discretion

Sipuleucel-T Q 2 weeks x 3

Asymptomatic or Minimally Symptomatic Metastatic

Castrate

Resistant

Prostate Cancer (N=512)

2:1

Treated at Physician discretion and/or Salvage Protocol

Placebo Q 2 weeks x 3

Primary endpoint: Overall Survival

Secondary endpoint: Time to Objective Disease

Progression


Sipuleucel t patient specific therapy
Sipuleucel-T: Patient-Specific Therapy Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

Day 1

Leukapheresis

sipuleucel-T is manufactured

Day 3-4

Patient is infused

Apheresis Center

Dendreon

Doctor’s Office

COMPLETE COURSE OF THERAPY:

Weeks 0, 2, 4


Provenge summary
Provenge Summary Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

First active immunotherapy to demonstrate improvement in overall survival for prostate cancer

Favorable benefit to risk profile

Short duration of therapy

Problems: Compared to placebo and not to chemotherapy, (docetaxel was compared to mitoxantrone). Easier to show benefit.

Fairly cumbersome, with pheresis.

No data regarding palliation, and worrisome that no improvement in time to objective progression.

Represents another therapy in the armamentarium against prostate cancer.


What next after docetaxel failure
What Next After Docetaxel Failure? Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

  • Usually treat for symptom progression and not by PSA

  • Look for clinical trials of novel agents

  • Cabazitaxel prolongs life span after docetaxel therapy

  • FDA approved for use after docetaxel therapy.

  • Side effects similar to docetaxel therapy with infection, tiredness, nausea, being the most likely.

  • Long term benefit is being evaluated.


Persistent hormone sensitivity
Persistent hormone sensitivity Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

  • 10% of circulating testosterone remains after conventional hormone therapy

  • Conversion of adrenal hormones to testosterone

  • Testosterone persists in prostate cancer microenvironment

  • Androgen receptor upregulation

  • Cyp17A, the enzyme that converts adrenal steroids to androgen is overexpressed in advanced prostate cancer and in bone biopsies from metastatic sites.

  • Hence cancer remains androgen dependent.


Abiraterone
Abiraterone Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

  • Oral Cyp-17 A inhibitor

  • Efficacy noted in phase I and II trials with responses in pretreated metastatic CRPC.

  • Tolerable medication.

  • Phase III study almost completed, of abiraterone vs placebo in patients with met CRPC after chemotherapy.

  • Proposed trial is evaluating the role of abiraterone in metastatic CRPC, prior to chemo, asymptomatic or mildly symptomatic.


Study design
Study Design Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

  • 1:1 randomization of abiraterone + prednisone vs prednisone + placebo.

  • Progression based on scans, symptoms and PSA.

  • Primary endpoint is OS

  • Secondary is rPFS, toxicity, correlates such as Circulating tumor cells and TMPRSS-2 gene.

  • Time to opiate administration, time to chemo will also be evaluated.

  • Sample size:1000 pts nationwide, study complete


The effects of mdv3100 on the androgen receptor are distinct from bicalutamide
The Effects of Randomized, Double-Blind, Placebo-Controlled Phase 3 TrialMDV3100 on the Androgen Receptor Are Distinct from Bicalutamide

  • AR Binding Affinity

    • DHT ~ 5nM

    • Bicalutamide ~160 nM

    • MDV3100 ~35 nM

1

Ligand

HSP 90

LBD

HD

  • Nuclear Import

    • DHT: ++++

    • Bicalutamide: ++++

    • MDV3100: ++

DBD

NTD

2

  • DNA Binding

    • DHT: ++++

    • Bicalutamide: ++

    • MDV3100: -

4

POL II

3

Chen, Clegg and Scher

DNA


Waterfall plot of best percent psa change from baseline
Waterfall Plot of Best Percent PSA Change from Baseline Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

Chemotherapy-Naïve (N=65)

Post-Chemotherapy (N=75)

51% (38/75)

>50% Decline

62% (40/65)

>50% Decline


Affirm p hase 3 registration trial of mdv3100 in post chemotherapy crpc patients
AFFIRM Randomized, Double-Blind, Placebo-Controlled Phase 3 TrialPhase 3 Registration Trial of MDV3100 in Post-Chemotherapy CRPC Patients

MDV3100 QD

2

R

Placebo QD

1

Primary Endpoint: 25% survival increase (12 to 15 months)

Sample size: ~1170 (780 and 390)

Statistics: 85% Power; p=0.05, two-sided

Scher, H. (North America) and De Bono, J. Co-PI, Medivation


Managing hormone sensitive non metastatic prostate cancer

Managing Hormone Sensitive, Non-Metastatic Prostate Cancer Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

No standard approved therapy

Clinical trials offer the best therapy in this setting.

Consider very carefully the risks vs benefits


Psa relapse non metastatic prostate cancer
PSA Relapse Non-metastatic Prostate Cancer Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

  • Rapidly growing population

  • Guidelines for therapy not completely established

  • Based on patient age, comorbid conditions, prior therapy etc.

  • Start hormone therapy early but not too early!

  • Retrospective study reveals that patients with PSA doubling time <12 months and high Gleason score have longer survival if hormones started when PSA<5ng/ml

  • Studies of adding chemotherapy early for high-risk patients are ongoing

Moul et al. Urologic Oncology:Sem and Original Investigations, 21; 292-304, 2003


Non metastatic psa only prostate cancer principles of management
Non metastatic PSA only prostate cancer: Principles of management

  • PSA rising

  • No spread visualized on CT scans and bone scan.

  • Consider multiple PSA levels and the rate of rise over time.

  • The actual value of PSA is not as important as the rate of rise; for instance a PSA rise from 38 to 40 to 45 in 6 months is less worrisome than a rise from 5 to 10 to 20 in 6 months.

  • PSA produces “Prostate Specific Anxiety” but otherwise the disease is not bothersome.

  • No therapy has proven benefit.


Non metastatic psa only prostate cancer principles of management1
Non metastatic PSA only prostate cancer: Principles of management

  • Secondary hormone therapies sometimes work, even for long periods of time; that would be standard therapy.

  • Caution about doing chemotherapy since:

  • Risks are higher

  • No proven benefit

  • Considering clinical trials

  • Look at side effects very carefully

  • Look at how much this will impact your daily life

  • Consider some of the background research done on the agent


Conclusions
Conclusions management

  • Metastatic disease: Back to hormone therapy with androgen receptor antagonist agents.

  • Immunotherapy such as Provenge is showing promise but cumbersome and expensive.

  • More chemotherapy options to prolong life and improve quality of life and pain control.