“Fighting Cancer: It’s All We Do.”™

Therapies in Androgen Resistant Therapies in Androgen Resistant Prostate cancer and non metastatic Prostate cancer and non metastatic

prostate cancerprostate cancer

Ulka Vaishampayan M.D.Chair, GU Multidisciplinary teamAssociate Professor Of Medicine

Detroit Medical CenterWayne State University/ Karmanos Cancer Institute,

Detroit MI.

TAX 327 Trial Results-1006 PtsTAX 327 Trial Results-1006 PtsMitox + Pred12mg/m2 Q 3 weeks

Docetaxel + Pred75mg/m2 Q 3weeks

Docetaxel + Pred30mg/m2 weekly 5/6

Pain response 22% 35% (p=0.01) 31% (p=0.08)

Response rate (PSA)

32% 45% (p=0.0005) 48% (p=0.0001)

Grade 3/4 neutropenia

21.7% 32% 1.5%

Median survival

16.5 months 18.9 months (p=0.009)

17.4 months(p=0.36)

Eisenberger et al. ASCO 2004, abstr#4Eisenberger et al. ASCO 2004, abstr#4

TAX 327: Docetaxel/Prednisone vs. TAX 327: Docetaxel/Prednisone vs. Mitoxantrone/Prednisone in AIPCMitoxantrone/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 Novel Agents Under Investigation in Androgen-Independent Metastatic Androgen-Independent Metastatic

Prostate CancerProstate Cancer

Chemobiologic combinationsVaccines

Novel hormone agents: abiraterone, Kinex, TAK-700 Androgen receptor blockers- MDV-3100

Integrin inhibitors: EMD525797

Docetaxel based combinations:Docetaxel based combinations:Disappointing!!Disappointing!!

• 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 therapyProvenge/Dendritic cell therapy[Small E. et al.JCO 2008][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

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

Phase 3 TrialPhase 3 Trial

Penson et al.

IMPACT Study Investigators

Presented atAmerican Urological Association Annual Meeting

April 28, 2009

Penson et al.

IMPACT Study Investigators

Presented atAmerican Urological Association Annual Meeting

April 28, 2009

IMPACT STUDY

Randomized Phase 3 IMPACT TrialRandomized Phase 3 IMPACT Trial(IMmunotherapy Prostate AdenoCarcinoma (IMmunotherapy Prostate AdenoCarcinoma

Treatment)Treatment)

Primary endpoint: Overall SurvivalSecondary endpoint: Time to Objective Disease

Progression

Asymptomatic or Minimally

Symptomatic Metastatic Castrate Resistant

Prostate Cancer (N=512)

Asymptomatic or Minimally

Symptomatic Metastatic Castrate Resistant

Prostate Cancer (N=512)

Placebo Q 2 weeks

x 3

Placebo Q 2 weeks

x 3

Sipuleucel-T Q 2 weeks x 3

Sipuleucel-T Q 2 weeks x 3

P R O

G R E S

S I O N

P R O

G R E S

S I O N

2:1

SURVIVAL

SURVIVAL

Treated at Physician discretion

and/or Salvage Protocol

Treated at Physician discretion

and/or Salvage Protocol

Treated at Physician discretion

Treated at Physician discretion

Sipuleucel-T: Patient-Specific TherapySipuleucel-T: Patient-Specific Therapy

Day 1

Leukapheresissipuleucel-T is manufactured

Day 3-4Patient is infused

Apheresis Center Dendreon Doctor’s Office

COMPLETE COURSE OF THERAPY:Weeks 0, 2, 4

Provenge SummaryProvenge Summary

• 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?

• 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 sensitivityPersistent hormone sensitivity

• 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.

AbirateroneAbiraterone

• 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 DesignStudy Design

• 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

Ligand

1. AR Binding Affinity• DHT ~ 5nM• Bicalutamide ~160 nM• MDV3100 ~35 nM

2. Nuclear Import• DHT: ++++• Bicalutamide: ++++• MDV3100: ++

3. DNA Binding• DHT: ++++• Bicalutamide: ++• MDV3100: -

The Effects of The Effects of MDV3100MDV3100 on the on the Androgen Receptor Are Distinct from BicalutamideAndrogen Receptor Are Distinct from Bicalutamide

1

2

Chen, Clegg and Scher

3

4

DNA

POL II

HS

P 9

0

LB

D

HD

DBD

NTD

Waterfall Plot of Best Percent PSA Change from Waterfall Plot of Best Percent PSA Change from BaselineBaseline

Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75)

62% (40/65)

>50% Decline

51% (38/75)

>50% Decline

AFFIRMAFFIRMPPhase 3 Registration Trial of MDV3100 in hase 3 Registration Trial of MDV3100 in

Post-Chemotherapy CRPC Patients Post-Chemotherapy CRPC Patients

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

R

MDV3100 QD

Placebo QD

2

1

Primary Endpoint: 25% survival increase (12 to 15 months)Sample size: ~1170 (780 and 390)Statistics: 85% Power; p=0.05, two-sided

Managing Hormone Sensitive, Non-Managing Hormone Sensitive, Non-Metastatic Prostate CancerMetastatic Prostate Cancer

No standard approved therapyClinical trials offer the best therapy in this

setting.Consider very carefully the risks vs benefits

PSA Relapse Non-metastatic PSA Relapse Non-metastatic Prostate CancerProstate Cancer

• 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 Non metastatic PSA only prostate cancer: Principles of managementcancer: 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 Non metastatic PSA only prostate cancer: Principles of managementcancer: Principles of management

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

• Caution about doing chemotherapy since:1) Risks are higher2) No proven benefit• Considering clinical trials1) Look at side effects very carefully2) Look at how much this will impact your daily life3) Consider some of the background research done on

the agent

ConclusionsConclusions

• 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.

“Fighting Cancer: It’s All We Do.”™