Prostate Cancer 2011-How Clinical Trials Have Led to New Options for

Patients

Philip Kantoff MDChief, Division of Solid Tumor Oncology

Dana-Farber Cancer InstituteProfessor of Medicine

Harvard Medical School

Background

• 220,000 men diagnosed with prostate cancer in 2010 in US

• 1 in 6 men• 32,000 men will die of prostate cancer

Incidence of Prostate Cancer: Population Comparisons

Outline

• You can prevent prostate cancer

• Screening saves lives

• Many men who are diagnosed with prostate cancer do not need to be treated

• Many exciting new developments-results of clinical trials

Outline

• You can prevent prostate cancer

Finasteride Chemoprevention Study (PCPT)

18,000 Men>55 nl DRE and PSA<3

finasteride

placebo

CaP

CaP

Finasteride Chemoprevention Study (PCPT)

PCPT-Conclusions

• Finasteride reduces risk of prostate cancer

• Morbidity is minimal– Possible and slight increase in high grade

cancer in finasteride arm

REDUCE Trial• 8,200 men who had PSA between 2.5 ng/mL

and 10 ng/mL• All men had one negative prostate biopsy

within six months prior to study entry. • Participants were randomly assigned to

dutasteride or placebo; the study mandated 10 core biopsies at two and four years.

• Dutasteride was associated with a 23% reduction in prostate cancer cases compared with placebo.

FDA Approval of 5-ARIs?

• FDA advisory panel recommended against approval as chemoprevention

• Concern regarding increased incidence of high-grade tumors

• “Met an un-need”, reducing low-risk tumors• 60 men would need to be treated in order

for one man to avoid developing a clinically relevant prostate cancer

Outline

• You can prevent prostate cancer

• Screening saves lives

Does PSA based Screening Work? Does it Reduce Mortality

From Prostate Cancer?

• ERSPC study

• PLCO

• Scandinavian study

European Randomized Study of Screening for Prostate Cancer

(ERSPC) NEJM 2009• 162,243 men age 50 and 69 from seven

different European countries starting in the early 1990s

• Randomly assigned to a screening group or control

• Men in the screening group received a PSA test an average of once every 4 years and the men in the control group did not receive PSA tests at all.

• Median 9 years of follow up-20% reduction in prostate cancer mortality p=0.04

PLCO NEJM 2009

• 150,000 persons 55 to 74 years old at entry were randomized to two study arms, half to undergo cancer screening

• Screening was annual PSA and DRE

• 52% contamination

• Median follow-up 7 years

• No difference in prostate cancer mortality

Göteborg randomized prostate-cancer screening trial

• 20,000 men randomly sampled from the population register, were randomized to either a screening group invited for PSA testing every 2 years (n=10,000) or to a control group

• During a median follow-up of 14 years, 1,138 men in the screening group and 718 in the control group were diagnosed with prostate cancer

• The risk reduction of death from prostate cancer at 14 years was 60% (p=0·0002).

Conclusions

• Low mortality of prostate cancer in first 10 years (few events)

• PSA screening reduces mortality

• Large amount of overtreatment– Seen in numerous other studies

Outline

• You can prevent prostate cancer

• Screening saves lives

• Many men who are diagnosed with prostate cancer do not need to be treated

Who should consider active surveillance-NCCN Guidelines?

• Men with low risk prostate cancer (Gleason 6 and PSA<10) who have a life expectancy of less than 10 years.

• Men with “very low risk” prostate cancer when life expectancy is less than 20 years.– a Gleason score of 6 or below; a PSA <

10 and fewer than 3 positive biopsy cores (with <50% cancer in each); and a PSA density below 0.15 ng/mL per g.

Outline

• You can prevent prostate cancer

• Screening saves lives

• Many men who are diagnosed with prostate cancer do not need to be treated

• Many exciting new developments-results of clinical trials

Sipuleucel-T (Provenge) for Metastatic CRPC

Provenge: Mechanism of Action

INFUSE PATIENT

sipuleucel-T activates T-cells in the body

APC takes up the antigen

Antigen (PAP-GMCSF) is exposed to an Antigen Presenting Cell (APC)

Fully activated, the APC is now sipuleucel-T and is collected

Antigen is processed and presented on surface of the APC

T-cells proliferate and attack cancer cells

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Sipuleucel-T: Logistics of TherapyDay 1

LeukapheresisDay 2-3

sipuleucel-T is manufacturedDay 3-4

Patient is infused

Apheresis Center Central Processing Doctor’s Office

COMPLETE COURSE OF THERAPY:Weeks 0, 2, 4

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Randomized Phase 3 IMPACT Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment)(IMmunotherapy Prostate AdenoCarcinoma Treatment)

Asymptomatic or Minimally

Symptomatic mCRPC (N=512)

Asymptomatic or Minimally

Symptomatic mCRPC (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

2:1

Treated at Physician Discretion

and/or Salvage Protocol

Treated at Physician Discretion

and/or Salvage Protocol

Treated at Physician Discretion

Treated at Physician Discretion

Primary Endpoint: Overall SurvivalSecondary Endpoint: Objective Disease Progression

PROGRESSION

PROGRESSION

SURVIVAL

SURVIVAL

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IMPACT Overall SurvivalFinal Analysis (349 events)

36.5 mo median f/u HR = 0.759 (95% CI: 0.606, 0.951)p = 0.017 (Cox model)Median Survival Benefit = 4.1 months

Sipuleucel-T (n = 341)Median Survival: 25.8 mo.36 mo. survival: 32.1%

Placebo (n = 171)Median Survival: 21.7 mo.36 mo. survival: 23.0%

No. at Risk

Sipuleucel-T 341 274 142 56 18 3

Placebo 171 123 59 22 5 2 Kantoff et al

Under-represented clinical trial populations

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• African American patient population

• 5.8% of patients

• Positive sipuleucel-T treatment effect in patient subgroup

• AE profile comparable

HR 0.288 (0.125, 0.662)

African American Subgroup -Overall SurvivalIMPACT, D9901, D9902A

PROSTVAC VF-Tricom

27

Background-The Development of PROSTVAC-VF-Tricom

• Inactivated smallpox and fowlpox virus carrying PSA gene

Schlom et al

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Randomized Phase II Study

Primary endpoint: Progression Free SurvivalSecondary endpoint: Overall Survival

Asymptomatic or Minimally

Symptomatic Metastatic Castrate Resistant

Prostate Cancer (N=125)

Asymptomatic or Minimally

Symptomatic Metastatic Castrate Resistant

Prostate Cancer (N=125)

Empty Vector + placebo

Empty Vector + placebo

PROSTVAC-VF Tricom + GM

PROSTVAC-VF Tricom + GM

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

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Overall Survival

P = 0.006 (stratified logrank)Hazard Ratio = 0.56 (95% CI 0.37 to 0.85)

0

20

40

60

80

100

0 12 24 36 48 60Months

ControlPROSTVAC

N4082

Deaths3765

Median16.625.1

Kantoff et al

Newer Hormonal Agents

• Lyase inhibitors-block all hormone production from testicles, adrenals and from the tumor– Abiraterone

COU-AA-301• Phase III initiated in April 2008, enrollment

completed.

• Post-docetaxel mCRPC

• (n = 1158)R 2:1

Primary endpoint is OS

Abiraterone acetate, 1000 mg/day (4 x 250 mg tablets) PO,5 mg prednisone/prednisolone

BID

Placebo plus 5 mg prednisone/prednisolone BID

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COU-AA-301: Abiraterone Acetate Improves OS in mCRPC

HR=0.646 (0.54-0.77) P <0.0001

Placebo: 10.9 months (95% CI: 10.2, 12.0)

0 100 200 300 400 500 600 700

0

20

40

60

80

100

Ove

rall

Su

rviv

al,

%

Days from Randomization

Abiraterone: 14.8 months (95% CI: 14.1, 15.4)

Abiraterone 797 728 631 475 204 25 0

Placebo 398 352 296 180 69 8 1

Outline

• You can prevent prostate cancer

• Screening saves lives

• Many men who are diagnosed with prostate cancer do not need to be treated

• Many exciting new developments-results of clinical trials

Thank you