Transcript PHEN1.12.11

Prostate Cancer 2011-How Clinical
Trials Have Led to New Options for
Patients
Philip Kantoff MD
Chief, Division of Solid Tumor Oncology
Dana-Farber Cancer Institute
Professor 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)
CaP
finasteride
18,000 Men>55 nl
DRE and PSA<3
placebo
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 prostatecancer 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
Antigen (PAPGMCSF) is
exposed to an
Antigen
Presenting
Cell (APC)
APC takes up
the antigen
Antigen is
processed and
presented on
surface of the
APC
Fully activated,
the APC is now
sipuleucel-T
and is collected
INFUSE
PATIENT
T-cells proliferate and attack
cancer cells
sipuleucel-T activates Tcells in the body
Sipuleucel-T: Logistics of Therapy
Day 1
Leukapheresis
Apheresis Center
Day 2-3
sipuleucel-T is manufactured
Central Processing
Day 3-4
Patient is infused
Doctor’s Office
COMPLETE COURSE OF THERAPY:
Weeks 0, 2, 4
22
Randomized Phase 3 IMPACT Trial
(IMmunotherapy Prostate AdenoCarcinoma Treatment)
Sipuleucel-T
Q 2 weeks x 3
Asymptomatic or
Minimally
Symptomatic
mCRPC (N=512)
2:1
Placebo
Q 2 weeks x 3
P
R
O
G
R
E
S
S
I
O
N
Treated at
Physician
Discretion
S
U
R
V
I
V
A
L
Treated at
Physician
Discretion
and/or Salvage
Protocol
Primary Endpoint: Overall Survival
Secondary Endpoint: Objective Disease Progression
23
IMPACT Overall Survival
Final 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
24
Kantoff et al
Under-represented clinical trial
populations
• African American patient population
• 5.8% of patients
• Positive sipuleucel-T treatment effect in patient subgroup
• AE profile comparable
African American Subgroup -Overall Survival
IMPACT, D9901, D9902A
HR 0.288 (0.125, 0.662)
25
PROSTVAC VF-Tricom
Background-The Development
of PROSTVAC-VF-Tricom
• Inactivated smallpox and fowlpox
virus carrying PSA gene
27
Schlom et al
28
Randomized Phase II Study
Asymptomatic or
Minimally
Symptomatic
Metastatic
Castrate
Resistant
Prostate Cancer
(N=125)
Primary endpoint:
Secondary endpoint:
PROSTVAC-VF
Tricom + GM
2:1
Empty Vector +
placebo
P
R
O
G
R
E
S
S
I
O
N
Progression Free Survival
Overall Survival
Treated at
physician
discretion
Treated at
physician
discretion
and/or Salvage
Protocol
S
U
R
V
I
V
A
L
Overall Survival
Hazard Ratio = 0.56 (95% CI 0.37 to 0.85)
P = 0.006 (stratified logrank)
100
Control
PROSTVAC
N
40
82
Deaths Median
37
16.6
65
25.1
80
60
40
20
0
0
12
24
36
Months
48
60
30
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)
Abiraterone acetate, 1000
mg/day (4 x 250 mg tablets) PO,
5 mg prednisone/prednisolone
BID
R 2:1
Placebo plus 5 mg
prednisone/prednisolone BID
Primary endpoint is OS
32
COU-AA-301: Abiraterone
Acetate Improves OS in mCRPC
100
HR=0.646 (0.54-0.77) P <0.0001
Abiraterone: 14.8 months
(95% CI: 14.1, 15.4)
Overall Survival, %
80
60
40
Placebo: 10.9 months
(95% CI: 10.2, 12.0)
20
0
0
100
200
300
500
400
Days from Randomization
600
Abiraterone
797
728
631
475
204
25
0
Placebo
398
352
296
180
69
8
1
700
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