Prostate Cancer - PowerPoint PPT Presentation

Loading...

PPT – Prostate Cancer PowerPoint presentation | free to view - id: 127134-YmFjZ



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Prostate Cancer

Description:

Prostate Cancer – PowerPoint PPT presentation

Number of Views:3966
Avg rating:3.0/5.0
Slides: 84
Provided by: willia304
Category:
Tags: cancer | prostate | yaw

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Prostate Cancer


1
Prostate Cancer
  • William Dahut, M.D.
  • Chief, Genitourinary CRS
  • MOB, CCR
  • National Cancer Institute

2
Prostate histology
3
Prostate Cancer Importance
  • Prostate Cancer is the most common non-cutaneous
    malignancy in men
  • 186,320 new cases and 28,660 deaths expected in
    2008
  • Despite some recent advances Castration Resistant
    Prostate Cancer (CRPC ) remains an incurable
    disease with few effective treatments

4
Prognosis
  • Prognosis is directly related to stage and grade
    of the tumor
  • The Gleason Grade is the most common grading
    system
  • Tumors are graded from 1-5 with the higher number
    indicative of a more aggressive tumor
  • In practice the two most predominant patterns are
    added together to give a score from 2-10

5
Gleason Grade(3) Well-Differentiated
6
Gleason grade (5) Poorly-Differentiated
7
Prognosis Related to PSA, Gleason Score, Stage
and Positive Biopsies
  • PSA at diagnosis, percent of tumor in a biopsy
    specimen, number of positive biopsies, Gleason
    Score and clinical stage are useful prognostic
    factors
  • Nomograms are now available to predict the
    likelihood of positive surgical margins, lymph
    node involvement and disease recurrence after
    local therapy.

8
Detection
  • May be detected due to symptoms, physical
    findings or through PSA screening
  • Most patients in the US are asymptomatic at the
    time of diagnosis.

9
Family History
  • Men with a father or brother affected are twice
    as likely to develop prostate cancer.
  • Men with two or three first degree relatives have
    a five and eleven-fold increased risk of
    developing prostate cancer.

10
Treatment
  • Patients with a life expectancy of less then 10
    years and/or low grade/ low stage lesions may be
    candidates for active surveillance
  • Primary hormone therapy is an option for patients
    not suitable for definitive local therapy

11
Treatment - continued
  • Eradication of the cancer is the goal of therapy
    in patients with a life expectancy greater than
    10 years
  • Radical Prostatectomy
  • External-beam Radiation
  • Brachytherapy

12
Radical Prostatectomy
  • Surgical removal of the prostate
  • May be done with a retropubic, perineal,
    laproscopic or robotic approach
  • Most common side effects are impotence and
    incontinence

13
Prostate histology
14
Prostate surgery
15
Randomized Trial Comparing Surgery and Watchful
Waiting
  • 695 men with early stage prostate cancer
    randomized to radical prostatectomy or watchful
    waiting
  • Median of 8.2 years of follow-up 83 deaths in
    surgery group and 106 in watchful waiting group
    (P0.04).
  • 30 of the 347 men assigned to surgery and 50 of
    the 348 men assigned to watchful waiting, death
    was due to prostate cancer
  • More advanced clinically then current patients

16
External-beam Radiation
  • Radiation to the prostate from outside the body
  • Evidence that higher doses are associated with
    better efficacy
  • Newer techniques (such as 3-D conformal) hope to
    increase radiation delivery and to decrease
    toxicity
  • Most common side effects are impotence and rectal
    irritation

17
Prostate histology
18
Prostate map
19
Brachytherapy
  • Radiation implants placed directly into the
    prostate under ultrasound or ct guidance
  • Very high dose radiation to the prostate with
    little radiation outside the prostatic bed
  • Acute urinary symptoms common, some patients with
    impotence
  • Procedure completed in one day

20
Brachytherapy seeds
21
Biochemical Recurrence
  • May be occult local or metastatic disease
  • Options include additional local therapy,
    hormonal treatment or watchful waiting
  • Little data to predict the impact of treatment on
    survival

22
Pound Data
  • Probably the most important report on this
    population because of the limited use of
    radiation and hormonal therapy
  • Over 15 years 1,997 patients underwent a radical
    prostatectomy, with 304 (15) experiencing a PSA
    relapse.
  • Of the 304, 103 (34 ) developed metastatic
    disease.

23
Pound Data (continued)
  • No patients received hormonal therapy without
    clinically evident metastatic disease.
  • Median time from PSA elevation to metastatic
    disease was 8 years
  • Median time to death after metastatic disease was
    5 years.
  • Prognostic factors predictive of outcome included
    the Gleason score on the surgical specimen, time
    to PSA recurrence and PSA doubling time.

24
Disseminated Disease (Hormone responsive)
  • Prostate Cancer tends to spread to bone and lymph
    nodes
  • However metastatic lesions have been found in
    virtually every part of the body including brain,
    liver and lungs.
  • Many patients do not have measurable lesions thus
    traditional response criteria (RECIST) is
    difficult to use.

25
Bone Scan in Metastatic Prostate Cancer
26
Treatment of Metastatic Disease
  • Leuprolide and Goserelin are most common
    GnRh-agonists
  • Both agents may cause a decrease in libido, hot
    flashes, bone loss and increased risks of DM and
    CVD.
  • May initially result in an increase in
    testosterone
  • Orchiectomy- side effects include hot flashes ,
    decreased libido and sexual potency

27
Osteoporosis Risk Factors for men
  • Hormonal changes associated with aging correlate
    with bone loss
  • Lower testosterone levels
  • Leads to less aromatization (conversion) of
    testosterone to estradiol
  • Estradiol protects / strengthens bone
  • Therefore lower levels less protection

E2
28
Hormonal Therapy
  • BMD loss with hormonal therapy
  • Decrease T by gt95
  • Decrease E2 by gt80
  • With orchiectomy the BMD loss is 2.4 at 1 year
    and 10 at 2 years
  • With GnRH Agonist, the BMD loss is 3.4 at 1 year
    and 6.5 at 2 years

29
Hormonal Therapy
  • This decrease in BMD is associated with an
    increase in fractures
  • Men without prostate cancer over the age of 65
    who are not on hormonal therapy have a fracture
    rate of 0.5 per year
  • With hormone therapy there was a 5 incidence of
    osteoporotic fractures seen in a median of 22
    months
  • In one series, within 7 years 28 of prostate
    cancer patients treated with orchiectomy had a
    fracture vs. 1 of patients who did not undergo
    orchiectomy

30
Castration Sensitive and Castration-Resistant
Progression of Prostate Cancer
31
Measurement of Response
  • Tremendous problem in prostate cancer
  • Often left with large trials with survival as an
    endpoint
  • Traditional markers such as PSA, Bone Scan and CT
    are all flawed

32
Bone scan
After 2 months
Prior to therapy
PSA 199
PSA 658
33
CT scan
Prior to therapy
After 2 months
PSA 130
PSA 294
34
Measurement of Response-Bone Scans
  • New lesions do not always represent progression
  • Can occur with healing, trauma or inflammation
  • New lesions may develop prior to adequate drug
    treatment and than not resolve
  • The importance of 1-2 asymptomatic new bone scan
    abnormalities remains unclear

35
Measurement of Response-CT
  • Improved and more frequent imaging has probably
    led to the discovery of more patients with
    measurable disease
  • However in many patients bone disease dominates
    the clinical course
  • RECIST response or progression may not be
    relevant
  • Progression in lymph nodes with stable bone scan
    occur

36
TAX327 A Multicenter, Randomized Phase III Study
of Intermittent Docetaxel Prednisone vs. Weekly
Docetaxel Prednisone vs. Mitoxantrone
Prednisone in Patients with Hormone-Refractory
Prostate Cancer ?Docetaxel 75mg/m2 Q3
Prednisone 10mg orally given daily? Docetaxel
30mg/m2 Wkly Prednisone 10mg orally given
daily ?Mitoxantrone 12mg/m2 Q3 Prednisone 10mg
orally given daily

37
Main Results of Study
  • TAX327 study showed significantly longer survival
    for the 3 weekly docetaxel (D3P) arm compared to
    mitoxantrone
  • No significant survival benefit with weekly
    docetaxel
  • D3P arm showed better palliation, as recorded by
    pain and quality of life responses
  • Greater number of patients had significant PSA
    declines

38
Docetaxel 3-weekly
39
Mitoxantrone
40
Docetaxel weekly
41
Conclusions
  • The updated survival analysis confirmed the
    previously reported results.
  • Similar hazard ratios among the analyzed
    subgroups are evidence for robust data.

42
Implications
  • Three weekly docetaxel and prednisone remains the
    preferred treatment option for most patients with
    mCRPC.

43
Satraplatin in patients with advanced
hormone-refractory prostate cancer (HRPC)
overall survival (OS) results from the phase III
Satraplatin and Prednisone Against Refractory
Cancer (SPARC) trial
44
Satraplatin
  • Novel oral platinum compound
  • Activity against cell lines
  • resistant to taxanes,
  • anthracyclines and
  • other platinum compounds
  • Activity in early prostate cancer trials

44
45
Study Endpoints
  • Primary Endpoints
  • Progression Free Survival (PFS)
  • Based on 802 events (June 2006 data cutoff)
  • Composite endpoint based on first occurrence of
    Tumor Progression, Skeletal Event, Symptomatic
    Progression, Death
  • PFS assessed by an Independent Review Committee
    (IRC)
  • PSA increase was NOT a criterion for progression
  • Overall Survival (OS)
  • Based on 713 events (September 2007 data cutoff)
  • Secondary Endpoint
  • Time to Pain Progression (TPP)

45
46
SPARC Progression Free SurvivalIntent-to-Treat
(ITT) Population Per IRC Satraplatin
PlaceboMedian (wks) 11.1
9.7HR 0.67 (95 CI 0.57 - 0.77)Log-Rank P
value lt0.0001
30
17
16
7
Weeks
At Risk
Sternberg CN et al. ASCO 43rd Annual Meeting
(Chicago, IL), June 4, 2007 (abstract 5019)
46
47
SPARC Overall SurvivalITT Population,
Unstratified AnalysisMedian (wks)Satraplatin 61.3
Placebo 61.4Unstratified HR 0.97 (95 CI 0.83,
1.13)Log-Rank P value 0.7011
100
100
90
90
80
80
70
70
60
60
Proportion Event Free ()
50
50
40
40
30
30
20
20
10
10
0
0
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150
160
170
180
190
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150
160
170
180
190
Weeks
Weeks
47
48
Conclusions
  • SPARC was the largest phase 3 trial in this
    patient population
  • The question remains what is a meaningful measure
    of clinical benefit in second line HRPC
  • Could better imaging (bone ?) help to define if
    there was a population of patients that actually
    might benefit from an agent such as this ?

48
49
Study M00-244 Design Objective To evaluate the
safety and efficacy of 10 mg atrasentan vs
placebo in patient with nonmetastatic HRPC
50
Study M00-244Efficacy Progression Free Survival
51
Patient Accountability? 494 Patients had disease
progression, 56 Placebo and 49 Atrasentan ?160
Patients were active at the end of study ? 278
Patients Discontinued Without Disease Progression
52
Study M00-244Efficacy Progression Free
Survival By Region
Non-USN561
USN380
53
?Report PSA changes using waterfall
plots.?Confirmation of bone scan findings with a
second scan.?Eliminate overall response as an
outcome measure. ?Insure a drug is no longer
working before stopping therapy.
54
Anti-angiogenesis, prostate cancer cell,
chemotherapy
55
Docetaxel Thalidomide Survival
P0.0407
Thalidomide Docetaxel median 26.9 months
Docetaxel Median 14 months
Dahut et al J Clin Oncol, 2004
56
Rationale
  • Tumor angiogenesis
  • Blocking one pathway may be inadequate for
    anti-tumor activity
  • Anti-angiogenic targets
  • Thalidomide bFGF, endothelial cells and TNF
  • Bevacizumab VEGF
  • Complex interplay of multiple angiogenic factors

57
Docetaxel, Bevacizumab, Thalidomide
  • Single-arm Phase II trial (n 60)
  • Metastatic CRPC
  • No prior chemotherapy for metastatic disease

58
Results
  • PSA 50 decline rate 90
  • RECIST Response rate 63
  • TTP 18.2 months

59
Best Response in PSA
60
CEC in PC3 Xenografts after Docetaxel and
Thalidomide
61
CEC changes at 6 weeks
p 0.02
0
CEC (6 wks - pre)
gt75
lt75
PSA Decrease
62
Conclusion
  • High durable response in PSA
  • Prolonged TTP
  • High ORR
  • Increased apoptotic CEC

63
Castration Sensitive and Castration-Resistant
Progression of Prostate Cancer
64
Phase 1-2 Study of MDV3100 in Patients with
Progressive Castration-Resistant Prostate Cancer

65
MDV3100
  • 1. Small molecule AR antagonist with a novel
    mechanism of action that blocks nuclear
    translocation of AR, DNA binding, with no agonist
    activity when AR is overexpressed.
  • 2. Identified from a cell-based screen that
    mimics castration-resistant tumors with
    overexpressed AR.
  • 3. Active in bicalutamide-resistant prostate
    cancer models.
  • 4. Currently under investigation in a Phase 1-2
    trial in patients with CRPC.

66
Waterfall Plot of PSA Change from Baseline to 12
Weeks for Chemotherapy-Naïve Patients Treated at
60, 150, and 240 mg/day
N42 Chemo-naïve
7 pt off study lt12 weeks
gt50 Decline 23/42 (55)
67
Waterfall Plot of PSA Change from Baseline to 12
Weeks for Post-Chemotherapy Patients Treated at
60, 150, and 240 mg/day
N31 Post-chemo
5 pt off study lt12 weeks
gt50 Decline 13/31 (42)
68
FDG and FDHT PET Scans Identify Areas of
ActiveProstate Cancer Spread
18F-DHT
FDHT
AR expression by immunohistochemistry
69
PRE- and POST-MDV3100 PET Imaging of Biopsy
Proven Metastatic Disease in a Lymph Node
SUV
70
Circulating Tumor Cell (CTC) in MDV3100
  • Baseline CTC lt5 n25 (58)
  • CTC gt5 n18 (42)
  • 92 in both dose levels have retained favorable
    cell counts (4 or less) pre- and post-treatment
  • 33 and 56 at 60 and 150 mg/day, respectively,
    converted from a pre-treatment unfavorable to a
    post-treatment favorable cell counts.
  • Associations with clinical outcomes are ongoing.

CellSearch Platform from Veridex, LLC
71
Abiraterone Acetate
72
Oral irreversible inhibitor of CYP17
(P450c17)17a hydroxylase C17,20-lyaseInhibits
testosterone production in testis, adrenal glands
and prostate
73
CYP17 blockade inhibits androgen synthesis
Attard et al, submitted for publication
74
COU-AA-001in chemotherapy-naïve CRPC
  • First-in-human, first-in-class continuous dosing
    proof-of-concept study
  • Phase I/II open-label, single-centre, dose-
    escalation clinical trial
  • Capsules (250mg) administered once daily
    continuously
  • Dose levels
  • 250mg, 500mg, 750mg, 1000mg, 2000mg
  • 28 days defined as 1 treatment course

De Bono, et al, Prostate Cancer Foundation, 2007
75
Anti-tumor Activity
  • PSA decline rate
  • 50 PSA declines in 27/44 patients (61)
  • 75 PSA declines in 22/44 patients (50)
  • 90 PSA declines in 11/44 patients (25)
  • One PSA rise but PR on CT scan
  • Median TTP by PSAWGC 252 days

Prior Phase II study of pertuzumab in this
population at our institution had a median TTP
by PSAWGC of 43 days (de Bono et al JCO 2007)
De Bono, et al, Prostate Cancer Foundation, 2007
76
Abiraterone Suppresses Steroids Downstream of
C17,20-lyase
6
Androstenedione
2
Testosterone (by LC-MS/MS)
5
4
ng/dl
3
Lower limit of sensitivity
No rise at progression
nmol/l
1
No rise at progression
2
1
0
0.07
60
10
20
70
At progression
Start of treatment
28
56
At progression
Start of treatment
Days
1
Days
DHEA
12.5
12.5
Oestradiol
10.0
10.0
7.5
No rise at progression
7.5
?mol/l
nmol/l
5.0
5.0
2.5
2.5
0
0
10
30
20
40
60
50
Start of treatment
28
56
At progression
Days post treatment
Days
Attard, et al, submitted for publication
77
Abiraterone Treatment Results in a Rise in C-21
Steroids Upstream of CYP17
ACTH
Deoxycorticosterone
Corticosterone
150
100
ng/dl
50
0
10
20
30
40
50
60
Days post treatment
78
Hormonal Impact of Abiraterone Alone or with Low
Dose Corticosteroids
Attard, et al, submitted for publication
79
Exploratory Study-Dexamethasone Salvage
Patient 1
Attard, et al, submitted for publication
80
COU-AA-003Phase II trial in post-docetaxel
patients
  • Status
  • 28 evaluable patients recruited to date
  • Patient disease characteristics
  • Median baseline PSA 523 (range 33.3-10325)
  • Presence of bone mets on bone scan 22/28 pts
  • Presence of measurable disease by RECIST 18/28
    pts

De Bono et al, Prostate Cancer Foundation 2007
81
PSA decline rate
  • 50 PSA declines in 14/28 (50) patients
  • 75 PSA declines in 9/28 patients (32)
  • 90 PSA declines in 5/28 patients (18)

De Bono et al, Prostate Cancer Foundation 2007
82
Phase III Trial in Post-docetaxel Chemotherapy
Placebo daily ? Abiraterone 1000 mg daily?
Prednisone 10 mg daily Prednisone 10 mg daily
Abiraterone 1000 mg daily Prednisone 10 mg daily
Randomization 21
Placebo daily Prednisone 10 mg daily
83
General Conclusions
  • Docetaxel and Prednisone (q3w) remains the
    standard
  • Several promising combinations are under
    investigation
  • Response criteria remains a problem in phase II
    trials
  • Insure a drug is no longer working before
    stopping therapy
  • Hormonal treatment can be active even post
    chemotherapy
About PowerShow.com