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Prostate cancer progression

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Title: Prostate cancer progression


1
Prostate cancer progression
2
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Probability of developing invasive prostate
cancer increases with age
  • Age (Male) All Sites Prostate
  • Birth?39 yr 1 in 73 1 in 12,833
  • 40?59 yr 1 in 12 1 in 44
  • 60?79 yr 1 in 3 1 in 7
  • Lifetime risk 1 in 2 1 in 6

American Cancer Society, Inc. Available at
http//www.cancer.org/downloads/STT/CAFF_finalPWSe
cured.pdf
8
Factors that may increase risk for developing
prostate cancer
  • Obesity
  • Dietary fat
  • Smoking
  • High testosterone levels
  • Diabetes
  • Infectious agents
  • Occupational exposures

Giovannucci E et al. J Natl Cancer Inst.
2003951240 Giovannucci E et al. J Natl Cancer
Inst. 1993851571 Sharpe CR et al. Epidemiology.
200112546 Hoffman RM et al. J Natl Cancer
Inst. 200193388 Siddiqui MK et al. Biomed
Environ Sci. 200215298
9
Epidemiology-Nutrition
  • Increased risk
  • High content of animal fat in the diet
  • Low intakes selenium, ligands and isoflavenoids
  • Inversely related to sun exposure (Vitamin D)
  • Deficient in vitamin E
  • Decreased risk
  • Diets rich with carotenoids (Vitamin A)

10
Familial aspects
  • Men with a first-degree affected are twice as
    likely to develop prostate cancer
  • Men with two or three first degree relatives have
    a 5 and 11-fold increased risk of developing
    prostate cancer

11
Hereditary aspects
  • Hereditary (gt 3 relatives or gt 2 with early-onset
    disease
  • Associated with early onset and a Mendelian
    autosomal dominant inheritance with incomplete
    penetrance
  • Less than 10 of all cases
  • More than 40 of cases in men younger than 55
    years

12
Racial aspects
  • Afro-American
  • Highest incidence of prostate cancer in the world
  • Diagnosis at a younger age
  • Higher tumor burdens
  • Lower survival rates
  • Asians
  • Migration to USA leads higher incidence of the
    disease, which increases with each succeeding
    generation

13
Hippocrates
  • It is more important to know what sort of person
    has a disease, than to know what sort of disease
    a person has.

14
Willet F. Whitmore
  • Is cure possible in those for whom it is
    necessary?
  • Is cure necessary in those for whom it is possible

15
American Cancer Society Guidelines for Screening
  • Annual Digital Rectal Exam/PSA Screening
  • Age 50
  • Age 45 family history or African American
  • PSA lt2.0 at yr 1 of screening, screen q 2 yr

American Cancer Society, Inc. Available
at http//www.cancer.org/downloads/STT/CAFF_final
PWSecured.pdf Han M et al. Med Clin North Am.
200488245
16
The Gleason scoring system for prostate cancer
  • Cells are assigned a no. between 1 and 5
  • The scores of the 2 most common cell patterns are
    added together

17
Gleason Grade
  • The Sum of the most common pattern plus the
    second most common pattern yields the Gleason
    score
  • lt 6 well differentiated
  • 7 moderately differentiated
  • gt 8 poorly differentiated

18
Prostatic Intraepithelial Neoplasia
  • 85 carcinomas have associated PIN
  • High grade PIN has 30-50 risk of CA on
    subsequent biopsies
  • PIN does not cause elevated PSA
  • Atypical foci in 3-5 of biopsies, 50 risk of
    cancer on repeat biopsy

19
Diagnosis
  • The need to pursue the diagnosis is based on
  • symptom
  • an abnormal DRE
  • an abnormal PSA level
  • The diagnosis is established by a TRUS-guided
    transrectal needle biopsy.
  • Any palpable abnormality should be pursued,
  • only 25 to 50 of men with an abnormal DRE prove
    to have prostate cancer
  • a normal DRE does not exclude presence of cancer

20
Symptoms of Prostate Cancer
  • Frequent urination
  • Inability to urinate
  • Trouble starting and stopping urination
  • Painful or burning urination
  • Blood in the urine or semen
  • Painful ejaculation
  • Impotence
  • Today, men rarely present with symptoms of
    metastatic disease

21
Digital Rectal Exam
  • Poorly reproducible
  • Lacks sensitivity and specificity
  • 25 of men with an abnormal DRE and a PSA lt 4.0
    have prostate cancer
  • 50 of DRE-detected prostate cancer is non-organ
    confined

22
DRE examination
T3
T1
T2
T4
23
PSA
  • PSA is a 28-kD protein of the kallikrein family,
    a group of serine proteases whose genes are found
    on chromosome 19q13
  • PSA induces liquefaction of seminal fluid and the
    release of mobile spermatozoa
  • PSA is synthesized in the ductal and acinar
    epithelium and is secreted into the lumina
  • PSA is organ specific and not cancer specific

24
PCA 3
  • A segment of noncoding mRNA from chromosome
    9q2122 that is overexpressed by more than 95 of
    all prostate cancers tested .
  • PCA3 expression is normalized against a
    background of PSA mRNA PCA3 score
  • The PCA3 score is much more cancer-specific than
    serum PSA levels

25
Factors Increasing PSA
  • Cycling
  • Prostate massage
  • Cystoscopy
  • Ejaculation
  • Prostate biopsy
  • Transrectal Ultrasound

26
Serum PSA
  • Normal PSA lt4.0 ng/mL
  • Age- and race-basedreference ranges
  • Sensitivity 67.5?80
  • Improve sensitivity use lower PSA cut-off level
    of 2.5 ng/mL (higher false positive, decreased
    speficity)
  • Improve specificity measure free
    PSA,complexed PSA (c-PSA)

American Urological Association. Oncology.
200014267 Tanguay S. Urology.
200259261 Okihara K. J Urol. 20021672017
27
PSA
  • The normal range of PSA lt 4 ng/mL
  • The sensitivity for detecting cancer with PSA gt 4
    ng/mL is approximately 80
  • 20 of men with a normal DRE and PSA level
    between 2.5 and 4.0 have cancer.
  • With PSA 4 - 10 ng/mL, TRUS biopsies detect
    cancer in 25, of which 75 are pathologically
    confined
  • Men with a PSA of 2 to 3 ng/mL are 5.5 times more
    likely to be diagnosed with cancer within 5 years
    than men with a PSA less than 1 ng/mL

28
PSA Derivatives
  • PSA velocity rise in PSA over time (gt0.75
    ng/ml/yr associated with cancer useful for men
    with PSA lt4)
  • PSA Doubling Time
  • PSA density PSA/prostate volume (gt0.15 is
    associated with cancer useful in men with large
    glands)
  • Free PSA measures unbound PSA (lt25 is
    associated with cancer useful in men with PSA
    between 4-10 ng/ml)

Circulating PSA is complexed covalently
(irreversibly) to the protease inhibitor
1-antichymotrypsin, which covers a specific
epitope on the kallikrein loop, allowing
immunoassays for the "free" form representing 10
to 35 of the total PSA
29
Transrectal Ultrasound - TRUS
  • Classic picture of a hypoechoic area
  • Many cancers are isoechoic and only detectable
    through systemic biopsies.
  • TRUS has two potential roles in the diagnosis of
    CaP
  • To identify lesions suspected of malignancy
  • To improve the accuracy of prostate biopsy.
  • TRUS detects 50 more patients with CaP than DRE

30
Radiographic staging
  • CT
  • Rarely useful for staging
  • Bone scan
  • more sensitive than plain films
  • Lacks specificity
  • Abnormal bone scans are often followed by other
    technology

31
CT-PET
32
Endorectla MRI
  • More accurately identifies the presence of ECE
    and seminal vesicle invasion (SVI)
  • Identifies invasion in the area of the
    neurovascular bundles (NVBs)
  • Improves staging accuracy

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34
Early detection
  • Healthy men should be informed of the risks and
    benefits of screening if they are older than 50
    years and have a life expectancy of at least 10
    years
  • If they agree, these men should have a DRE and
    PSA test annually
  • Goals
  • Reduction of CaP-specific mortality
  • Not to detect more and more carcinomas
  • Not survival because survival is heavily
    influenced by lead-time
  • Improvement in quality of life (QUALYs)

35
Early Diagnosis and Outcomes
  • Majority (86) of cases diagnosed in local and
    regional stages
  • Usually no symptoms
  • 5-yr survival with early detection 100
  • Survival rates for all stages combined
    5 yr 98, 10 yr 84, 15 yr 56
  • Sites of metastases lymph nodes, bone

American Cancer Society, Inc. Available
at http//www.cancer.org/downloads/STT/CAFF_final
PWSecured.pdf
36
CaPSURE Risk Category at Diagnosis
100
High risk
16.0
25.1
30.2
36.6
80
37.2
60
38.5
Intermediate risk
37.3
Patients ()
33.8
40
46.8
Low risk
20
36.4
32.5
29.5
0
Reprinted with permission from Cooperberg MR et
al. J Urol. 2003170S21
37
Preventing Prostate Cancer
  • Prostate Cancer Prevention Trial (PCPT)
  • Evaluated the potential of finasteride to
    decrease the incidence of PRCA
  • Result reduces the overall risk of prostate
    cancer by 30
  • Selenium and Vitamin E Chemoprevention Trial
    (SELECT)
  • Evaluating the role of selenium and vitamin E in
    preventing PRCA
  • Results Negative
  • Dietary modification(?) soy, lycopene

38
Localized prostate cancer What to do?
Dealing with localized prostate cancer
Requires a balancingact
39
Prognostic models
  • Partin tables
  • Kattan nomograms
  • Damicco prognostic groups

40
Risk Classification for PSA Failure After RP or RT
Classification Criteria 5-yr
Outcome Low Risk PSA lt10 ng/mL and
Gleason lt7 lt25 PSA and AJCC T2a
Failure
Intermediate PSA 1020 ng/mL or Gleason
7 25?50 Risk or AJCC T2b
PSA Failure High Risk PSA ?20 ng/mL or
Gleason gt50 PSA gt7 or AJCC T2c Failure
The most clinically relevant prognostic factors
are Gleason, PSA and stage
Adapted with permission from D'Amico AV et al.
JAMA. 1998280969
41
Localized prostate cancerMedical decision making
  • Life expectancy (age, comorbidity) of the patient
  • Probability of metastases and death from prostate
    cancer over time for the untreated (or
    conservatively managed) patient
  • Particular characteristics of the primary tumor
    (prognostic features)
  • Effectiveness of the treatment being considered
  • Complication rates and side effects from the
    treatment
  • Patient uses (values) for each health state
    affected by the cancer and its treatment

42
Primary treatments for localizedprostate cancer
  • Watchful waiting
  • Active surveillance
  • Interstitial brachytherapy
  • External beam radiotherapy
  • Radical prostatectomy
  • Primary hormonal therapy
  • Others (e.g., cryotherapy, HIFU)

43
Radical prostatectomyMultiple approaches
  • Transperineal (uncommon)
  • Retropubic (most common)
  • Laparoscopic (pure, robot assisted)

44
Active surveillance
  • Definition selected men are managed expectantly
    with the intention to apply curative treatment if
    signs of progression occur

45
Active Surveillance Criteria
  • Epstein criteria for insignificant disease
  • Gleason score of 6 or less
  • lt 1/3 of positive cores
  • An involvement of 50 or less of individual cores
  • The criteria for tumor volume can be relaxed for
    patients over the age of 65 years
  • Patients over 75 years might be candidates if
    they have a Gleason score of 7 (3 4)
  • PSA DT gt 3 years
  • PSA velocity lt 2.0 ng/ml per year

46
Active surveillance monitoring disease and
continuation criteria
  • PSA test (every 3 months) / PSA (kinetics)
  • DRE (every 6 months)
  • Biopsy (every 1,4,7, and 10 years, according to
    biopsy scheme)
  • Patient content to continue active surveillance

47
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

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49
Radical Prostatectomy Outcomes
Long-Term Survival Following Anatomic Radical
Retropubic Prostatectomy
1.00
T1a
T1c
0.75
T1b
T2a
Likelihood ofUndetectable PSA
T2c
0.50
T2b
T3a
0.25
0
0
5
10
15
20
Years Post-operative
Reprinted with permission from Han M et al. Urol
Clin North Am. 200128555
50
Long-term biochemical disease-free Survival
following Radical Retropubic ProstatectomyPSA
Progression-Free vs Gleason Score
  • Han,Partin,Pound,Epstein,Walsh Urol Clin N Am
    28(3)555, 2001

51
Pathological findings
  • Approximately 8 to 15 of cancers confined to
    the prostate pathologically do recur.
  • Extracapsular invasion
  • Seminal Vesicles involvement
  • Positive surgical margins

52
COMPLICATIONS
  • Up to 80 will be impotent
  • 57 of patients will be temporarily incontinent
  • 10 urethral scarring
  • 10 mild incontinence
  • 7 rectal injury
  • 3 severe incontinence
  • 2 will be permanently incontinent

53
Erectile disfunction
  • Recovery
  • Extent of preservation
  • Age
  • Quality of erections before the operation
  • Experience of the operating surgeon
  • With preservation of both nerves
  • First erection- 4 months
  • Continue to improve for 2 to 3 years

54
Radiation Therapy
  • 3D
  • IMRT, IGRT
  • Brachytherapy
  • External irradiation offers the same long-term
    survival results as surgery
  • External irradiation provides a quality of life
    at least as good as that provided by surgery

55
Radiation therapy dose effect
  • Multiple studies support the notion that local
    tumor control is directly related to dose and
    indicate that more than 70 Gy is needed to
    control prostate cancer

56
EORTC Trial
  • Bolla et al NEJM 1997
  • 415 patients with locally advanced prostate
    cancer were randomized to radiotherapy alone or
    radiotherapy plus immediate hormone therapy
  • Therapy continued for 3 years
  • Median follow-up 45 months
  • Local control, metastases free and overall
    survival advantage to the adjuvant hormonal group

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58
New approaches
  • Cryotherapy
  • Patients with low-risk or intermediate-risk
    represent potential candidates for CSAP.
  • Prostate size should be lt 40 mL
  • Long-term results are lacking and 5-year
    biochemical progression-free rates are inferior
    to those achieved by radical prostatectomy in
    low-risk patients
  • Patients have to be informed according
  • HYPO
  • Radiofrequency interstitial tumour ablation (RITA)

59
PSA progression after local therapy
  • After prostatectomy
  • PSA is expected to be undetectable within 3 weeks
    after a successful radical prostatectomy
  • Two consecutive values of 0.2 ng/mL or greater
  • After radiotherapy
  • PSA level typically declines over 1-2 years and
    may not reach undetectable levels
  • ASTRO defines failure after radiation therapy as
    3 consecutive rises in PSA level, gt 2 ng/ml,
    irrespective of the nadir value

60
After the local therapy
61
Natural history of progression afterPSA
elevation following radical prostatectomy
  • 1997 men, 15 years after surgery
  • Cancer-specific survival 91
  • Biochemical disease-free survival 85
  • Pound, Partin, Walsh, et al JAMA 2811591, 1999
  • PSA elevation 15
  • Of these, developed metastases 34
  • Median actuarial time to metastases
  • 8 years from time of PSA elevation
  • Median actuarial time to death
  • 5 years from developing metastases

62
Post Radical ProstatectomyRising PSA
63
Evaluation of PSA progression
  • PSA DT
  • DRE is not useful
  • ? 5 had an abnormal DRE
  • Endorectal coiled MRI
  • local recurrence was correctly identified in 81,
    with the mean PSA at time of diagnosis being 2
    ng/mL
  • TRUS and biopsy
  • In the presence of a palpable lesion or a
    hypoechoic lesion on transrectal ultrasound yield
    ? 80
  • Bone scintigraphy and CT scans
  • Of no additional diagnostic value unless the PSA
    gt 20 ng/mL or unless the PSA velocity gt 20
    ng/mL/year
  • CT-PET

64
Management of biochemical progression after local
therapy
  • After radical prostatectomy
  • Salvage radiation therapy at a PSA serum level
    1.5 ng/mL
  • Expectant management is an option
  • Early hormonal therapy reduces frequency of
    clinical metastases therapy (grade A
    recommendation
  • After radiation therapy
  • Salvage radical prostatectomy in carefully
    selected patients
  • Cryotherapy and interstitial brachytherapy are
    alternative experimental procedures in patients
    not suitable for surgery
  • Hormonal therapy

65
Metastatic prostate cancer
66
CHARLES HUGGINS
67
Evolution of Hormone Blockade
LHRHAgonist Anti-androgen (CAB)
LHRHAgonist
GnRHAntagonists
DES
Orchiectomy
lt1940
1940
1985
1989
200203

68
Hormonal therapy
Hypothalamus
LHRH
Abiraterone
LHRH Agonists/ Antagonists Orchiectomy
Pituitary
Ketoconazole
FHS, LH
Adrenals
Testicles
Testosterone
Direct antagonists DES
Prostate cancer cell
69
Hormonal Therapy
  • LHRH Agonists
  • LHRH agonists initially act at the level of the
    pituitary  to stimulate LH release , resulting in
    a temporary surge in serum testosterone levels
  • Subsequent LHRH downregulation to castrate
    levels of testosterone
  • Onset 2-4 weeks

70
Hormonal therapy
  • Bilateral orchiectomy
  • Rapid effect 2-6 hrs.
  • Eliminates 95 of sex steroids
  • Emotional effect
  • Estrogens
  • down-regulation of LHRH secretion, androgen
    inactivation, direct suppression of Leydig cell
    function and direct cytotoxicity to the prostate
    epithelium
  • Cardiotoxic (parental, topical application)

71
Hormonal therapy
  • LHRH Antagonist
  • Binds immediately and competitively to LHRH
    receptors in the pituitary gland
  • Effect is a rapid decrease in LH, FSH and
    testosterone levels without any flare

72
Hormonal therapy
  • Antiandrogens
  • Steroidal
  • synthetic derivatives of hydroxyprogesterone
  • Block androgen receptors
  • Progestational properties and inhibit
    gonadotrophin (LH and FSH) release and suppress
    adrenal activity
  • Non-steroidal
  • Adds to LHRH therapy
  • High dose monotherapy emerged as an alternative
    to castration for patients with locally advanced
    (M0) and in highly selected, well-informed cases
    of M1

73
Combination hormonal therapy
  • Complete androgen-blockage
  • Minimal androgen blockage
  • Finasteride antiandrogen
  • Peripheral androgen blockage
  • High dose Casodex
  • Intermittent therapy
  • Immediate vs differed
  • Adjuvant for microscopic nodal disease
  • MRC trial

74
The patient-based meta-analysis showed no
significant benefit of MAB after 8000 pts and 27
trials
MAB is expensive, has increased toxicity and
should not be used
75
2nd and 3rd line hormonal therapy
  • About 90 of men respond to initial therapy with
    orchidectomy or LHRH agonist
  • At progression about one third respond to
    addition of a peripheral antiandrogen (e.g.
    flutamide, bicalutamide)
  • Of those who respond and then progress about 20
    respond to withdrawal of the peripheral
    antiandrogen
  • Men may respond to further hormonal treatments
    such as dexamethasone, estrogen, or ketoconazole
    and hydrocortisone

76
Adrenal androgen suppressions
77
Abiraterone in Androgen-independent prostate
cancer
  • After androgen suppression
  • PSA response 27/44 (61)
  • RECIST response 12/21 (57)
  • After Taxotere
  • PSA response 14/28 (50)
  • RECIST response 4/18 (22)

78
Side Effects of Androgen-supression
  • Hot flashes
  • Loss of libido
  • Impotence
  • Gynecomastia and breast tenderness
  • Increased appetite
  • Weight redistribution
  • Muscle wasting
  • Bone loss

79
Metabolic Syndrome and Prostate Ca
80
gt73,000 men agegt65 treated for localized Ca
prostate 1992-1999, observed through 2001
gt1 in 3 received ADT
81
Bisphosphonates Conclusions
82
Castration resistant prostate cancer
83
Hormone Refractory Prostate Cancer Characteristics
  • Median survival of 9-12 months
  • Only 20-30 have measurable disease
  • Bone only disease in 90-95
  • Considerable decrease of life quality
    Intense bone pain, Pathological fractures,
    Spinal Cord Compression, Myelosuppression
    Bone hunger syndrome, Hyper/hypocalcemia
    Oncogenic Hypophosphatemia,Osteomalacia, Anemia,
    cachexia, sepsis, death

84
Brief History of FDA Approval of Agents for
Prostate Cancer
  • AGENT YEAR ENDPT.
  • Docetaxel 2004 survival
  • Zomera 2003 QOL
  • Mitoxantrone 1996 QOL
  • Estramustine 1981 old rules

85
Phase III Docetaxel Studies in HRPC Demonstrating
Survival Benefit
Mitoxantrone 12 mg/m2 Prednisone 10 mg q day Q 21
days up to 10 cycles
TAX 327
Randomize
Docetaxel 30 mg/m2/wk Prednisone 10 mg q day 5
on 1 off x 6 cycles
N1006
Docetaxel 75 mg/m2 Prednisone 10 mg q day Q 21
days up to 10 cycles
SWOG 9916
Mitoxantrone 12 mg/m2 Prednisone 5 mg bid Q 21
days
Randomize
N770
Docetaxel 60 mg/m2 d 2 Estramustine 280 mg
d1-5 Dexamethasone 20 mg, tid d 1 2
Warfarin and aspirin
Tannock et al. N Engl J Med 20043511502-1512
Petrylak et al. N Engl J Med 20043511513-1520.
86
Chemotherapy for HRPC
87
Castration resistant prostate cancerTargets for
development
  • Angiogenesis
  • Androgen axis
  • Endothelin receptor
  • SRC Inhibitors
  • Immunotherapy

88
VEGF The Key Mediator of Angiogenesis,
Endothelial Cell Growth and Vascular Permeability
Environmental factors (Hypoxia, pH) Growth
factors (EGF, bFGF, PDGF, IGF-1, IL-1?,
IL-6) HIF-1a
Genes involved in tumorigenesis (p53, p73, src,
ras, vHL, Bcr-Abl)
Upregulated VEGF binds and activates its receptor
Docetaxel
Stimulating signaling cascades
Endothelial cell activation
Overexpression of VEGF and PDGF receptors in bone
metastasis Elevated VEGF independent prognostic
factor in CRPC
89
CALGB 9040 Phase III study of Docetaxel/-
Bevacizumab in HRPC (n1,020 pts)
Docetaxel 75 mg/m2 Q3 wks Prednisone 10 mg po
daily Bevacizumab 15 mg/Kg Q3 wks
R A N D O M I Z E
Stratification Halabi nomogram
Docetaxel 75 mg/m2 Q3 wks Prednisone 10 mg po
daily Placebo

CALGB, ECOG, NCIC
Primary end point- PFS
90
VEGF Trap afliberceptA unique anti-angiogenic
agent
Fully human insoluble VEGF receptor fusion protein
  • Innovative concept
  • Increased affinity for VEGF compared to mAbs
  • Blocks VEGF-A, and placental growth factor

Bound VEGF
  • Potential for broader/better spectrum of activity

VEGF Trap
mAb - monoclonal Antibody VEGF - Vascular
Endothelial Growth Factor PIGF - Placental Growth
Factor
Verheul HM, Clin Cancer Res. 2007 Jul
1513(14)4201-8
91
VEGF-Trap-aflibercept in CRPC VENICE Study
Design (n1,200)
Aflibercept 6 mg/kg IV, over 1hr Docetaxel 75
mg/m2 , Q3 wks Prednisone 10 mg po daily
R A N D O M I Z E
CRPC 1st line
Stratification PS 0, 1 vs. 2
Docetaxel 75 mg/m2 Q3 wks Prednisone 10 mg po
daily Placebo

Primary end point- OS
Tannock I, coordinator
92
Sunitinib for CRPC following Docetaxel
  • PFS- 21.1 weeks
  • 95 C.I 14.3-33.3
  • 12 weeks PFS- 78.9
  • 50 PSA response-
  • 9, 18

Periman, ASCO 2008 Smith, ASCO 2008
93
Phase III Trial Post Docetaxel-Based Chemotherapy
(n819)
R A N D O M I Z E
Sunitinb 37.5 Prednisone 5 mg po bid (n546)
CRPC docetaxel up to 1 prior chemo regimen

Placebo Prednisone 5 mg po bid (n273)
21
Primary end point- OS 35 increase in OS (12 mo
vs. 16.2 mo) Secondary- PFS,RR, QoL
94
AR in CRPC
A- gene amplification and increased expression
of the AR mRNA and protein
B- selection of mutations in the AR that confer
broader ligand specificity
C- changes in the ratios or expression between
the AR and its coregulators
E- up-regulation of cross-talk signal
transduction pathways that can activate the AR in
a ligand-independent manner
D- increased expression of steroidogenic enzymes
95
MDV3100AR antagonist
  • Novel mechanism of action
  • blocks nuclear translocation of AR
  • no agonist activity when AR is overexpressed
  • Identified from a cell-based screen that mimics
    castration-resistant tumors with overexpressed AR
  • Active in bicalutamide-resistant prostate cancer
    models overexpressing AR

C.L Sayers, ASCO 2007
96
MDV3100Second generation Antiandrogen
  • Engineered for activity in prostate cancer cells
    that over express androgen receptor (AR)
  • Binds AR more potently than Casodex
  • Unlike Casodex, MDV3100 inhibits nuclear
    translocation of the AR and its binding to DNA
  • Induces apoptosis in prostate cancer cells

97
Response with MDV3100
Scher, ASCO 2009
98
Phase III Trial Post Docetaxel-Based
Chemotherapy- AFFIRM (n1,200)
R A N D O M I Z E
MDV3100 160 mg/day
CRPC

placebo
Primary end point OS Secondary Endpoints
progression-free survival, safety and
tolerability
21
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