Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National - PowerPoint PPT Presentation

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National

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Title: Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National


1
Prostate Cancer Clinical Update James
L. Gulley M.D., Ph.D., F.A.C.P.Director,
Clinical Trials Group Deputy Chief Laboratory
of Tumor Immunology and BiologySenior
Investigator, Medical Oncology BranchCenter for
Cancer ResearchNational Cancer Institute, NIH
2
Presentation Outline
  • Prostate Cancer detection and prognosis
  • Standard Local Therapy
  • Standard Systemic Therapy
  • Androgen deprivation therapy (ADT)
  • Chemotherapy
  • Bone targeted therapy
  • Immunotherapy
  • Future Directions

3
Disease Continuum in Prostate Cancer
Death
Docetaxel
Castration
Tumor volume
LocalTherapy
Cabazitaxel Abiraterone Enzalutamide
2nd-line Hormonal therapy
Alpharadin?
Sipuleucel-T
Symptoms
Asymptomatic
Metastatic
Non-Metastatic
Castration Resistant
Castration Sensitive
Death from Prostate Cancer
Time
4
Introduction
  • 241,740 new cases in 2012
  • 28,170 deaths in 2012
  • 1 in 6 men will develop clinically significant
    prostate cancer

5
Risk Factors
Age (median age 71 y/o lt15
younger than 65)Family HistoryGeographic
locationRaceFor caucasians 16.6 of the men
get prostate cancer and 3.5 die. For african
americans 18.1 get prostate cancer and 4.3 die.
6
Detection
May be detected due to symptoms, physical finding
or through PSA screening.Most patients in the US
are asymptomatic at the time of diagnosis.
7
Digital Rectal Exam
8
Incidence vs. MortalityProstate Cancer in the
U.S.
PSA Screening
250
200
150
New cases
New Prostate Cancer Cases and Deaths (per 100,000
men)
100
50
Deaths
0
1975
1980
1985
1990
1995
2000
(G. Welch, Should I Be Tested for Cancer?, 2004)
9
Does Screening Save Lives?
  • PLCO Trial
  • N76,693 men (screen vs. no screen)
  • After 7 years 50 vs. 44 deaths from PC
  • ?Too early
  • PSA test too available?
  • ERSPC Trial
  • N182,000 (screen vs. no screen)
  • At a median of 9 years, a 20 reduction in PC
    death
  • Different patient population than US?

10
Histologic Grading
  • Gleason Grade
  • most common grading system
  • Tumors are graded from 1-5 with the
  • higher number indicates a more aggressive tumor
  • Two most predominant patterns added together for
    a score from 2-10

11
Staging
Stage I(A) has a T1a and is localized.
Stage II (B) has a
T1b, T1c, T2a, T2b and T2c and is localized to
the prostate.
Stage III (C) has a T3a and Teb and is locally
advanced.
Stage IV(D) has a T4N1M1 and is
metastatic.
12
Prognosis
  • 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 available to predict the likelihood
    of positive surgical margins, lymph node
    involvement and disease recurrence after local
    therapy.

13
Treatment
  • Patients with a life expectancy of less than 10
    years and low grade/ low stage lesions may be
    candidates for active surveillance

14
Active SurveillanceThe chance of dying of
prostate cancer decreases withLower Gleason
scoreOlder age (more competing causes of
mortality)
15
ADT as Primary Therapy
  • For patients who are not candidates for local
    therapy, immediate ADT offers better OS than
    waiting until symptomatic disease
  • 985 pts randomized in EORTC trial
  • HR 1.25 (favoring immediate ADT)
  • No earlier time to CRPC despite earlier ADT
  • Disease specific survival reportedly not
    different in this trial raising some questions

16
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

17
Radical Prostatectomy
  • Surgical removal of the prostate
  • May be done with a retropubic, perineal, or
    laproscopic approach
  • Most common side effects are impotence and
    incontinence

18
Randomized Trial Comparing Surgery and Watchful
Waiting
19
Randomized Trial Comparing Surgery and Watchful
Waiting
20
External-beam Radiation
  • Radiation to the prostate (and pelvis) from
    outside the body
  • Evidence that higher doses are associated with
    better efficacy
  • IMRT aims to increase radiation delivery and to
    decrease toxicity
  • Most common side effects are impotence and rectal
    irritation

21
Average multi-item sexual domain summary scores
22
Prostate anatomy
23
Average multi-item incontinence summary scores
24
Average multi-item bowel summary scores
25
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

26
Treatment of Locally Advanced Disease
  • Conservative management
  • Hormonal therapy plus radiation
  • Hormonal therapy plus surgery

27
EORTC Trial
  • Randomized trial of radiotherapy ADT
  • Locally advanced prostate cancer (n415)
  • Concurrent adjuvant ADT continued for 3 years
  • Improved outcomes for combination
  • Local control
  • metastases free survival
  • overall survival (62 vs. 78 5 yr survival
    p0.0002)

28
ECOG (Messing et al.)
  • Randomized trial of immediate hormonal therapy
    vs. observation in men undergoing radical
    prostatectomy with evidence of positive lymph
    nodes
  • 98 eligible patients enrolled
  • Deaths by 11.9 years f/u
  • 17/47 immediate anti-androgen
  • 28/51 delayed therapy group (HR 1.84 p0.04)
  • Criticisms

29
Adjuvant RT
Randomized study of adjuvant RT vs. observation
for T3N0M0 (n425) For adjuvant RT of 214
patients 53 had Metastasis free survival and 59
had overall survival. For observation of 211
patients 46 had metastasis free survival and 48
had overall survival.
30
Disease Continuum in Prostate Cancer
Tumor volume
LocalTherapy
Symptoms
Asymptomatic
Metastatic
Non-Metastatic
Castration Resistant
Castration Sensitive
31
Biochemical Recurrence
  • May be occult local or metastatic disease
  • Options include additional local therapy,
    hormonal treatment or watchful waiting
  • Virtually impossible to predict the impact of
    treatment on survival

32
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.

33
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 in the surgical specimen, and
    PSA doubling time.

34
Disease Continuum in Prostate Cancer
Tumor volume
LocalTherapy
Symptoms
Asymptomatic
Metastatic
Non-Metastatic
Castration Resistant
Castration Sensitive
35
Metastatic PC
  • 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) are
    difficult to use.

36
ADT Treatment of metastatic PC
  • 1941 Charles Huggins showed that advanced PC was
    inhibited by decreasing Testosterone (castration
    or estrogen) and activated by adding
    testosterone.
  • 1966 Nobel Prize in Medicine

37
Action of Androgens in Prostate Cells.
Testosterone is metabolized to DHT
38
Action of Androgens in Prostate Cells. DHT
receptor complex enters nucleus.
39
Action of Androgens in Prostate Cells. DHT
receptor complex alters gene expression
40
Action of Androgens in Prostate Cells. mRNA is
translated in cytosol into protein.
41
ADT Treatment of metastatic PC
  • Testosterone lowering therapies
  • GnRH agonists (e.g., Leuprolide and Goserelin)
  • Both agents are expensive
  • May initially result in an increase in
    testosterone
  • GnRH antagonist (e.g., Degarelix)
  • Similar cost issues without an increase in
    testosterone
  • Monthly injections
  • Orchiectomy- outpatient procedure. Cost
    effective if ADT for 6 months or more.

42
Side Effects of ADT. ?Sexual
effects include decreased libido and erectile
dysfunction.
?Physical effects include hot
flashes, fatigue, weight gain, hair changes,
breast pain, decreased muscle mass, bone mineral
density and penis size.
?Metabolic changes include lipid changes,
anemia and diabetes mellitus.
?Mental changes
include lack of initiative, emotional lability,
and decreased memory and cognitive function.
43
Androgen Receptor Antagonists
  • bicalutamide, nilutamide, flutamide and
    enzalutamide
  • Do not ?Testosterone, bind androgen receptor and
    prevent anabolic (growth related) effects
  • Different dosing schedules and potency
  • Different side effect profile
  • Similar activity and all may show withdrawal
    response

44
Combined Androgen Blockade
  • Combination of anti-androgen with orchiectomy or
    GnRH-A
  • Controversial results
  • Not significantly more effective, but more
    expensive and may add toxicity

45
5-Year Survival in the 20 Randomized Trials of
CAB (AS plus Nilutamide or Flutamide) vs AS Alone
6500 Men in 20 Trials of Nilutamide/Flutamide
Androgen Suppression Only Androgen Suppression
Antiandrogen
Proportion Alive ()
Treatment Better by 2.9 (SE 1.3) Logrank
P0.005
27.6
24.7
Time Since Randomization (Years)
46
Other Hormonal Agents
  • Ketoconazole
  • Abiraterone (recently approved)
  • Patients may respond to multiple sequential
    hormonal manipulations

47
Disease Continuum in Prostate Cancer
Tumor volume
LocalTherapy
Symptoms
Asymptomatic
Metastatic
Non-Metastatic
Castration Resistant
Castration Sensitive
48
Chemotherapy
  • Studies prior to 2004 disappointing
  • Quality of life measurements
  • Difficulty in evaluating response

49
Mitoxantrone Glucocorticoids
  • Improved quality of life when compared to
    Glucocorticoids alone
  • No survival advantage
  • FDA approval for the palliation of painful
    lesions in 1996

50
TAX327A 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
Castration Resistant ProstateCancer
Docetaxel 30mg/m2 Wkly Prednisone 10mg orally
given daily
RANDOMIZE
Mitoxantrone 12mg/m2 Q3 Prednisone 10mg orally
given daily
1006 Patients Entered
51
TAX 327 Survival Advantage Only Shown for Q3W
Docetaxel
1.0
Docetaxel 3 wkly
0.9
Docetaxel wkly
0.8
Mitoxantrone
0.7
0.6
Probability of Surviving
0.5
Median survival Hazard
(mos) ratio P-value D 3wkly
18.9 0.76 0.009 D wkly 17.3 0.91 0.3 Mitoxan
trone 16.4
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
Months
52
Cabazitaxel
  • Novel taxane active in docetaxel resistant cell
    lines
  • 755 men with metastatic CRPC who had progressed
    on or following docetaxel randomized to
    cabazitaxel vs. mitoxantrone. Patients in both
    arms received prednisone.
  • Worse toxicity in Cabazitaxel arm with grade 3/4
    neutropenia in 82 vs. 58. About 5 treatment
    related deaths in Cabazitaxel arm.

53
Primary Endpoint Overall Survival (ITT Analysis)
54
Progression-Free Survival (PFS) Results
55
Abiraterone
56
Randomized trial of Prednisone with Abiraterone
vs. Placebo
57
Randomized trial of Prednisone with Abiraterone
vs. Polaceb
58
Effects of MDV3100 on the Androgen Receptor Are
Distinct from Bicalutamide
59
Waterfall Plot of Percent PSA Change from Baseline
Chemotherapy-Naïve (N65)
Post-Chemotherapy (N75)
51 (38/75) gt50 Decline
62 (40/65) gt50 Decline
60
Prostate cancer survival curve
61
Alpharadin
62
Survival curve
63
Therapeutic Vaccines
64
APC Vaccine Sipuleucel-T (Provenge). On day 1
Leukapheresis is is performed at a Center. On
day 2-3 sipuleucel-T is manufactured at a
company.
On day 3-4 the patient is
infused at the Doctors office.
65
IMPACT Randomized Phase 3 Trial(IMmunotherapy
Prostate AdenoCarcinoma Treatment). Patients
(342) will be treated with Sipuleucel-T (Q 2
weeks x 3). Patients (170) will be treated with
Placebo (Q2 weeks x 3). The primary endpoint is
overall survival and the secondary endpoint it
time to objective disease progression.

66
Sipuleucel-T IMPACT Overall Survival Primary
Endpoint Intent-to-Treat Population
P 0.032 (Cox model) HR 0.775 95 CI 0.614,
0.979 Median Survival Benefit 4.1 Mos.
67
Pox Vector Vaccine PSA TRICOM (PROSTVAC)
PSA
Developed at NCI CRADA with BN
68
Randomized Controlled Double Blind Phase II
Study. Patients (84) will be
treated with PSA-TRICOM GM-CSF. Patients (42)
will be treated with empty vector placebo. The
primary endpoint is progression free survival.
The secondary endpoint is overall survival.


69
PROSTVAC Significantly Extended Overall Survival
by 8.5 months
100
80
60
Overall survival ( patients)
40
20
PROSTVAC
Control
0
Months
70
Therapeutic vaccines vs. Conventional therapy.
?Conventional therapy targets the tumor or its
microenvironment. The action is immediate but is
limited by toxicity.
?Therapeutic vaccines target the
immune system. The action requires a memory
response and is delayed but requires an adequate
immune system.
71
Tumor Growth Rate



Vaccine
Cytotoxic Therapy
Tumor Burden
Time
72
PROSTVAC Interesting Case History
PSA
Second vaccine treatment
Vaccine treatment
Radical prostatectomy
External beam radiation
Age
-No other therapy for prostate cancer -Normal
testosterone
73
Current and Emerging Therapies in CRPC
74
Planned Phase III
Randomize patients into
Arm A PSA TRICOM vaccine with GM-CSF
(n 400)
Arm B PSA TRICOM
vaccine placebo (n 400)

Arm C Empty Vector placebo GM-CSF (n
400)
Primary endpoint
OSPower  90  a  0.005Critical HR 0.82
75
Summary
  • Localized Disease
  • RP, EBRT, Brachytherapy
  • Androgen Deprivation Therapy (ADT)
  • High risk disease with EBRT
  • LN disease following RP
  • Metastatic disease
  • Sipuleucel-T
  • Chemotherapy
  • Docetaxel with prednisone
  • Cabazitaxel with prednisone
  • Abiraterone
  • Enzalutamide
  • Zoledronate or denosumab (decrease skeletal
    related events)

76
Future Directions
  • Which patient needs treatment?
  • Adjuvant systemic therapy for high risk patients
  • Timing of hormonal therapy
  • Multimodality therapy
  • New agents / combinations / sequencing
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