Download 2 1 - The Prostate Net

“Fighting Cancer: It’s All We Do.”™
Therapies in Androgen Resistant
Prostate cancer and non metastatic
prostate cancer
Ulka Vaishampayan M.D.
Chair, GU Multidisciplinary team
Associate Professor Of Medicine
Detroit Medical Center
Wayne State University/ Karmanos Cancer Institute,
Detroit MI.
TAX 327 Trial Results-1006 Pts
Mitox + Pred
12mg/m2
Q 3 weeks
Docetaxel + Pred
75mg/m2
Q 3weeks
Docetaxel + Pred
30mg/m2
weekly 5/6
Pain response
22%
35% (p=0.01)
31% (p=0.08)
Response rate
(PSA)
32%
45% (p=0.0005)
48% (p=0.0001)
Grade 3/4
neutropenia
21.7%
32%
1.5%
Median
survival
16.5 months
18.9 months
(p=0.009)
17.4 months
(p=0.36)
Eisenberger et al. ASCO 2004, abstr#4
TAX 327: Docetaxel/Prednisone vs.
Mitoxantrone/Prednisone in AIPC
De Wit et al. Presented at the Annual Meeting of the American Society for Clinical
Oncology, 2004. Plenary Session [abstract 4]
Eisenberger MA et al. J Clin Oncol. 2004 ASCO Annual Meeting Proceedings
(Post-Meeting Edition). Vol 22, No 14S (July 15 suppl), 2004:4 [Kathy to style
refs]
Novel Agents Under Investigation in
Androgen-Independent Metastatic
Prostate Cancer
Chemobiologic combinations
Vaccines
Novel hormone agents: abiraterone, Kinex, TAK-700
Androgen receptor blockers- MDV-3100
Integrin inhibitors: EMD525797
Docetaxel based combinations:
Disappointing!!
• Docetaxel and calcitriol (Vit D)- Showed increased
death rate with the combination.
• Docetaxel and Avastin:No benefit with combination
• Docetaxel and G Vax (vaccine made from prostate
cancer cells) Trial completed, again increased risk of
death with combination as compared to docetaxel
alone.
• So far no therapy has proven benefit when added to
docetaxel alone.
Provenge/Dendritic cell therapy
[Small E. et al.JCO 2008]
• Peripheral stem cells collected and pulsed
with prostatic acid phosphatase antigen and
GMCSF
• Antigen loaded, dendritic cells enriched
preparation infused to patients
• Patients with asymptomatic CRPC
randomized to Provenge versus placebo in a
2:1 ratio
• Administration was IV infusion every 2
weeks for 3 doses
Sipuleucel-T Immunotherapy for Advanced Prostate
Cancer: A Randomized, Double-Blind, Placebo-Controlled
Phase 3 Trial
IMPACT STUDY
Penson et al.
IMPACT Study Investigators
Presented at
American Urological Association Annual Meeting
April 28, 2009
Randomized Phase 3 IMPACT Trial
(IMmunotherapy Prostate AdenoCarcinoma
Treatment)
Asymptomatic or
Minimally
Symptomatic
Metastatic
Castrate
Resistant
Prostate Cancer
(N=512)
Primary endpoint:
Secondary endpoint:
Sipuleucel-T
Q 2 weeks x 3
2:1
Placebo
Q 2 weeks x 3
P
R
O
G
R
E
S
S
I
O
N
Overall Survival
Time to Objective Disease
Progression
Treated at
Physician
discretion
Treated at
Physician
discretion
and/or Salvage
Protocol
S
U
R
V
I
V
A
L
Sipuleucel-T: Patient-Specific Therapy
Day 1
Leukapheresis
Apheresis Center
sipuleucel-T is
manufactured
Dendreon
Day 3-4
Patient is infused
Doctor’s Office
COMPLETE COURSE OF THERAPY:
Weeks 0, 2, 4
Provenge Summary
• First active immunotherapy to demonstrate
improvement in overall survival for prostate cancer
• Favorable benefit to risk profile
• Short duration of therapy
• Problems: Compared to placebo and not to
chemotherapy, (docetaxel was compared to
mitoxantrone). Easier to show benefit.
• Fairly cumbersome, with pheresis.
• No data regarding palliation, and worrisome that no
improvement in time to objective progression.
• Represents another therapy in the armamentarium
against prostate cancer.
What Next After Docetaxel Failure?
• Usually treat for symptom progression and not by
PSA
• Look for clinical trials of novel agents
• Cabazitaxel prolongs life span after docetaxel therapy
• FDA approved for use after docetaxel therapy.
• Side effects similar to docetaxel therapy with
infection, tiredness, nausea, being the most likely.
• Long term benefit is being evaluated.
Persistent hormone sensitivity
• 10% of circulating testosterone remains after
conventional hormone therapy
• Conversion of adrenal hormones to testosterone
• Testosterone persists in prostate cancer
microenvironment
• Androgen receptor upregulation
• Cyp17A, the enzyme that converts adrenal steroids to
androgen is overexpressed in advanced prostate cancer
and in bone biopsies from metastatic sites.
• Hence cancer remains androgen dependent.
Abiraterone
• Oral Cyp-17 A inhibitor
• Efficacy noted in phase I and II trials with responses
in pretreated metastatic CRPC.
• Tolerable medication.
• Phase III study almost completed, of abiraterone vs
placebo in patients with met CRPC after
chemotherapy.
• Proposed trial is evaluating the role of abiraterone in
metastatic CRPC, prior to chemo, asymptomatic or
mildly symptomatic.
Study Design
• 1:1 randomization of abiraterone + prednisone vs
prednisone + placebo.
• Progression based on scans, symptoms and PSA.
• Primary endpoint is OS
• Secondary is rPFS, toxicity, correlates such as
Circulating tumor cells and TMPRSS-2 gene.
• Time to opiate administration, time to chemo will also
be evaluated.
• Sample size:1000 pts nationwide, study complete
The Effects of MDV3100 on the
Androgen Receptor Are Distinct from Bicalutamide
LBD
HSP 90
1. AR Binding Affinity
Ligand
1
HD
DBD
•
•
•
DHT
~ 5nM
Bicalutamide ~160 nM
MDV3100
~35 nM
2. Nuclear Import
•
•
•
NTD
2
DHT:
Bicalutamide:
MDV3100:
++++
++++
++
3. DNA Binding
•
•
•
4
DHT:
Bicalutamide:
MDV3100:
++++
++
-
POL II
3
DNA
Chen, Clegg and Scher
Waterfall Plot of Best Percent PSA Change from
Baseline
Chemotherapy-Naïve (N=65)
62% (40/65)
>50% Decline
Post-Chemotherapy (N=75)
51% (38/75)
>50% Decline
AFFIRM
Phase 3 Registration Trial of MDV3100 in
Post-Chemotherapy CRPC Patients
2
MDV3100 QD
R
1
Placebo QD
Primary Endpoint: 25% survival increase (12 to 15 months)
Sample size:
~1170 (780 and 390)
Statistics:
85% Power; p=0.05, two-sided
Scher, H. (North America) and De Bono, J. Co-PI, Medivation
Managing Hormone Sensitive, NonMetastatic Prostate Cancer
No standard approved therapy
Clinical trials offer the best therapy in this
setting.
Consider very carefully the risks vs benefits
PSA Relapse Non-metastatic
Prostate Cancer
• Rapidly growing population
• Guidelines for therapy not completely established
• Based on patient age, comorbid conditions, prior
therapy etc.
• Start hormone therapy early but not too early!
• Retrospective study reveals that patients with PSA
doubling time <12 months and high Gleason score
have longer survival if hormones started when
PSA<5ng/ml
• Studies of adding chemotherapy early for high-risk
patients are ongoing
Moul et al. Urologic Oncology:Sem and Original Investigations, 21; 292-304, 2003
Non metastatic PSA only prostate
cancer: Principles of management
• PSA rising
• No spread visualized on CT scans and bone scan.
• Consider multiple PSA levels and the rate of rise over
time.
• The actual value of PSA is not as important as the rate
of rise; for instance a PSA rise from 38 to 40 to 45 in
6 months is less worrisome than a rise from 5 to 10 to
20 in 6 months.
• PSA produces “Prostate Specific Anxiety” but
otherwise the disease is not bothersome.
• No therapy has proven benefit.
Non metastatic PSA only prostate
cancer: Principles of management
•
•
1)
2)
•
1)
2)
3)
Secondary hormone therapies sometimes work, even
for long periods of time; that would be standard
therapy.
Caution about doing chemotherapy since:
Risks are higher
No proven benefit
Considering clinical trials
Look at side effects very carefully
Look at how much this will impact your daily life
Consider some of the background research done on
the agent
Conclusions
• Metastatic disease: Back to hormone
therapy with androgen receptor antagonist
agents.
• Immunotherapy such as Provenge is
showing promise but cumbersome and
expensive.
• More chemotherapy options to prolong life
and improve quality of life and pain control.
“Fighting Cancer: It’s All We Do.”™