Transcript Monday Night with Research To Practice: An 8

Monday Night with Research To
Practice: An 8-Part Live CME
Webcast Series
Part VIII: Management of Advanced
Prostate Cancer
Monday, November 8, 2010
7:30 PM - 8:30 PM ET
Copyright © 2010, Research To Practice, All rights reserved.
Daniel J George, MD
Associate Professor of Medicine and Surgery
Director of Genitourinary Oncology
Duke Medical Center
Durham, North Carolina
William K Oh, MD
Chief, Division of Hematology and Medical Oncology
Professor of Medicine and Urology
Ezra M Greenspan, MD Professor in Clinical Cancer
Therapeutics, Mount Sinai School of Medicine
Associate Director of Clinical Research
The Tisch Cancer Institute
New York, New York
Neil Love, MD
Moderator
Research To Practice
Miami, Florida
Disclosures for Moderator Neil Love, MD
Dr Love is president and CEO of Research To Practice, which
receives funds in the form of educational grants to develop CME
activities from the following commercial interests: Abraxis
BioScience Inc, a wholly owned subsidiary of Celgene Corporation,
Allos Therapeutics, Amgen Inc, AstraZeneca Pharmaceuticals LP,
Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx
Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim
Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene
Corporation, Cephalon Inc, Dendreon Corporation, Eisai Inc, EMD
Serono Inc, Genentech BioOncology, Genomic Health Inc, Lilly
USA LLC, Millennium Pharmaceuticals Inc, Myriad Genetics Inc,
Novartis Pharmaceuticals Corporation, OSI Oncology, SanofiAventis and Spectrum Pharmaceuticals Inc.
Disclosures for Daniel J George, MD
Advisory Committee
Novartis Pharmaceuticals Corporation,
Pfizer Inc
Consulting
Agreements
Genentech BioOncology, Novartis
Pharmaceuticals Corporation, Pfizer Inc,
Roche Laboratories Inc
Speakers Bureau
Genentech BioOncology, Novartis
Pharmaceuticals Corporation, Pfizer Inc,
Sanofi-Aventis
Disclosures for William K Oh, MD
Consulting
Agreements
Amgen Inc, Medivation, Poniard
Pharmaceuticals
Data and Safety
Monitoring Board
Pfizer Inc
With permission from Longo DL.
N Engl J Med 2010;363(5):479-81.
Copyright © 2010 Massachusetts Medical
Society. All rights reserved.
Approximately how many new patients with
prostate cancer came to your practice in the
past year with the following?
Median
Symptomatic
metastatic PCa
11
Asymptomatic
metastatic PCa
10
9
PSA-only recurrence
Other
3
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
Median Number of Patients in Your Practice
Over the Last Year
38
New patients with PCa
Deaths from PCa
5
Deaths of other causes
in patients with PCa
5
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
Case History: Dr Oh
•
2006: A 75-year-old man with locally-advanced PCa
(Gleason 8, PSA 10 ng/ml)
– Patient is in good health
1) What is this patient’s life expectancy without
prostate cancer?
80
4%
82
29%
85
44%
15%
87
89
4%
≥90
4%
0%
10%
20%
30%
40%
50%
Management of Prostate Cancer in
Older Men: Recommendations of a
Working Group of the International
Society of Geriatric Oncology
Droz JP et al.
BJU Int 2010; 106(4):462-9.
Copyright © 2010, Research To Practice, All rights reserved.
Life Expectancy in Older Men According to
Health Status
88
Age = 70
90.8
82.4
Age = 80
86.7
76.7
70
75
83.3
80
85
90
95
80
85
90
89.2
92.9
84.3
Age = 75
Age = 85
79.9
75
80
95
89.7
87.2
85
90
95
85
Life expectancy, years
Top 25th percentile (healthy)
50th percentile (median)
Walter LC, Covinsky KE. JAMA 2001;285:2750-6.
90
95
Life expectancy, years
Lowest 25th percentile (frail)
Intergroup Randomized Phase III Study
of Androgen Deprivation Therapy
(ADT) Plus Radiation Therapy (RT) in
Locally Advanced Prostate Cancer
(CaP) (NCIC-CTG, SWOG, MRC-UK,
INT: T94-0110; NCT00002633)
Warde PR et al.
Proc ASCO 2010;Abstract CRA4504.
Copyright © 2010, Research To Practice, All rights reserved.
Efficacy and Late Toxicity of ADT versus RT +
ADT
ADT
(n = 602)
ADT + RT
(n = 603)
Hazard
ratio
p-value
7-year overall survival
66%
74%
0.77
0.0331
7-year disease-specific survival
79%
90%
0.57
0.001
Efficacy
Late Toxicity
ADT
RT + ADT
Grade < 2
Grade > 3
Grade < 2
Grade > 3
Diarrhea
8%
0.7%
14%
1.3%
Rectal bleeding
5%
0.5%
12%
0.3%
Genitourinary
42%
2.3%
44%
2.3%
Warde PR et al. Proc ASCO 2010;Abstract CRA4504.
2) What duration of hormonal therapy would
you recommend?
Three months
1%
Six months
17%
Nine months
6%
One year
21%
18 months
6%
Two years
45%
4%
Other
0%
10%
20%
30%
40%
50%
Case History: Dr Oh (case continued)
•
Patient receives leuprolide x 9 months
•
2009: PSA recurrence
•
Multiple hormonal therapies, including ketoconazole
•
Rising PSA, intermittent hematuria and bulky pelvic
lymphadenopathy causing ureteral obstruction
3) In addition to possible local treatment for ureteral
obstruction, what systemic treatment would you
generally recommend at this time, assuming the
patient is not eligible for a clinical trial?
Observation
3%
Docetaxel-based
regimen
81%
Cabazitaxel-based
regimen
6%
Mitoxantrone-prednisone
4%
6%
Sipuleucel-T
Other
0%
0%
20%
40%
60%
80%
100%
Case History: Dr Oh (case continued)
•
Patient receives weekly docetaxel
– Amelioration of symptoms, but PSA increased
to 628 ng/ml
•
Aug 2010, cabazitaxel started
– After 3 cycles, PSA decreased to 579 ng/ml
– Fatigue responsive to methylphenidate
– Nausea responsive to pretreatment with aprepitant and
ondansetron
I have an 80-year-old patient with metastatic
prostate cancer to the thoracic spine only s/p
RT for symptomatic disease with good results.
The patient is given a trial of ketoconazole.
What would be your next step after
ketoconazole failure and when would you start
chemotherapy?
I have an 82-year-old patient who is otherwise
healthy following one year of testosterone
suppression on a GnRH agonist and
bicalutamide. He is asymptomatic and had a
negative bone scan. His PSA is rising and
doubling every 4 months.
Should I consider sipuleucel-T or abiraterone
acetate?
I have a 76-year-old patient with extensive
bone metastases from hormone-refractory
prostate cancer with a PSA of 362 ng/ml who
has docetaxel and cabazitaxel failure?
What treatment should be considered?
Castration Resistant Prostate Cancer:
Treatment Options
CRPC (No metastasis)
CRPC (M1; Initial Therapy)
Observation
Anti-androgen withdrawal
Secondary ADT
• Anti-androgen
• Adrenal enzyme inhibitor
• Estrogen therapy
Docetaxel-based regimen
Sipuleucel-T
Mitoxantrone-prednisone
Secondary ADT
• Anti-androgen
• Adrenal enzyme inhibitor
• Estrogen therapy
CRPC (M1; Later line therapy)
Best supportive care
Cabazitaxel-prednisone
Mitoxantrone-prednisone
ADT = Androgen Deprivation Therapy
CRPC = Castration-Resistant Prostate Cancer
M1= Positive Metastasis
Taxanes for Metastatic Prostate Cancer
Docetaxel
FDA Indication: In combination with prednisone for the treatment of patients
with androgen independent (hormone refractory) metastatic prostate cancer.
Dose: 75 mg/m2 q-3 wks. Prednisone 5 mg PO BID continuously.
Cabazitaxel
FDA Indication: In combination with prednisone for hormone-refractory
metastatic prostate cancer prior treatment with docetaxel.
Dose: 25 mg/m2 q-3 wks. Prednisone 10 mg PO daily.
Docetaxel plus Prednisone or
Mitoxantrone plus Prednisone for
Advanced Prostate Cancer
Tannock IF et al.
N Engl J Med 2004;351(15):1502-12.
Copyright © 2010, Research To Practice, All rights reserved.
Efficacy of Docetaxel-Prednisone in Initial
Therapy of Castrate-Resistant Prostate Cancer
MitoxantronePrednisone
(n = 337)
Weekly
DocetaxelPrednisone
(n = 334)
Three-Weekly
DocetaxelPrednisone
(n = 335)
Median Survival
16.5 months
17.4 months
18.9 months
Updated Median
Survival1
16.3 months
17.8 months
19.2 months
PSA-Response
32%
48%
45%
Pain-Response
22%
31%
35%
Improved QoL
13%
23%
22%
1Berthold
DR et al. J Clin Oncol 2008;26(8):242-5
Tannock IF et al. N Engl J Med 2004;351(15):1502-12.
Phase II Study of Docetaxel Re-treatment
in Docetaxel-Pretreated CastrationResistant Prostate Cancer
Di Lorenzo G et al.
BJU Int 2010 [Epub ahead of print].
Docetaxel — Rechallenge at PSA Relapse
after Docetaxel Chemotherapy at Hormone
Refractory Prostate Cancer
Firek P et al.
Proc AUA 2010;Abstract 673.
Copyright © 2010, Research To Practice, All rights reserved.
Efficacy of Docetaxel Re-treatment in
Docetaxel-Pretreated CRPC
PSA-Response1
1Di
Median Progression-Free Survival
5 months
Median Overall Survival
13 months
PSA-Response2 (All Responders
to 1st-Line Docetaxel)
65%
Median Progression-Free Survival
6.2 months
Median Overall Survival
15.3 months
Lorenzo G et al. BJU Int 2010 [Epub ahead of print].
P et al. Proc AUA 2010;Abstract 673.
2Firek
24.5%
Approximately what percent of your patients with
prostate cancer who receive docetaxel experience the
following in terms of side effects?
“Cruise through” —
minimal/no problems
42%
Problems requiring
management, not
enough to stop
or alter treatment
Significant problems
requiring dose
modification or
discontinuation
39%
19%
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
Approximately what percent of your patients with
prostate cancer who receive docetaxel experience the
following in terms of tumor response?
Beneficial, prolonged
tumor response
45%
Modest tumor
response but
clear-cut benefit
No response or
clinically insignificant
response
30%
25%
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
Approximately what percent of your patients with
prostate cancer who receive docetaxel experience the
following impact on QOL?
Improvements
44%
33%
No change
Decrease
23%
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
Cabazitaxel: A novel taxoid developed to overcome drug resistance.
One mechanism of taxane resistance is overexpression of the Pgp drug
efflux pump, which expels first-generation taxanes.
Cabazitaxel: Designed to be a poor substrate to the Pgp efflux pump.
Cabazitaxel: Less likely to be expelled than first-generation taxanes.
Prednisone plus Cabazitaxel or
Mitoxantrone for Metastatic CastrationResistant Prostate Cancer Progressing
After Docetaxel Treatment: A
Randomised Open-Label Trial
de Bono JS et al.
Lancet 2010;376(9747):1147-54.
Copyright © 2010, Research To Practice, All rights reserved.
Efficacy of Cabazitaxel in Second-Line CastrateResistant Prostate Cancer
MitoxantronePrednisone
(n = 377)
CabazitaxelPrednisone
(n = 378)
Hazard Ratio
p-value
Median Survival
12.7 months
15.1 months
0.70
< 0.0001
Median PFS
1.4 months
2.8 months
0.74
< 0.0001
RECIST
Response Rate
4.4%
14.4%
0.0005
PSA-Response
17.8%
39.2%
0.0002
Time to Tumor
Progression
5.4 months
8.8 months
de Bono JS et al. Lancet 2010;376(9747):1147-54.
0.61
< 0.0001
Safety of Cabazitaxel in Second-Line CastrateResistant Prostate Cancer
MitoxantronePrednisone
(n = 371)
CabazitaxelPrednisone
(n = 371)
Grade ≥ 3 Neutropenia
58%
82%
Febrile Neutropenia
1%
8%
Grade ≥ 3 Anemia
5%
11%
Grade ≥ 3 Thrombocytopenia
2%
4%
Grade ≥ 3 Diarrhea
< 1%
6%
Grade ≥ 3 Nausea
< 1%
2%
Grade ≥ 3 Vomiting
0%
2%
Grade ≥ 3 Pain
2%
1%
de Bono JS et al. Lancet 2010;376(9747):1147-54.
Have you administered cabazitaxel to a patient
in your practice (on or off protocol)?
Yes
I am not familiar
with this agent
42%
8%
What is your perception regarding how cabazitaxel
compares to docetaxel?
Efficacy
Tolerability
Equal
30%
39%
Cabazitaxel better
41%
24%
Docetaxel better
2%
17%
I don’t know
27%
20%
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
I have a 64-year-old patient with Gleason 4+4=8 PCa, which
occupied the entire right lobe and part of the right seminal
vesicle. He was treated with conformal radiation therapy 3.5
years ago and zoledronic acid every 3 months for 2 years. PSA
after RT was 0.01 ng/ml.
Due to cognitive difficulties, he elected to discontinue the
zoledronic acid and declined further systemic therapy unless he
had recurrent disease. His PSA began to rise after stopping
therapy. Yearly bone scans have been negative. PET/CT
performed at the end of 2007 was normal. MSCT performed in
2007 and 2010 did not reveal any abnormalities.
By September 2010, his PSA is 0.2 ng/ml. He has urinary
urgency after 3-4 hours and urinates 1-2 times per night.
Since his prostate is still in place, is a PSA of 0.2 ng/ml
dangerous or could it be attributed directly to known
prostate hypertrophy? Is treatment necessary? If so, what
treatment options are available?
— Egidio Cepulic
Case History: Dr George
•
A 62-year-old man presents with dysuria, a weak urine stream
and an enlarged prostate
•
PSA: 35 ng/ml
•
Biopsies: 4 + 4 = 8 Gleason score
•
Bone scan: Uptake in the left sacroiliac region consistent with
metastasis
•
Treated with androgen deprivation therapy (leuprolide)
– PSA declines to 0.4 ng/ml after 8 months
(testosterone < 20 ng/dl)
•
Two years later PSA rises to 6.5 ng/ml
•
Bicalutamide stopped and PSA rises to 8 ng/ml 6 weeks later
•
Patient remains asymptomatic
4) How would you classify this patient’s
endocrine status?
Castration-resistant
37%
Castration-resistant
and androgen
insensitive
37%
Androgen insensitive
20%
None of the above
6%
0%
5%
10%
15%
20%
25%
30%
35%
40%
There is a clinically meaningful difference
between androgen-independent PCa and
castration-resistant PCa.
Agree
40%
42%
Disagree
12%
In between
I’m not sure
6%
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
Case History: Dr George (case continued)
• A restaging bone scan reveals new lesions in the 3rd
rib and right scapula
– Patient is asymptomatic
5) What would you generally recommend for
this patient (in addition to bisphosphonate)?
None
24%
Secondary hormonal agent
(eg, ketoconazole,
DES, nilutamide)
37%
17%
Sipuleucel-T
Docetaxel regimen
15%
Cabazitaxel regimen
4%
3%
Other
0%
5%
10%
15%
20%
25%
30%
35%
40%
Case History: Dr George (case continued)
•
The patient is started on zoledronic acid and placed on a
waiting list for sipuleucel-T
•
Three months later the patient receives 3 doses of
sipuleucel-T x 3 doses two weeks apart
– Tolerates therapy well, except for transient fever, chills
and back pain
•
Returns to the clinic after 4 weeks with PSA = 18 ng/ml
– Remains asymptomatic
Available Agents for Castrate-Resistant
Prostate Cancer (continued)
Sipuleucel-T
Autologous cellular immunotherapy
FDA Indication
Treatment of asymptomatic or minimally symptomatic metastatic
castrate-resistant (hormone-refractory) prostate cancer
Recommended Administration
Three doses approximately every 2 weeks, over approximately 1 hour
Premedication
Acetaminophen, antihistamine
Each dose contains a minimum of 50 x 106 autologous CD54+ cells
activated with PAP-GM-CSF, suspended in 250 ml of Ringer’s Lactate
Sipuleucel-T: Mechanism of Action
Antigen (PAP-GMCSF) 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
Courtesy of Philip Kantoff, MD
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
Courtesy of Philip Kantoff, MD
COMPLETE COURSE OF THERAPY:
Weeks 0, 2, 4
Are you familiar with sipuleucel-T?
96%
Yes
Which patients, if any, would you consider for treatment
with sipuleucel-T? (may choose more than one)
None
6%
Select pts with PSA-only
recurrent disease
27%
Select pts with asymptomatic
metastatic PCa
67%
Select pts with symptomatic
metastatic PCa
I’m not sure
21%
2%
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
Assuming you had access to sipuleucel-T,
moving forward, how would you plan to
incorporate it into the treatment algorithm?
Generally before chemo
with chemo to follow
immediately
14%
Generally before chemo
with chemo to follow on
disease progression
58%
23%
Generally after chemo
I’m not sure
5%
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
Sipuleucel-T Immunotherapy for
Castration-Resistant Prostate Cancer
Kantoff PW et al.
N Engl J Med 2010;363(5):411-22.
Copyright © 2010, Research To Practice, All rights reserved.
Efficacy of Sipuleucel-T in Castrate-Resistant
Prostate Cancer
Placebo
(n = 171)
Sipuleucel-T
(n = 341)
Hazard Ratio
p-value
Median Survival
21.7 months
25.8 months
0.78
0.03
3-Year Survival
23.0%
31.7%
NR
NR
PSA-Response
1.3%
2.6%
NR
NR
Time to DiseaseProgression
3.6 months
3.7 months
0.95
NS
Time to
Docetaxel Use
13.9 months
12.3 months
NR
NR
NR = Not Reported, NS = Non-Significant
Kantoff PW et al. N Engl J Med 2010;363(5):411-22.
Select Safety Events with Sipuleucel-T in
Castrate-Resistant Prostate Cancer
Placebo
(n = 168)
Sipuleucel-T
(n = 338)
Chills
All Grade
Grade 3-5
12.5%
0%
54.1%
1.2%
Pyrexia
All Grade
Grade 3-5
13.7%
1.8%
29.3%
0.3%
Headache
All Grade
Grade 3-5
4.8%
0%
16.0%
0.3%
Influenza-Like Illness
All Grade
Grade 3-5
3.6%
0%
9.8%
0%
Kantoff PW et al. N Engl J Med 2010;363(5):411-22.
Predictors of Outcome and
Subgroup Results from the
Integrated Analysis of Sipuleucel-T
Trials in Metastatic CastrationResistant Prostate Cancer
Higano CS et al.
Proc ASCO 2010;Abstract 4550.
Copyright © 2010, Research To Practice, All rights reserved.
Predictors of Outcome in Sipuleucel-T Trials in
Metastatic CRPC
Treatment Effect of Sipuleucel-T in the Integrated Analysis of the
Three Trials
Hazard Ratio
p-value
0.735
< 0.001
A positive treatment effect (HR<1) was observed in all subgroups representing
≥10% of patients, including those defined by age, race, ECOG performance
status, number of bone metastases, and previous chemotherapy use.
Higano CS et al. Proc ASCO 2010;Abstract 4550.
Persistence of Immunotherapy
Survival Effects of Sipuleucel-T and
Relationship to Post-Randomization
Docetaxel Use in Phase III Studies
Petrylak DP et al.
Proc ASCO 2010;Abstract 4551.
Copyright © 2010, Research To Practice, All rights reserved.
Integrated Analysis of the Effect of PostRandomization Docetaxel Use on Overall Survival
Hazard Ratio with
Sipuleucel-T Use
p-value
All Randomized Patients (n = 737)
0.735
< 0.001
Analysis of Patients Censored at Time of
Docetaxel Use
0.714
0.006
Post-Randomization Docetaxel Use
(n = 363)
0.825
Significant1
No Docetaxel Use Post-Randomization
(n = 374)
0.693
Significant1
1 Actual
p-values not reported; however, abstract states that difference is significant
Petrylak DP et al. Proc ASCO 2010;Abstract 4551.
Correlation Between Product
Parameters and Overall Survival in
Three Trials of Sipuleucel-T, an
Autologous Active Cellular
Immunotherapy for the Treatment
of Prostate Cancer
Stewart FP et al.
Proc ASCO 2010;Abstract 4552.
Copyright © 2010, Research To Practice, All rights reserved.
Correlation Between Product Parameters and
Overall Survival in Sipuleucel-T Trials
p-value
Cell Product Parameter
Unadjusted
(N = 476)
Adjusted for PSA
and LDH (N = 476)
Cumulative TNC (x 109)
< 0.001
< 0.001
Cumulative CD54+ cell count (x 109)
0.016
0.005
Cumulative CD54 upregulation
0.002
0.041
TNC = Total Nucleated Cells
There was a significant correlation between OS and each of the three cell product
parameters, which appeared to be independent of baseline prognostic factors.
These data support the conclusion that broad engagement of the immune system
contributes to the sipuleucel-T survival findings.
Stewart FP et al. Proc ASCO 2010;Abstract 4552.
Significant and Sustained Antitumor Activity in
Post-Docetaxel, Castration-Resistant Prostate
Cancer with the CYP17 Inhibitor Abiraterone Acetate
Reid AH et al.
J Clin Oncol 2010;28(9):1489-95.
Phase II Multicenter Study of Abiraterone Acetate
plus Prednisone Therapy in Patients with DocetaxelTreated Castration-Resistant Prostate Cancer
Danila DC et al.
J Clin Oncol 2010;28(9):1496-501.
Copyright © 2010, Research To Practice, All rights reserved.
Abiraterone Acetate (AA) Plus Low Dose
Prednisone (P) Improves Overall Survival (OS)
in Patients (Pts) with Metastatic CastrationResistant Prostate Cancer (MCRPC) Who
Have Progressed After Docetaxel-Based
Chemotherapy (Chemo): Results of COU-AA301, A Randomized Double-Blind PlaceboControlled Phase III Study
de Bono JS et al.
Proc ESMO 2010;Abstract LBA5.
Copyright © 2010, Research To Practice, All rights reserved.