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Copyright © 2010, Research To Practice, All rights reserved.
Part VIII: Management of Advanced Prostate Cancer Monday, November 8, 20107:30 PM - 8:30 PM ET
Monday Night with Research To Practice: An 8-Part Live CME Webcast Series
Daniel J George, MDAssociate Professor of Medicine and SurgeryDirector of Genitourinary OncologyDuke Medical CenterDurham, North Carolina
William K Oh, MDChief, Division of Hematology and Medical OncologyProfessor of Medicine and UrologyEzra M Greenspan, MD Professor in Clinical Cancer Therapeutics, Mount Sinai School of MedicineAssociate Director of Clinical ResearchThe Tisch Cancer InstituteNew York, New York
Neil Love, MDModeratorResearch To PracticeMiami, 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, Sanofi-Aventis and Spectrum Pharmaceuticals Inc.
Disclosures for Daniel J George, MD
Advisory CommitteeNovartis Pharmaceuticals Corporation, Pfizer Inc
Consulting Agreements
Genentech BioOncology, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche Laboratories Inc
Speakers BureauGenentech 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?
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
3
9
10
11Symptomatic
metastatic PCa
Asymptomatic metastatic PCa
PSA-only recurrence
Other
Median
Median Number of Patients in Your Practice Over the Last Year
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
5
5
38New patients with PCa
Deaths from PCa
Deaths of other causes in patients with PCa
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?
4%
4%
15%
44%
29%
4%
0% 10% 20% 30% 40% 50%
80
82
85
87
89
≥90
Copyright © 2010, Research To Practice, All rights reserved.
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.
87.2
89.7
92.9
85 90 95
Age = 85
Life Expectancy in Older Men According to Health Status
Walter LC, Covinsky KE. JAMA 2001;285:2750-6.
Top 25th percentile (healthy) 50th percentile (median) Lowest 25th percentile (frail)
Life expectancy, years
83.3
86.7
90.8
80 85 90 95
Age = 80
76.7
82.4
88
70 75 80 85 95
Age = 70
79.9
84.3
89.2
75 80 85 90 95
Age = 75
90
Life expectancy, years
Copyright © 2010, Research To Practice, All rights reserved.
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.
Efficacy and Late Toxicity of ADT versus RT + ADT
EfficacyADT
(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
Warde PR et al. Proc ASCO 2010;Abstract CRA4504.
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%
2) What duration of hormonal therapy would you recommend?
4%
45%
6%
21%
6%
17%
1%
0% 10% 20% 30% 40% 50%
Three months
Six months
Nine months
One year
18 months
Two years
Other
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?
6%
4%
6%
81%
3%
0%
0% 20% 40% 60% 80% 100%
Observation
Docetaxel-based regimen
Cabazitaxel-based regimen
Mitoxantrone-prednisone
Sipuleucel-T
Other
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)
ObservationAnti-androgen withdrawalSecondary ADT• Anti-androgen• Adrenal enzyme inhibitor• Estrogen therapy
CRPC (M1; Initial Therapy)
Docetaxel-based regimenSipuleucel-TMitoxantrone-prednisoneSecondary ADT• Anti-androgen• Adrenal enzyme inhibitor• Estrogen therapy
CRPC (M1; Later line therapy)
Best supportive careCabazitaxel-prednisoneMitoxantrone-prednisone
ADT = Androgen Deprivation TherapyCRPC = Castration-Resistant Prostate CancerM1= 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.
Copyright © 2010, Research To Practice, All rights reserved.
Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer
Tannock IF et al.N Engl J Med 2004;351(15):1502-12.
Efficacy of Docetaxel-Prednisone in Initial Therapy of Castrate-Resistant Prostate Cancer
Tannock IF et al. N Engl J Med 2004;351(15):1502-12.
Mitoxantrone-Prednisone
(n = 337)
Weekly Docetaxel-Prednisone
(n = 334)
Three-Weekly Docetaxel-
Prednisone (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
Copyright © 2010, Research To Practice, All rights reserved.
Phase II Study of Docetaxel Re-treatment in Docetaxel-Pretreated Castration-Resistant Prostate CancerDi 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.
Efficacy of Docetaxel Re-treatment in Docetaxel-Pretreated CRPC
1Di Lorenzo G et al. BJU Int 2010 [Epub ahead of print].2Firek P et al. Proc AUA 2010;Abstract 673.
PSA-Response1 24.5%
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
Approximately what percent of your patients with prostate cancer who receive docetaxel experience the following in terms of side effects?
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
19%
39%
42%“Cruise through” —
minimal/no problems
Problems requiring management, not
enough to stopor alter treatment
Significant problems requiring dose
modification or discontinuation
Approximately what percent of your patients with prostate cancer who receive docetaxel experience the following in terms of tumor response?
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
25%
30%
45%Beneficial, prolonged
tumor response
Modest tumor response but
clear-cut benefit
No response or clinically insignificant
response
Approximately what percent of your patients with prostate cancer who receive docetaxel experience the following impact on QOL?
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
23%
33%
44%Improvements
No change
Decrease
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.
Copyright © 2010, Research To Practice, All rights reserved.
Prednisone plus Cabazitaxel or Mitoxantrone for Metastatic Castration-Resistant Prostate Cancer Progressing After Docetaxel Treatment: A Randomised Open-Label Trial
de Bono JS et al.Lancet 2010;376(9747):1147-54.
Efficacy of Cabazitaxel in Second-Line Castrate- Resistant Prostate Cancer
de Bono JS et al. Lancet 2010;376(9747):1147-54.
Mitoxantrone-Prednisone
(n = 377)
Cabazitaxel- Prednisone
(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 0.61 < 0.0001
Safety of Cabazitaxel in Second-Line Castrate- Resistant Prostate Cancer
de Bono JS et al. Lancet 2010;376(9747):1147-54.
Mitoxantrone-Prednisone
(n = 371)
Cabazitaxel- Prednisone
(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%
Have you administered cabazitaxel to a patient in your practice (on or off protocol)?
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
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%
8%42%Yes
I am not familiar with this agent
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?
6%
20%
37%
37%
0% 5% 10% 15% 20% 25% 30% 35% 40%
Castration-resistant
Castration-resistant and androgen
insensitive
Androgen insensitive
None of the above
There is a clinically meaningful difference between androgen-independent PCa and castration-resistant PCa.
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
6%
12%
42%
40%Agree
Disagree
I’m not sure
In between
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)?
3%
4%
15%
17%
37%
24%
0% 5% 10% 15% 20% 25% 30% 35% 40%
None
Secondary hormonal agent (eg, ketoconazole,
DES, nilutamide)
Sipuleucel-T
Docetaxel regimen
Cabazitaxel regimen
Other
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-TAutologous cellular immunotherapy
FDA IndicationTreatment of asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer
Recommended Administration Three doses approximately every 2 weeks, over approximately 1 hour
PremedicationAcetaminophen, 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
Courtesy of Philip Kantoff, MD
INFUSE PATIENT
Sipuleucel-T activates T-cells in the body
APC takes up the antigen
Antigen (PAP-GM-CSF) is exposed to an antigen presenting cell (APC)
Fully activated, the APC is now sipuleucel-T and is collected
Antigen is processed and presented on surface of the APC
T-cells proliferate and attack cancer cells
Sipuleucel-T: Logistics of Therapy
Day 1Leukapheresis
Day 2-3Sipuleucel-T is manufactured
Day 3-4Patient is infused
Apheresis Center Central Processing Doctor’s Office
COMPLETE COURSE OF THERAPY:Weeks 0, 2, 4
Courtesy of Philip Kantoff, MD
Are you familiar with sipuleucel-T?
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
Which patients, if any, would you consider for treatment with sipuleucel-T? (may choose more than one)
2%
21%
67%
27%
6%None
Select pts with PSA-only recurrent disease
Select pts with symptomatic metastatic PCa
Select pts with asymptomatic metastatic PCa
96%Yes
I’m not sure
Assuming you had access to sipuleucel-T, moving forward, how would you plan to incorporate it into the treatment algorithm?
Patterns of Care Survey of US-Based Practicing Oncologists (n = 50), 2010.
5%
23%
58%
14%Generally before chemo
with chemo to follow immediately
Generally before chemo with chemo to follow on
disease progression
I’m not sure
Generally after chemo
Copyright © 2010, Research To Practice, All rights reserved.
Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer
Kantoff PW et al.N Engl J Med 2010;363(5):411-22.
Efficacy of Sipuleucel-T in Castrate-Resistant Prostate Cancer
Kantoff PW et al. N Engl J Med 2010;363(5):411-22.
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 Disease-Progression
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
Select Safety Events with Sipuleucel-T in Castrate-Resistant Prostate Cancer
Kantoff PW et al. N Engl J Med 2010;363(5):411-22.
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%
Copyright © 2010, Research To Practice, All rights reserved.
Predictors of Outcome and Subgroup Results from the Integrated Analysis of Sipuleucel-T Trials in Metastatic Castration-Resistant Prostate CancerHigano CS et al.Proc ASCO 2010;Abstract 4550.
Predictors of Outcome in Sipuleucel-T Trials in Metastatic CRPC
Higano CS et al. Proc ASCO 2010;Abstract 4550.
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.
Copyright © 2010, Research To Practice, All rights reserved.
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.
Integrated Analysis of the Effect of Post-Randomization Docetaxel Use on Overall Survival
Petrylak DP et al. Proc ASCO 2010;Abstract 4551.
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
Copyright © 2010, Research To Practice, All rights reserved.
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.
Correlation Between Product Parameters and Overall Survival in Sipuleucel-T Trials
Stewart FP et al. Proc ASCO 2010;Abstract 4552.
Cell Product Parameter
p-value
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.
Copyright © 2010, Research To Practice, All rights reserved.
Significant and Sustained Antitumor Activity inPost-Docetaxel, Castration-Resistant ProstateCancer 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 Docetaxel-Treated 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 Castration-Resistant Prostate Cancer (MCRPC) Who Have Progressed After Docetaxel-Based Chemotherapy (Chemo): Results of COU-AA-301, A Randomized Double-Blind Placebo-Controlled Phase III Studyde Bono JS et al.Proc ESMO 2010;Abstract LBA5.