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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.