copyright © 2010, research to practice, all rights reserved. part viii: management of advanced...

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


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


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


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.


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


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?


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?


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?


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.


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.


(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.


(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)?


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.


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?


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?


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


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%


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.


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


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.


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.


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.

copyright © 2010, research to practice, all rights reserved. part viii: management of advanced...

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