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Prostate Cancer 2011-How Clinical Trials Have Led to New Options for Patients

Prostate Cancer 2011-How Clinical Trials Have Led to New Options for Patients. Philip Kantoff MD Chief, Division of Solid Tumor Oncology Dana-Farber Cancer Institute Professor of Medicine Harvard Medical School. Background. 220,000 men diagnosed with prostate cancer in 2010 in US

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Prostate Cancer 2011-How Clinical Trials Have Led to New Options for Patients

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  1. Prostate Cancer 2011-How Clinical Trials Have Led to New Options for Patients Philip Kantoff MD Chief, Division of Solid Tumor Oncology Dana-Farber Cancer Institute Professor of Medicine Harvard Medical School

  2. Background • 220,000 men diagnosed with prostate cancer in 2010 in US • 1 in 6 men • 32,000 men will die of prostate cancer

  3. Incidence of Prostate Cancer: Population Comparisons

  4. Outline You can prevent prostate cancer Screening saves lives Many men who are diagnosed with prostate cancer do not need to be treated Many exciting new developments-results of clinical trials

  5. Outline You can prevent prostate cancer

  6. Finasteride Chemoprevention Study (PCPT) CaP finasteride 18,000 Men>55 nl DRE and PSA<3 placebo CaP

  7. Finasteride Chemoprevention Study (PCPT)

  8. PCPT-Conclusions Finasteride reduces risk of prostate cancer Morbidity is minimal Possible and slight increase in high grade cancer in finasteride arm

  9. REDUCE Trial 8,200 men who had PSA between 2.5 ng/mL and 10 ng/mL All men had one negative prostate biopsy within six months prior to study entry. Participants were randomly assigned to dutasteride or placebo; the study mandated 10 core biopsies at two and four years. Dutasteride was associated with a 23% reduction in prostate cancer cases compared with placebo.

  10. FDA Approval of 5-ARIs? FDA advisory panel recommended against approval as chemoprevention Concern regarding increased incidence of high-grade tumors “Met an un-need”, reducing low-risk tumors 60 men would need to be treated in order for one man to avoid developing a clinically relevant prostate cancer

  11. Outline You can prevent prostate cancer Screening saves lives

  12. Does PSA based Screening Work? Does it Reduce Mortality From Prostate Cancer? ERSPC study PLCO Scandinavian study

  13. European Randomized Study of Screening for Prostate Cancer (ERSPC) NEJM 2009 162,243 men age 50 and 69 from seven different European countries starting in the early 1990s Randomly assigned to a screening group or control Men in the screening group received a PSA test an average of once every 4 years and the men in the control group did not receive PSA tests at all. Median 9 years of follow up-20% reduction in prostate cancer mortality p=0.04

  14. PLCO NEJM 2009 150,000 persons 55 to 74 years old at entry were randomized to two study arms, half to undergo cancer screening Screening was annual PSA and DRE 52% contamination Median follow-up 7 years No difference in prostate cancer mortality

  15. Göteborg randomized prostate-cancer screening trial 20,000 men randomly sampled from the population register, were randomized to either a screening group invited for PSA testing every 2 years (n=10,000) or to a control group During a median follow-up of 14 years, 1,138 men in the screening group and 718 in the control group were diagnosed with prostate cancer The risk reduction of death from prostate cancer at 14 years was 60% (p=0·0002).

  16. Conclusions Low mortality of prostate cancer in first 10 years (few events) PSA screening reduces mortality Large amount of overtreatment Seen in numerous other studies

  17. Outline You can prevent prostate cancer Screening saves lives Many men who are diagnosed with prostate cancer do not need to be treated

  18. Who should consider active surveillance-NCCN Guidelines? Men with low risk prostate cancer (Gleason 6 and PSA<10) who have a life expectancy of less than 10 years. Men with “very low risk” prostate cancer when life expectancy is less than 20 years. a Gleason score of 6 or below; a PSA < 10 and fewer than 3 positive biopsy cores (with <50% cancer in each); and a PSA density below 0.15 ng/mL per g.

  19. Outline You can prevent prostate cancer Screening saves lives Many men who are diagnosed with prostate cancer do not need to be treated Many exciting new developments-results of clinical trials

  20. Sipuleucel-T (Provenge) for Metastatic CRPC

  21. Provenge: 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 sipuleucel-T activates T-cells in the body

  22. Sipuleucel-T: Logistics of Therapy Day 2-3 sipuleucel-T is manufactured Day 3-4 Patient is infused Day 1 Leukapheresis Apheresis Center Central Processing Doctor’s Office COMPLETE COURSE OF THERAPY: Weeks 0, 2, 4 22

  23. Randomized Phase 3 IMPACT Trial(IMmunotherapy Prostate AdenoCarcinoma Treatment) P R O G R E S S I O N SURVIVAL Treated at Physician Discretion Sipuleucel-T Q 2 weeks x 3 Asymptomatic or Minimally Symptomatic mCRPC (N=512) 2:1 Treated at Physician Discretion and/or Salvage Protocol Placebo Q 2 weeks x 3 Primary Endpoint: Overall Survival Secondary Endpoint: Objective Disease Progression 23

  24. IMPACT Overall SurvivalFinal Analysis (349 events) 36.5 mo median f/u HR = 0.759(95% CI: 0.606, 0.951) p = 0.017 (Cox model) Median Survival Benefit = 4.1 months Sipuleucel-T (n = 341) Median Survival: 25.8 mo. 36 mo. survival: 32.1% Placebo (n = 171) Median Survival: 21.7 mo. 36 mo. survival: 23.0% 24 Kantoff et al

  25. Under-represented clinical trial populations • African American patient population • 5.8% of patients • Positive sipuleucel-T treatment effect in patient subgroup • AE profile comparable African American Subgroup -Overall Survival IMPACT, D9901, D9902A HR 0.288 (0.125, 0.662) 25

  26. PROSTVAC VF-Tricom

  27. Background-The Development of PROSTVAC-VF-Tricom Inactivated smallpox and fowlpox virus carrying PSA gene 27 Schlom et al

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  29. Randomized Phase II Study P R O G R E S S I O N S U R V I V A L Treated at physician discretion PROSTVAC-VF Tricom + GM Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=125) 2:1 Treated at physician discretion and/or Salvage Protocol Empty Vector + placebo Primary endpoint: Progression Free Survival Secondary endpoint: Overall Survival

  30. Overall Survival 30 Kantoff et al

  31. Newer Hormonal Agents Lyase inhibitors-block all hormone production from testicles, adrenals and from the tumor Abiraterone

  32. COU-AA-301 Phase III initiated in April 2008, enrollment completed. Abiraterone acetate, 1000 mg/day (4 x 250 mg tablets) PO, 5 mg prednisone/prednisolone BID • Post-docetaxel mCRPC • (n = 1158) R 2:1 Placebo plus 5 mg prednisone/prednisolone BID Primary endpoint is OS 32

  33. COU-AA-301: Abiraterone Acetate Improves OS in mCRPC 100 HR=0.646 (0.54-0.77) P <0.0001 Abiraterone: 14.8 months (95% CI: 14.1, 15.4) 80 60 Overall Survival, % 40 Placebo: 10.9 months (95% CI: 10.2, 12.0) 20 0 300 500 0 400 600 700 100 200 Days from Randomization

  34. Outline You can prevent prostate cancer Screening saves lives Many men who are diagnosed with prostate cancer do not need to be treated Many exciting new developments-results of clinical trials

  35. Thank you

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