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YEAR IN REVIEW 2012: GU

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YEAR IN REVIEW 2012: GU

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  1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

  2. David I Quinn, MBBS, PhD Medical Director, Norris Cancer Hospital and Clinics Leader, Developmental Therapeutics Head, GU Cancer Section Division of Cancer Medicine and Blood Diseases USC/Norris Comprehensive Cancer Center YEAR IN REVIEW 2012: GU

  3. Cabozantinib has resulted in bone scan and symptom improvements in prostate cancer but no other solid tumor.

  4. Which agent are you most likely to recommend for a patient with asymptomatic metastatic prostate cancer progressing on androgen deprivation?

  5. To what extent does radium-223 chloride cause myelosuppression?

  6. Updated Analysis of the Phase III, Double-Blind, Randomized, Multinational Study of Radium‑223 Chloride in Castration-Resistant Prostate Cancer (CRPC) Patients with Bone Metastases (ALSYMPCA) Proc ASCO 2012;Abstract LBA 4512 C. Parker, S. Nilsson, D. Heinrich, J.M. O’Sullivan, S. Fosså, A. Chodacki, P. Wiechno, J. Logue, M. Seke, A. Widmark, D.C. Johannessen, P. Hoskin, D. Bottomley, R. Coleman, N. Vogelzang, C.G. O’Bryan-Tear, J. Garcia-Vargas, M. Shan, and O. Sartor

  7. Radium-223 Targets Bone Metastases • Alpha-particles induce double-strand DNA breaks in adjacent tumor cells1 • Short penetration of alpha emitters (2-10 cell diameters) = highly localized tumor cell killing and minimal damage to surrounding normal tissue 1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103.

  8. ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design STRATIFICATION PATIENTS TREATMENT 6 injections at 4-week intervals • Confirmed symptomatic CRPC • ≥ 2 bone metastases • No known visceral metastases • Post-docetaxel or unfit for docetaxel RANDOMIZED 2:1 Radium-223 (50 kBq/kg) + Best standard of care • Total ALP: < 220 U/L vs ≥ 220 U/L • Bisphosphonate use: Yes vs No • Prior docetaxel: Yes vs No Placebo (saline) + Best standard of care N = 921 Planned follow-up is 3 years Clinicaltrials.gov identifier: NCT00699751.

  9. ALSYMPCA Updated Analysis: Overall Survival 100 HR = 0.695 95% CI, 0.581, 0.832P = 0.00007 90 80 70 60 % 50 Radium-223, n = 614 Median OS: 14.9 months 40 30 20 Placebo, n = 307 Median OS: 11.3 months 10 0 With permission from Parker C et al. Proc ASCO 2012;Abstract LBA4512.

  10. ESMO 2012 – Prostate • ALSYMPCA: Radium-223 Chloride in mCRPCParker C et al. Proc ESMO 2012;Abstract 898PD. • Updated analysis substantiates Ra-223 as an effective therapy that significantly improves OS and time to first SRE, with a highly favorable safety profile • Ra-223 showed significantly better preservation of QOL, with improved functioning and well-being, compared to Pbo in pts with bone metastasis

  11. Increased Survival with Enzalutamide in Prostate Cancer After Chemotherapy Scher HI et al. N Engl J Med 2012;367(13):1187-97.

  12. AFFIRM: Interim Analysis of Enzalutamide versus Placebo in Patients with CRPC *According to radiographic evidence Scher HI et al. N Engl J Med 2012;367(13):1187-97.

  13. AFFIRM: Frequent Adverse Events More Common with Enzalutamide Seizures were reported in 5 patients (0.6%) receiving enzalutamide. Scher HI et al. N Engl J Med 2012;367(13):1187-97.

  14. Interim Analysis (IA) Results of COU-AA-302, a Randomized, Phase 3 Study of Abiraterone Acetate (AA) in Chemotherapy-Naïve Patients (pts) with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Proc ASCO 2012;Abstract LBA 4518 Charles J. Ryan, Matthew Raymond Smith, Johann Sebastian De Bono, Arturo Molina, Christopher Logothetis, Paul L. De Souza, Karim Fizazi, Paul N. Mainwaring, Jose Maria Piulats Rodriguez, Siobhan Ng, Joan Carles, Peter Mulders, Thian San Kheoh, Thomas W. Griffin, Eric Jay Small, Howard I. Scher, Dana E. Rathkopf, on behalf of the COU-AA-302 Investigators

  15. Overall Study Design of COU-AA-302 RANDOMIZED 1:1 • Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada • Stratification by ECOG performance status 0 vs 1 Efficacy end points Patients AA 1000 mg daily Prednisone 5 mg BID (Actual n = 546) • Co-Primary: • rPFS by central review • OS • Secondary: • Time to opiate use (cancer-related pain) • Time to initiation of chemotherapy • Time to ECOG-PS deterioration • TTPP • Progressive chemo-naïve mCRPC patients(Planned N = 1,088) • Asymptomatic or mildly symptomatic Placebo daily Prednisone 5 mg BID (Actual n = 542) Ryan CJ et al. Proc ASCO 2012;Abstract LBA4518.

  16. Statistically Significant Improvement in rPFS not OS 100 100 80 80 60 60 Progression-Free (%) Survival (%) 40 40 20 20 AA + P PL + P AA + P PL + P 0 0 3 6 9 12 15 18 0 0 3 6 9 12 15 18 21 24 27 30 33 Time to Progression or Death (Months) Time to Death (Months) AA PL 546 542 489 400 340 204 164 90 46 30 12 3 0 0 AA PL 546 542 538 534 524 509 503 493 482 465 452 437 412 387 258 237 120 106 27 25 0 2 0 0 Pre-specified significance level by O’Brien-Fleming Boundary = 0.0008. Data cutoff 12/20/2010. Data cutoff 12/20/2011. NR, not reached; PL, placebo; rPFS, radiographic PFS. With permission from Ryan CJ et al. Proc ASCO 2012;Abstract LBA4518.

  17. Phase III (SYNERGY) GU 68/OGX-011-11: Comparison of Standard First-Line Docetaxel/Prednisone to Docetaxel/Prednisone in Combination with Custirsen (OGX-011) in mCRPC Eligibility: Metastatic castration-resistant prostate cancer progressing while on or after androgen ablation Custirsen: • Clusterin is an antiapoptotic protein that is upregulated in response to various cell-death triggers such as chemotherapy • Custirsen is an oligonucleotide antisense to the mRNA for clusterin

  18. First-Line Use of Cabazitaxel in Chemotherapy-Naïve Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Three-Arm Study in Comparison with Docetaxel Proc ASCO 2012;Abstract TPS4696 Stephane Oudard, Lisa Sengelov, Paul N. Mainwaring, Antoine Thiery-Vuillemin, Christine Theodore, Evgeny Kulikov, Jeffrey Yachnin, Ivo Kocak, Vesa V. Kataja, Marjaana Luukkaa, Aleander Nosov, Marie Hjelm-Eriksson, Jeffrey Bubis, Liji Shen, Marie-Laure Risse, A. Oliver Sartor

  19. Phase III FIRSTANA Study (NCT01308567) RANDOMIZED 1:1:1 Efficacy end points Patients CBZ 25 mg/m2 IV Q3W Prednisone 10 mg QD • Primary: • OS • Secondary: • PCWG2 PFS • rPFS by central review • Tumor response (RECIST) • PSA response • PSA PFS • Pain response • Pain PFS • TTP SRE • QOL • Progressive chemo-naïve mCRPC patients(Planned N = 1,170) • Stratified by: • ECOG (0, 1 vs 2) • Measurable Dz • Region CBZ 20 mg/m2 IV Q3W Prednisone 10 mg QD DOC 75 mg/m2 IV Q3W Prednisone 10 mg QD CBZ = cabazitaxel; DOC = docetaxel Oudard S et al. Proc ASCO 2012;Abstract TPS4696.

  20. CALGB-90802: Everolimus With or Without Bevacizumab in Advanced Kidney Cancer After First-Line Therapy • Key Eligibility Criteria: • Metastatic or unresectable RCC • Some clear cell histology • Measurable disease • Treated with ≥ 1 prior VEGFR TKI and have progressed or are intolerant to treatment RANDOMIZE Everolimus Everolimus + Bevacizumab N = 700 Primary Endpoint: Overall survival Secondary Endpoints: PFS, ORR, ≥ Grade 3 toxicity www.clinicaltrials.gov, October 2012.

  21. Randomized, Open Label, Phase III Trial of Pazopanib versus Sunitinib in First-Line Treatment of Patients with Metastatic Renal Cell Carcinoma (mRCC): Results of the COMPARZ Trial Robert Motzer, T. E. Hutson, James Reeves, Robert Hawkins, Jun Guo, Paul Nathan, Michael Staehler, Paul de Souza, Jaime R. Merchan, Kate Fife, Jie Jin, Robert Jones, Hirotsugu Uemura, Ugo De Giorgi, Ulrika Harmenberg, Jinwan Wang, David Cella, Lauren McCann, Keith Deen, and Toni K. Choueiri Proc ESMO 2012;Abstract LBA8_PR

  22. Primary Endpoint: Progression-Free Survival (Independent Review) Proportion Progression-Free Pazopanib Sunitinib Months With permission from Motzer R et al. Proc ESMO 2012;Abstract LBA8_PR.

  23. Relative Risk in Adverse Events AE occurrence ≥10% in either arm; 95% CI for RR does not cross 1    Favors pazopanib Favors sunitinib With permission from Motzer R et al. Proc ESMO 2012;Abstract LBA8_PR.

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