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YEAR IN REVIEW 2012: GU

David I Quinn, MBBS, PhDMedical Director, Norris Cancer Hospital and ClinicsLeader, Developmental TherapeuticsHead, GU Cancer SectionDivision of Cancer Medicine and Blood DiseasesUSC/Norris Comprehensive Cancer Center

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

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

To what extent does radium-223 chloride cause myelosuppression?

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 4512C. 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

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.

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design

TREATMENT

6 injections at 4-week intervals

Radium-223 (50 kBq/kg) + Best standard of care

Placebo (saline) + Best standard of care

N = 921

PATIENTS

• Confirmed symptomatic CRPC

• ≥ 2 bone metastases

• No known visceral metastases

• Post-docetaxel or unfit for docetaxel

Planned follow-up is 3 years

• Total ALP: < 220 U/L vs ≥ 220 U/L• Bisphosphonate use: Yes vs No• Prior docetaxel: Yes vs No

STRATIFICATION

Clinicaltrials.gov identifier: NCT00699751.

RANDOMIZED

2:1

ALSYMPCA Updated Analysis: Overall Survival

Radium-223, n = 614Median OS: 14.9 months

Placebo, n = 307Median OS: 11.3 months

HR = 0.69595% CI, 0.581, 0.832P = 0.00007

Month 0 3 6 9 12 15 18 21 24 27 30 33 36 390

10

20

30

40

50

60

70

80

90

100

%

With permission from Parker C et al. Proc ASCO 2012;Abstract LBA4512.

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

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

AFFIRM: Interim Analysis of Enzalutamide versus Placebo in Patients with CRPC

Scher HI et al. N Engl J Med 2012;367(13):1187-97.

Enzalutamide(n = 800)

Placebo(n = 399)

Hazard ratio p-value

Overall survival 18.4 mo 13.6 mo 0.63 < 0.001Progression-free survival* 8.3 mo 2.9 mo 0.40 < 0.001Time to PSA progression 8.3 mo 3.0 mo 0.25 < 0.001PSA response rate 54% 2% —

< 0.001

*According to radiographic evidence

AFFIRM: Frequent Adverse Events More Common with Enzalutamide

Scher HI et al. N Engl J Med 2012;367(13):1187-97.

Adverse event

Enzalutamide(n = 800)

Placebo(n = 399)

Any grade Grade ≥3

Any grade Grade ≥3

Fatigue 34% 6% 29% 7%

Diarrhea 21% 1% 18% < 1%

Hot flash 20% 0% 10% 0%

Musculoskeletal pain 14% 1% 10% < 1%Headache 12% < 1% 6% 0%

Seizures were reported in 5 patients (0.6%) receiving enzalutamide.

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 4518Charles 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

Overall Study Design of COU-AA-302

• 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

AA 1000 mg dailyPrednisone 5 mg BID

(Actual n = 546)

Co-Primary:• rPFS by central review• OSSecondary:• Time to opiate use

(cancer-related pain)• Time to initiation of

chemotherapy• Time to ECOG-PS

deterioration• TTPP

Efficacy end points

Placebo dailyPrednisone 5 mg BID

(Actual n = 542)

RANDOMIZED

1:1

• Progressive chemo-naïve mCRPC patients(Planned N = 1,088)

• Asymptomatic or mildly symptomatic

Patients

Ryan CJ et al. Proc ASCO 2012;Abstract LBA4518.

Statistically Significant Improvement in rPFS not OS

NR, not reached; PL, placebo; rPFS, radiographic PFS.Data cutoff 12/20/2010.

100

80

60

40

20

00

Prog

ress

ion-

Free

(%)

3 6 9 15 1812

546542

489400

340204

16490

123

00

AAPL

4630

Time to Progression or Death (Months)

AA + PPL + P

AA + P (median, mos): NRPL + P (median, mos): 8.3

HR (95% CI): 0.43 (0.35-0.52)P value: < 0.0001

AA + P (median, mos): NRPL + P (median, mos): 27.2

HR (95% CI): 0.75 (0.61-0.93)P value: 0.0097

546542

538534

482465

452437

2725

00

524509

503493

02

120106

258237

412387

100

80

60

40

20

00

Surv

ival

(%)

3 12 15 27Time to Death (Months)

33

AA + PPL + P

6 9 30242118

AA PL

Pre-specified significance level by O’Brien-Fleming Boundary = 0.0008.

Data cutoff 12/20/2011.

With permission from Ryan CJ et al. Proc ASCO 2012;Abstract LBA4518.

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

First-Line Use of Cabazitaxel in Chemotherapy-Naïve Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Three-Arm Study in Comparison with DocetaxelProc 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

Phase III FIRSTANA Study (NCT01308567)

Primary:• OSSecondary:• PCWG2 PFS• rPFS by central review• Tumor response

(RECIST)• PSA response• PSA PFS• Pain response• Pain PFS• TTP SRE• QOL

Efficacy end points

• Progressive chemo-naïve mCRPC patients(Planned N = 1,170)

• Stratified by:• ECOG (0, 1 vs 2)• Measurable Dz• Region

Patients

CBZ = cabazitaxel; DOC = docetaxel

RANDOMIZED

1:1:1 DOC 75 mg/m2 IV Q3WPrednisone 10 mg QD

CBZ 20 mg/m2 IV Q3WPrednisone 10 mg QD

CBZ 25 mg/m2 IV Q3WPrednisone 10 mg QD

Oudard S et al. Proc ASCO 2012;Abstract TPS4696.

CALGB-90802: Everolimus With or Without Bevacizumab in Advanced Kidney Cancer After First-Line Therapy

www.clinicaltrials.gov, October 2012.

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 = 700Primary Endpoint: Overall survivalSecondary Endpoints: PFS, ORR, ≥ Grade 3 toxicity

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

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

PazopanibSunitinib

N Median PFS Pazopanib 557 8.4 mo Sunitinib 553 9.5 mo

HR = 1.047

With permission from Motzer R et al. Proc ESMO 2012;Abstract LBA8_PR.

Months

Prop

ortio

n Pr

ogre

ssio

n-Fr

eePrimary Endpoint: Progression-Free Survival

(Independent Review)

Hair color changeWeight decreasedSerum ALT increasedAlopeciaUpper abdominal painSerum AST increased

FatigueRashPain in extremityConstipationTaste alterationLDH increasedSerum creatinine increasedPeripheral edema

Hand-foot syndromeDyspepsiaPyrexiaLeukopeniaHypothyroidismEpistaxisSerum TSH increased

MucositisNeutropeniaAnemiaThrombocytopenia

Relative Risk in Adverse EventsAE 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.