Retreatment With Radium-223 Safe, Showing Activity in Patients With CRPC and Bone Metastases CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. CRPC, castration-resistant prostate cancer. This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

Radium-223 Retreatment in CRPC: Study Background Radium-223: alpha-emitting radiopharmaceutical that exerts potent cytotoxic effects on bone metastases In phase III ALSYMPCA trial, improved OS by 3.6 mos (P < .001), delayed time to first symptomatic skeletal event by 5.8 mos (P < .001), and had favorable safety profile for CRPC pts with bone metastases[1,2] Outcomes based on one 50-kBq/kg injection Q4W for 6 injections[1,2] Data suggest radium-223 retreatment may provide added benefit to pts who received initial 6-injection course[3] Current international, prospective, open-label phase I/II study evaluated efficacy and safety of radium-223 retreatment in pts with CRPC and bone metastases[4] CRPC, castration-resistant prostate cancer. 1. Parker C, et al. N Engl J Med. 2013;369:213-223. 2. Sartor O, et al. Lancet Oncol. 2014;15:738-746. 3. Sartor O, et al. ASCO GU 2016. Abstract 197. 4. Sartor O, et al. ASCO 2016. Abstract 5074. Slide credit: clinicaloptions.com

Radium-223 Retreatment in CRPC: Study Design Pts (N = 44) with metastatic CRPC who experienced radiographic or clinical progression following initial radium-223 treatment enrolled January 2014 to June 2015 Second 6-injection course of radium-223 50-kBq/kg Q4W administered > 30 days after end of initial course Pts actively followed up to 2 yrs after last radium-223 injection, with long- term follow up carried out to 7 yrs Primary endpoint: safety Exploratory endpoints: time to radiographic bone progression, radiographic PFS, OS, time to first SSE, SSE-free survival, time to pain progression Findings from this study compared with those from phase III ALSYMPCA trial CRPC, castration-resistant prostate cancer; SSE, symptomatic skeletal event. Slide credit: clinicaloptions.com Sartor O, et al. ASCO 2016. Abstract 5074.

Radium-223 Retreatment in CRPC: Eligibility Criteria CRPC and bone metastases Completion of 6 initial radium-223 injections with: No bone progression during initial treatment Radiographic or clinical progression after initial treatment Adequate hematologic function Pts ineligible if grade 3/4 AEs during or after initial radium-223 treatment that did not resolve or led to discontinuation Concomitant chemotherapy or initiation of abiraterone or enzalutamide treatment not permitted Other agents allowed based on investigator discretion AE, adverse event; CRPC, castration-resistant prostate cancer. Slide credit: clinicaloptions.com Sartor O, et al. ASCO 2016. Abstract 5074.

Radium-223 Retreatment in CRPC: Baseline Characteristics Retreatment Study (N = 44) ALSYMPCA (N = 614) Median age, yrs (range) 71 (52-91) 71 (49-90) ECOG PS 0/1/≥ 2, % 32/61/7 27/60/13 < 6/6-20/> 20 bone metastases, % 41/34/25 16/43/41 Prior treatment, % Docetaxel Abiraterone Enzalutamide Bisphosphonates Denosumab 45 61 30 11 48 57 NA 20 Concurrent treatment, % 27 9 16 Median PSA, μg/L 68 146 CRPC, castration-resistant prostate cancer; ECOG, Eastern Cooperative Oncology Group; NA, not applicable; PS, performance status; PSA, prostate-specific antigen. Slide credit: clinicaloptions.com Sartor O, et al. ASCO 2016. Abstract 5074.

Radium-223 Retreatment in CRPC: Treatment Experience Of the 44 pts who received retreatment: All had received ≥ 2 prior hormonal regimens 45% had received ≥ 1 prior chemotherapy regimen 73% had failed novel hormonal agents (abiraterone, enzalutamide) 66% completed retreatment with all 6 injections Median time from end of initial regimen to retreatment: 6 mos (range: 1.2-17.1 mos) CRPC, castration-resistant prostate cancer. Slide credit: clinicaloptions.com Sartor O, et al. ASCO 2016. Abstract 5074.

Radium-223 Retreatment in CRPC: Safety TEAEs, % Retreatment Study (N = 44) ALSYMPCA (N = 600) All Grades Grade 3 Grade 4 Pts with ≥ 1 TEAE 93 41 7 35 9 Hematologic Anemia Thrombocytopenia Leukopenia Neutropenia 14 2 5 31 12 4 11 3 1 < 1 Nonhematologic (in > 10% of retreatment pts) Fatigue Nausea Diarrhea Decreased appetite Arthralgia Hypertension Back pain Fall Vomiting 27 25 21 18 26 36 6 19 CRPC, castration-resistant prostate cancer; TEAE, treatment-emergent adverse event. Slide credit: clinicaloptions.com Sartor O, et al. ASCO 2016. Abstract 5074.

Radium-223 Retreatment in CRPC: Efficacy Median time to several endpoints not yet reached: radiographic bone progression, OS, time to first SSE, SSE-FS, time to pain progression 5 pts (11%) died through 15.5-mo max OS follow-up 8 pts (14%) experienced first SSE through 14.1-mo max SSE, SSE-free survival follow-up 5 of 36 evaluable pts (14%) had pain progression through 7.3-mo max pain progression follow-up Wk 24 pain progression event rate: 20% CRPC, castration-resistant prostate cancer; SSE, symptomatic skeletal event. Slide credit: clinicaloptions.com Sartor O, et al. ASCO 2016. Abstract 5074.

Radium-223 Retreatment in CRPC: rPFS Median rPFS: 9.9 mos 13 pts had rPFS events, largely consisting of soft tissue tumor progression (n = 8) Only 1 pt with confirmed radiographic bone progression 12.8-mos max follow- up time for rPFS and radiographic bone progression Radiographic PFS 100 80 60 rPFS (%) 40 20 2 4 6 8 10 12 14 CRPC, castration-resistant prostate cancer; rPFS, radiographic PFS. Mos Patients at risk 44 36 29 20 14 3 1 Slide credit: clinicaloptions.com Sartor O, et al. ASCO 2016. Abstract 5074.

Radium-223 Retreatment CRCP: Conclusions Second round of radium-223 treatment following initial course safe and feasible[1] Well tolerated, with minimal hematologic toxicity Low rate of radiographic bone progression Encouraging early effects on OS, time to SSE, pain Investigators conclude positive data warrant analysis of radium-223 retreatment in larger prospective trials[1] Ongoing study to address expanded radium-223 dosing and duration of treatment[2] CRPC, castration-resistant prostate cancer; SSE, symptomatic skeletal event. 1. Sartor O, et al. ASCO 2016. Abstract 5074. 2. ClinicalTrials.gov. NCT02023697. Slide credit: clinicaloptions.com

Go Online for More CCO Coverage of ASCO 2016! Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in: Breast, genitourinary, and lung cancers Hematologic malignancies Immunotherapy clinicaloptions.com/oncology