DOWNLOAD THE SLIDES at www.educationalconcepts.net PHYSICIAN CONTINUING EDUCATION ACCREDITATION STATEMENT Educational Concepts Group, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CREDIT DESIGNATION STATEMENT Educational Concepts Group, LLC designates this live activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. CME Credits There are no fees for participating and receiving CME credits for this activity. Participants who complete an activity evaluation form and return it to Educational Concepts Group, LLC may view and print their credit letter or statement of credit via the website, www.educationalconcepts.net, 6 weeks after the activity. CME INQUIRIES Educational Concepts Group, LLC 1300 Parkwood Circle SE, Suite 325 | Atlanta, GA 30339 Phone: 1.866.933.1681 | Fax: 1.866.933.1692 www.educationalconcepts.net Target Audience The target audience for this activity is medical oncologists, urologists, radiation oncologists, radiologists, nuclear medicine physicians, and oncology specialty pharmacists involved in the management of individuals with CRPC. Educational Objectives At the conclusion of this activity, participants should be able to: • Review the biology of bone metastases, skeletal morbidity, and recent advances in bone-targeted therapies for bone-metastatic CRPC • Analyze the results of pivotal trials introducing radium-223 dichloride (R-223) for bone-metastatic CRPC and identify its impact on existing treatment algorithms • Apply the benefits and limitations of contemporary strategies for the optimal treatment of men with bone-metastatic CRPC ineligible or unfit for chemotherapy into patient care recommendations • Review ongoing and planned clinical trials evaluating novel bone-targeted therapies for bone-metastatic CRPC and the potential impact on the treatment landscape This activity is supported by an educational grant from Algeta US and Bayer HealthCare Pharmaceuticals, Inc.

Approved Therapies for mCRPC Drug Class Agent(s) Basis of Approval Androgen receptor antagonists Enzalutamide Prolonged survival Androgen synthesis inhibitors Abiraterone acetate Bisphosphonates Zoledronic acid SRE reduction Chemotherapy Docetaxel Cabazitaxel Mitoxantrone Pain reduction Immunotherapy Sipuleucel-T RANK ligand inhibitors Denosumab Radioisotopes Samarium-153 (153Sm) Strontium-89 (89Sr) Radium-223 dichloride Bone pain reduction RANK: nuclear factor kappa B ligand; SRE: skeletal-related event; SSE: symptomatic skeletal event Food and Drug Administration. Available at: www.FDA.gov.

Chronology of FDA Approvals in mCRPC Docetaxel + Prednisone Abiraterone + Prednisone Post-Docetaxel Mitoxantrone + Prednisone Abiraterone + Prednisone Pre-Docetaxel Zoledronic Acid Sipuleucel-T Strontium89 Samarium153 Denosumab Radium-223 1981 1993 1996 1997 2002 2004 2010 2011 2012 2013 Estramustine Cabazitaxel + Prednisone Enzalutamide Post-Docetaxel

2010-2013: OS Benefit in Recent CRPC Trials Agent Trial Disease State Comparator Median OS (mo) HR (P) Sipuleucel-T IMPACT Chemo-naïve CRPC Placebo 25.8 0.759 (0.017) Docetaxel TAX327 Chemo-naïve CRPC Mitoxantrone Prednisone 18.9 0.76 (0.009) Cabazitaxel TROPIC Post-docetaxel CRPC 15.1 0.70 (< 0.0001) Abiraterone acetate + prednisone COU-AA-301 Post-docetaxel Placebo Prednisone 14.8 0.646 Abiraterone acetate + prednisone COU-AA-302 Progressive chemo-naïve CRPC Placebo + Prednisone Not Reached 0.75 (0.01) Enzalutamide AFFIRM 18.4 0.631 PREVAIL 32.4 Radium-223 ALSYMPCA 14.9 0.695 (0.002) J Clin Oncol 31, 2013 (suppl 6; abstr 63) Mark T. Fleming, Dana E. Rathkopf, Jackie Gibbons, Amy C. Peterson, Alison Hannah, David Forer, Howard I. Scher, Michael J. Morris; Virginia Oncology Associates, Norfolk, VA; Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY; Medivation, Inc., San Francisco, CA CRPC, castration-resistant prostate cancer; HR, hazard ratio; OS, overall survival. Kantoff PW, et al. N Engl J Med. 2010;363:411-422; Tannock IF, et al. N Engl J Med. 2004;351:1502-1512; de Bono JS, et al. Lancet. 2010;376:1147-1154; de Bono J, et al. N Engl J Med. 2011;364:1995-2005; Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148; Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197; Medivation and Astellas Press Release, October 22, 2013; Parker C, et al. N Engl J Med. 2013;369(3):213-223.

Metastatic CRPC: First-Line Options Agents approved for first-line use Sipuleucel-T Abiraterone / prednisone Docetaxel Radium-223 Anticipated Enzalutamide To date, no head-to-head comparative studies of these agents

Bone Metastases in Prostate Cancer Progressive disease Bone pain Pathologic fractures Spinal cord compression Marrow suppression Slide that follows: Insert a set-up slide

Metastatic CRPC: Where Are We?

Sipuleucel-T vs Placebo: IMPACT Study Design (IMmunotherapy Prostate AdenoCarcinoma Treatment) Treated at physician discretion P R O G E S I N Asymptomatic or minimally symptomatic mCRPC (N = 512) R A N D O M I Z E D 2:1 Sipuleucel-T q2 weeks x 3 Treated at physician discretion and / or salvage protocol Placebo q2 weeks x 3 Primary endpoint: Overall survival Secondary endpoint: Objective disease progression Kantoff PW, et al. N Engl J Med. 2010;363(5):411-422. 9

IMPACT: Overall Survival Final Analysis (349 events) 100% 80% 60% Percent Survival S i pu l e u cel - T ( n = 341) 40% M e d i a n s ur v i v a l : 25 . 8 mo 36 mo s ur v i v a l : 32 . 1 % 20% P l ace bo ( n = 171) M e d i a n s ur v i v a l : 21 . 7 mo 36 mo s ur v i v a l : 23 . % 0% 12 24 36 48 60 72 Time From Randomization (months) Median Follow-up = 36.5 months HR = 0.759 (95% CI, 0.606, 0.951), P = 0.017 (Cox model) Kantoff PW, et al. N Engl J Med. 2010;363(5):411-422. 10

IMPACT: Adverse Events Sipuleucel-T (N = 338) Placebo (N = 168) All Grades No. (%) Grade 3-5 Any 334 (98.8) 107 (31.7) 162 (96.4) 59 (35.1) Chills 183 (54.1) 4 (1.2) 21 (12.5) Fatigue 132 (39.1) 64 (38.1) 3 (1.8) Back pain 116 (34.3) 12 (3.6) 61 (36.3) 8 (4.8) Pyrexia 99 (29.3) 1 (0.3) 23 (13.7) Nausea 95 (28.1) 2 (0.6) 35 (20.8) Arthralgia 70 (20.7) 7 (2.1) 40 (23.8) 5 (3.0) Citrate toxicity 68 (20.1) 34 (20.2) Vomiting 60 (17.8) 20 (11.9) Headache 54 (16.0) Pain 44 (13.0) 6 (1.8) 12 (7.1) 2 (1.2) Influenza-like illness 33 (9.8) 6 (3.6) Bone pain 32 (9.5) 3 (0.9) 18 (10.7) Hypertension 25 (7.4) Hyperhidrosis 18 (5.3) 1 (0.6) Groin pain 17 (5.0) 4 (2.4) Kantoff PW, et al. N Engl J Med. 2010;363(5):411-422.

Cabazitaxel + Prednisone vs Mitoxantrone + Prednisone: The TROPIC Study R A N D O M I Z E D Cabazitaxel 25 mg/m2 IV Q3wk + Prednisone for 10 courses (N = 378) Mitoxantrone 12 mg/m2 IV Q3wk (N = 377) Patients Patients with mCRPC progressing during and after docetaxel (N = 755) Primary endpoint: Overall survival Secondary endpoints:  PFS  Response rate  Safety de Bono J, et al. Lancet. 2010;376(9747):1174-1154.

TROPIC: Overall Survival TROPIC slide deck. Slide5 Mitoxantrone Prednisone Cabazitaxel Median OS (months) 12.7 15.1 Hazard ratio 0.72 95% CI 0.61-0.84 P value < 0.0001 100 80 60 40 20 Proportion of OS (%) Censored MP CBZP Combined median follow-up: 13.7 months 6 12 18 24 30 Time (months) de Bono J, et al. Lancet. 2010;376(9747):1174-1154.

TROPIC: Hematological Adverse Events Mitoxantrone (n = 371) Cabazitaxel All Grades n (%) Grade ≥ 3 Neutropenia 325 (88) 215 (58) 347 (94) 303 (82) Febrile neutropenia  5 (1) 28 (8) Leukopenia 343 (92) 157 (42) 355 (96) 253 (68) Anemia 302 (81) 18 (5) 361 (97) 39 (11) Thrombocytopenia 160 (43) 6 (2) 176 (47) 15 (4) de Bono J, et al. Lancet. 2010;376(9747):1174-1154.

TROPIC: Non-Hematological Adverse Events Mitoxantrone (n = 371) Cabazitaxel (n = 371) All Grades n (%) Grade ≥ 3 Diarrhea 39 (11) 1 (< 1) 173 (47) 23 (6) Fatigue 102 (27) 11 (3) 136 (37) 18 (5) Asthenia 46 (12) 9 (2) 76 (20) 17 (5) Back pain 45 (12) 60 (16) 14 (4) Nausea 85 (23) 127 (34) 7 (2) Vomiting 38 (10) 84 (23) Hematuria 2 (1) 62 (17) Abdominal pain 13 (4) 43 (12) Pain in extremity 27 (7) 4 (1) 30 (8) 6 (2) Dyspnea 3 (1) 44 (12) 5 (1) Constipation 57 (15) Pyrexia Arthralgia 31 (8) Urinary tract infection Pain 20 (5) Bone pain 19 (5) de Bono J, et al. Lancet. 2010;376(9747):1174-1154.

Abiraterone + Prednisone vs Prednisone + Placebo: COU-AA-301 Study Design Abiraterone acetate 4 250-mg tablets QD 1 hr before or 2 hrs after meal + Prednisone 5 mg BID x 28 days (N = 797) R A N D O M I Z E D 1:1 Endpoints Primary Overall survival Secondary PSA response rate Time to PSA progression Radiographic evidence of PFS Patients Histologically or cytologically confirmed prostate cancer, previously treated with docetaxel ECOG performance status score ≤ 2 Placebo 4 tablets QD 1 hr before or 2 hrs after meal + Prednisone 5 mg BID x 28 days (N = 398) Phase III, randomized, double-blind, placebo-controlled trial conducted at 147 sites in 13 countries de Bono J, et al. N Engl J Med. 2011;364:1995-2005. 16

COU-AA-301: Patient Characteristics Abiraterone + Prednisone (N = 797) Placebo + Prednisone (N = 398) Median range (yr) 69 (42-95) 69 (39-90) Disease location – no. of patients (%) Bone Node Liver 709 (89) 361 (45) 90 (11) 357 (90) 164 (41) 30 (8) Brief Pain Inventory (Short Form) score for pain No. of patients Median score (range) 792 3.0 (0-10) 394 No. of previous cytotoxic chemotherapy regimens – no. of patients (%) 1 2 558 (70) 239 (30) 275 (69) 123 (31) ECOG performance status – no. of patients (%) 0 or 1 715 (90) 82 (10) 353 (89) 45 (11) Prostate-specific antigen Median (range) – ng/mL 788 128.8 (0.4-9253.0) 393 137.7 (0.6-10114.0) ECOG: Eastern Cooperative Oncology Group de Bono J, et al. N Engl J Med. 2011;364:1995-2005.

COU-AA-301: Overall Survival Abiraterone acetate: 14.8 months 100 80 HR = 0.646 (0.54-0.77) P < 0.0001 60 Survival (%) 40 Placebo: 10.9 months 20 AA Placebo 100 200 300 400 500 600 700 Days From Randomization de Bono J, et al. N Engl J Med. 2011;364:1995-2005.

COU-AA-301: Adverse Events Abiraterone (N = 791) Placebo (N = 394) All Grades No. (%) Fatigue 346 (44) 169 (43) Fluid retention and edema 241 (31) 88 (22) Back pain 233 (30) 129 (33) Nausea 124 (32) Arthralgia 215 (27) 89 (23) Constipation 206 (26) 120 (31) Bone pain 194 (25) 110 (28) Vomiting 168 (21) 97 (25) Diarrhea 139 (18) 53 (14) Hypokalemia 135 (17) 33 (8) Pain in arm or leg 134 (17) 79 (20) Cardiac disorder 106 (13) 42 (11) Asthenia 104 (13) 52 (13) Dyspnea 102 (13) 46 (12) Abdominal pain 95 (12) 44 (11) Urinary tract infection 91 (12) 28 (7) Liver function test abnormalities 82 (10) 32 (8) de Bono J, et al. N Engl J Med. 2011;364:1995-2005.

Prednisone + Abiraterone vs Prednisone + Placebo: COU-AA-302 Study Design R A N D O M I Z E D 1:1 Abiraterone acetate 1000 mg daily + Prednisone 5 mg BID (N = 546) Endpoints 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 Patients Progressive chemo-naïve mCRPC patients (Planned N = 1088) Asymptomatic or mildly symptomatic Placebo daily + Prednisone 5 mg BID (N = 542) Phase III 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 Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148. 20

COU-AA-302: Radiographic Progression-Free and Overall Survival Curatio PowerPoint Template 11/11/2018 6:47 AM COU-AA-302: Radiographic Progression-Free and Overall Survival Radiographic Progression-Free Survival Overall Survival 100 100 Hazard ratio, 0.75 (95% CI, 0.61-0.93) Hazard ratio, 0.53 (95% CI, 0.45-0.62) P < 0.01 P < 0.001 80 80 Abiraterone-prednisone, not reached Abiraterone-prednisone, 16.5 mo 60 60 Progression-Free Survival (%) Overall Survival (%) 40 40 Prednisone alone, 8.3 mo Prednisone alone, 27.2 mo 20 No. of Events 20 No. of Events Fact check: These data are similar to but not identical with those just published. Fig 1a (# at risk differences) Other differences: OS Abiraterone-prednisone: 271 Abiraterone-prednisone: 147 Prednisone alone: 336 Prednisone alone: 186 3 6 9 12 15 18 21 24 27 30 3 6 9 12 15 18 21 24 27 30 33 Months Months Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148. 21 21

COU-AA-302: Adverse Events of Special Interest Grade 3 or 4 Adverse Event Abiraterone + Prednisone N = 542, n (%) Placebo + Prednisone N = 540, n (%) Fluid retention or edema 4 (< 1) 9 (2) Hypokalemia 13 (2) 10 (2) Hypertension 21 (4) 16 (3) Cardiac disorder 31 (6) 18 (3) Atrial fibrillation 7 (1) 5 (< 1) ALT increased 29 (5) AST increased ALT: alanine aminotransferase; AST: aspartate aminotransferase Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148.

Enzalutamide vs Placebo: AFFIRM Study Design R A N D O M I Z E D 2:1 Enzalutamide 160 mg daily (N = 800) Placebo (N = 399) Endpoints Primary: Overall survival Secondary: rPFS Time to PSA progression Time to first SSE Patients 1199 patients with progressive mCRPC Disease progression after docetaxel Phase III, double-blind, placebo-controlled trial conducted at 156 sites in 15 countries Stratification according to:  ECOG performance status (0 vs 1-2)  Average pain over prior 7 days (Brief Pain Inventory [Short Form]; 0-3 [absent] vs 4-10 [present]) ECOG: Eastern Cooperative Oncology Group. Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197.

AFFIRM: Prior Hormonal and Chemotherapy Treatments Enzalutamide N = 800 Placebo N = 399 Prior lines of hormonal drug therapy* 1 2 ≥ 3 8.2% 42.3% 49.1% 8.8% 37.9% 53.1% Number of prior chemotherapy regimens 72.4% 24.5% 3.1% 74.2% 23.8% 2.0% Median number of prior docetaxel cycles 8.5 8.0 LEAVE THIS IN *Abiraterone naïve. Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197.

AFFIRM: Overall Survival 100 90 Enzalutamide: 18.4 months (95% CI: 17.3, NYR) 80 70 60 Survival, % 50 40 Placebo: 13.6 months (95% CI: 11.3, 15.8) 30 20 Stephen to redraw 10 3 6 9 12 15 18 21 24 Duration of Overall Survival, Months HR = 0.631 (0.529, 0.752) P < 0.0001, 37% reduction in risk of death Scher HI, et al. N Engl J Med. 2012;367:1187-1197.

AFFIRM: Adverse Events Enzalutamide (N = 800) Placebo (N = 399) Any Grade No. (%) Grade ≥ 3 ≥ 1 adverse event 785 (98) 362 (45) 390 (98) 212 (53) Any serious adverse event 268 (34) 227 (28) 154 (39) 134 (34) Discontinuation owing to adverse event 61 (8) 37 (5) 39 (10) 28 (7) Adverse event leading to death 23 (3) 14 (4) Frequent adverse events more common with enzalutamide Fatigue 269 (34) 50 (6) 116 (29) 29 (7) Diarrhea 171 (21) 9 (1) 70 (18) 1 (< 1) Hot flash 162 (20) 41 (10) Musculoskeletal pain 109 (14) 8 (1) 40 (10) Headache 93 (12) 6 (< 1) 22 (6) Clinically significant adverse events Cardiac disorder Any 49 (6) 7 (1) 30 (8) 8 (2) Myocardial infarction 2 (< 1) Abnormality on liver-function testing 3 (< 1) 6 (2) Seizure 5 (< 1) Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197.

Enzalutamide vs Placebo in Chemotherapy-Naïve Metastatic Prostate Cancer: The PREVAIL Study Progressive mCRPC Asymptomatic or mildly symptomatic Chemotherapy-naïve Steroids allowed but not required N = 1717 Enzalutamide 160 mg/day (capsules) n = 872 R A N D O M I Z E D Co-Primary Endpoints OS rPFS Placebo n = 845 Halted October 2010 halted by DMC and patient offered crossover Oct 2014 ClinicalTrials.gov identifier: NCT01212991 mCRPC: metastatic castrate-resistant prostate cancer; OS: overall survival; rPFS: radiographic progression-free survival Beer T, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA 1.

PREVAIL: Radiographic Progression-Free Survival 100 90 Hazard Ratio: 0.186 (95% CI: 0.15, 0.23) 80 P < 0.0001 70 60 50 Radiographic Progression-Free Survival (%) 40 30 20 10 Enzalutamide Placebo 3 6 9 12 15 18 21 Radiographic Progression-Free Survival (Months) Median rPFS: Enzalutamide, not reached Placebo, 3.9 months Beer T, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA 1.

PREVAIL: Radiographic PFS Across Subgroups All patients ECOG performance status at baseline = 0 Age < 75 Geographic region - North America Geographic region - Europe Geographic region - Rest of world V isceral disease (Lung and or liver) at screening - Y es isceral disease (Lung and or liver) at screening - No 832 / 801 557 / 549 275 / 252 529 / 517 303 / 284 214 / 204 456 / 435 162 / 162 97 / 101 735 / 700 0.19 (0.15-0.23) 0.15 (0. 1 1-0.20) 0.27 (0.19-0.37) 0.20 (0.15-0.26) 0.17 (0.12-0.24) 0.17 (0.12-0.25) 0.21 (0.15-0.28) 0.14 (0.08-0.25) 0.28 (0.16-0.49) 0.17 (0.14-0.22) Number of Patients Enzalutamide / Placebo Hazard Ratio (95% CI) 1.0 0.5 Favors Enzalutamide Placebo 1.5 Beer T, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA 1.

PREVAIL: Overall Survival 100 90 80 Hazard Ratio: 0.706 70 (95% CI: 0.60, 0.84) 60 P < 0.0001 Survival (%) 50 40 30 20 Enzalutamide 10 Patients still alive at data cut off Placebo Enzalutamide: 72%; Placebo: 63% 3 6 9 12 15 18 21 24 27 30 33 36 Duration of Overall Survival (Months) Median OS: Enzalutamide, 32.4 Months; Placebo, 30.2 months Beer T, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA 1.

PREVAIL: Most Common Adverse Events All Grades (%) Grade ≥ 3 (%) Enzalutamide n = 871 Placebo n = 844 Fatigue 36 26 2 Back Pain 27 22 2.5 3 Constipation 17 0.5 0.4 Arthralgia 20 16 1.4 1.1 Cardiac AE 10 8 Hypertension 13 4 7 ↑ ALT 0.9 0.6 0.2 0.1 Seizure Beer T, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA 1.

The Challenge of Bone Metastases

CRPC & Bone Metastases Of the major solid tumors, prostate cancer is the most bone tropic 85-90% occurrence of bone metastases in phase III trials of CRPC Bone metastases major cause of morbidity and mortality  Pain most common  Immobility / quality of life  Cause pathologic fractures, spinal cord compression

Progress in Metastatic Prostate Cancer: Bone-Targeted Therapies FDA Approvals in Castrate-Resistant Prostate Cancer Radium-223 Survival Enzalutamide Cabazitaxel Docetaxel Abiraterone Sipuleucel- T 1992 1996 2000 2004 2008 2012 Strontium-89 Samarium-153 Zoledronic acid Denosumab Mitoxantrone Palliation 34

Strontium-89 vs Placebo The TransCanada Strontium-89 Study R A N D O M I Z E D Castrate-resistant Bone metastases (N = 126) Strontium-89 (10.8 mCi x 1) + Local field radiotherapy Placebo + Local field radiotherapy Primary Endpoint: Pain Porter AT, et al. Int J Radiat Oncol Biol Phys. 1993;25(5):805-813.

The TransCanada Strontium-89 Study: Months Post-Treatment New Pain Sites Placebo Control (n = 22) 1.4 – 1.2 – 1.0 – 0.8 – 0.6 – 0.4 – 0.2 – (n = 42) (n = 26) (n = 23) [P < 0.002] Mean New Pain Sites / Patient (n = 46) (n = 29) (n = 25) (n = 47) (n = 44) Strontium-89 (10.8 mCi) (n = 34) (n = 42) (n = 48) 0 1 2 3 4 5 6 7 Months Post-Treatment Porter AT, et al. Int J Radiat Oncol Biol Phys. 1993;25(5):805-813.

Samarium-153 EDTMP vs Placebo Curatio PowerPoint Template 11/11/2018 6:47 AM Samarium-153 EDTMP vs Placebo R A N D O M I Z E D 2:1 Samarium-153 mCRPC Bone metastases (N = 152) Placebo Fact check: In de Bono ESMO abstract- could not verify ECOG, pain, type of progression from abstract This was a Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study conducted at 147 sites in the United States/Europe/Australia/Canada comparing the efficacy and safety of abiraterone acetate plus prednisone with placebo plus prednisone in men with metastatic CRPC who had failed 1 or 2 chemotherapy regimens, one of which contained docetaxel. Subjects were randomized in a 2:1 ratio to receive abiraterone acetate plus prednisone or placebo plus prednisone, respectively, and were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs. 2), worst pain over the past 24 hours on The Brief Pain Inventory (BPI)-Short Form (0-3 [absent] vs. 4-10 [present]), prior chemotherapy regimens (1 vs. 2), and type of progression (PSA only vs. radiographic progression with or without PSA progression). Subjects could receive treatment until documented disease progression (of all 3 types including 1) PSA progression, 2) radiographic progression and 3) symptomatic or clinical progression) or unacceptable toxicity. Efficacy analysis set: ITT (intent-to-treat). Primary efficacy endpoint: Overall survival (OS). Secondary efficacy endpoints: prostate‑specific antigen (PSA) response rate, time to PSA progression, and radiographic progression-free survival (R_PFS). Prospective, randomized, double-blind trial Primary endpoint: pain response Sartor O, et al. Urology. 2004;63(5):940-945. 37 37 37

Samarium-153 EDTMP vs Placebo: Palliative Effects VAS Measured Pain Scores PDS Measured Pain Scores -4 -12 -8 Week 0.5 1.5 2.0 2.5 3.0 3.5 -2 -6 -10 4.0 1.0 AUPC VAS -8 -4 Week 0.5 1.5 2.0 2.5 3.0 3.5 2 -2 -6 4.0 1.0 AUPC PDS Analgesic Consumption 40 -40 Week 0.5 1.5 2.0 2.5 3.0 3.5 20 -20 4.0 1.0 Morphine Equiv/Day Sartor O, et al. Urology. 2004;63(5):940-945.

Hematological Adverse Events of Strontium-89 and Samarium-153 Studies TransCanada Study Samarium-153 Study Strontium-89 (n = 67) n (%) Placebo (n = 58) Samarium-153 (n = 93) (n = 47) Platelets Grade 3 Grade 4 15 (22.4) 7 (10.4) 1 (1.72) 3 (3) 0 (0) White blood cells 1 (1.49) 5 (5) Porter AT, et al. Int J Radiat Oncol Biol Phys. 1993;25(5):805-813. Sartor O, et al. Urology. 2004;63(5):940-945.

Time to First On-Study SSE Bisphosphonates and Symptomatic Skeletal Event: Denosumab vs Zoledronic Acid Time to First On-Study SSE 1.00 HR: 0.82 (95% CI: 0.71-0.95 P = 0.0002 non-inferiority P = 0.008 superiority Risk reduction 18% 0.75 Proportion of Subjects Without SSE 0.50 KM Estimate of Median Mos 0.25 No difference in overall survival or disease progression between denos and zole---delete Slide 38 CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier. Denosumab 20.7 Zoledronic acid 17.1 3 6 9 12 15 18 21 24 27 Study Month Pts at Risk, N Zoledronic acid 951 733 544 407 299 207 140 93 64 47 Denosumab 950 758 582 472 361 259 168 115 70 39 SSE: symptomatic skeletal event Fizazi K, et al. Lancet. 2011;377:813-822. 40

Summary of Adverse Events Denosumab vs Zoledronic Acid: Adverse Events Adverse Event Zoledronic Acid (n = 945) n (%) Denosumab (n = 943) Any adverse event 918 (97) 916 (97) Most common adverse events in either arm Anemia 341 (36) 337 (36) Back pain 287 (30) 304 (32) Decreased appetite 274 (29) 267 (28) Constipation 251 (27) 236 (25) Bone pain 245 (26) 235 (25) Nausea 272 (29) Asthenia 239 (25) Fatigue 222 (24) 257 (27) CTCAE Grade 3 or 4 adverse events 672 (71) 718 (76) Serious adverse events 568 (60) 594 (63) Adverse events leading to treatment discontinuation 138 (15) 164 (17) Cumulative osteonecrosis of the jaw (total) Year 1 Year 2 12 (1) 5 (1) 8 (1) 22 (2) 10 (1) CTC, common toxicity criteria. CTCAE: Common Terminology for Adverse Events (version 3.0) Fizazi K, et al. Lancet. 2011;377:813-822. 41

Alpha Particle Treatment for Bone-Metastatic CRPC

Critical Differences in Alpha- and Beta-Particles Alpha Beta α β Relative particle mass 7300 1 Initial energy (MeV) per particle 3-8 0.01-2.5 Range in tissue (μm) 40-100 50-5000 LET (KeV/μm) 60-230 0.015-0.4 DNA hits to kill cells 1-10 100-1000 LET = linear energy transfer Henriksen, et al. J Nucl Med. 2003;44:252-259.

Bone-Seeking Radiopharmaceuticals in Human Clinical Trials Radionuclide Half-life Targeting Agents Main Particle Type Maximum Energy (MeV) Mean Energy Average Penetration Radium-223 11.4 days None required alpha 27.78 6.94 < 0.1 mm Strontium-89 50.5 days beta 1.46 0.58 2.4 mm Samarium-153 1.9 days EDTMP 0.81 0.22 0.5 mm Phosphorus-32 14.3 days 1.71 0.69 3.0 mm Yttrium-90 2.7 days Citrate 2.27 0.93 4.0 mm Lutetium-177 6.7 days 0.49 0.14 0.3 mm Iodine-131 8.0 days HDBP 0.61 0.19 0.8 mm Rhenium-186 3.8 days HEDP / etidronate 1.07 0.33 1.0 mm Rhenium-188 0.7 days HEDP 2.12 0.64 3.8 mm Holmium-166 1.1 days DOTMP / EDTMP 1.84 0.67 3.3 mm Tin-117m 13.6 days DTPA CE 0.15 0.2 mm

Radium Targets Osteoblastic Bone Metastases by Acting as a Calcium Mimetic Strontium Barium Radium McDevitt MR, et al. Eur J Nucl Med. 1998;25:1341-1351.

Radium: Bone-Seeking Calcium Mimetic That Binds to Hydroxyapatite [Ca10(PO4)6(OH)2] Hydroxyapatite is intertwined with osteoid and cancer cells in the osteoblastic lesion New Bone Cancer Cells Bruland, et al. Clin Cancer Res. 2006;12:6250s-6257s.

Note the short track length Radium-223: Preferential Uptake in the Stroma of Osteoblastic Lesions Compared With Normal Bone and Bone Marrow Normal bone Osteoblastic lesion Bone marrow Note the short track length Studies in Dog Tumours Bruland, et al. Clin Cancer Res. 2006;12:6250s-6257s. 47

Radium-223 Is Short-Range But High-Energy 2-10 cell diameter range of alpha-particle Radium-223 Highly localized cell damage with minimal damage to surrounding hematopoietic tissue Perez, et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007.

Radium-223 vs Placebo: ALSYMPCA (ALpharadin in SYMptomatic Prostate Cancer) Study Design STRATIFICATION TREATMENT PATIENTS R A N D OM I Z E D 2:1 Confirmed symptomatic CRPC ≥ 2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel (N = 922) 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 6 injections at 4-week intervals Placebo (saline) + Best standard of care Statistical assumption 90% power HR = 0.76 0.05 two-sided alpha Planned Interim Analysis Final Analysis Events 320 640 Alpha 0.00306 0.05 Parker C, et al. N Engl J Med. 2013;369(3):213-223.

ALSYMPCA Overall Survival (Updated Analysis) Radium-223 Dichloride, n = 614 Median OS: 14.9 months Placebo, n = 307 Median OS: 11.3 months HR = 0.695 95% CI, 0.581, 0.832 P = 0.00007 10 20 30 40 50 60 70 80 90 100 % Month 3 6 9 12 15 18 21 24 27 30 33 36 39 Radium-223 614 578 504 369 274 178 105 60 41 7 1 Placebo 307 288 228 157 103 67 14 4 2 May 2013, Radium-223 was FDA approved for patients with castrate-resistant prostate cancer who have bone metastases and no known visceral metastases Parker C, et al. NEJM. 2013;369(3):213-223.

ALSYMPCA: Time to First SSE (Updated Analysis) HR = 0.658 95% CI, 0.522, 0.830 P = 0.00037 Radium-223, n = 614 Median: 15.6 months Placebo, n = 307 Median: 9.8 months 10 20 30 40 50 60 70 80 90 100 % Months 3 6 9 12 15 18 21 24 27 30 Parker C, et al. NEJM. 2013;369(3):213-223.

ALSYMPCA: Subgroup Analysis Parker C, et al. N Engl J Med. 2013;369:213-223.

ALSYMPCA: Adverse Events All Grades Grades 3 or 4 Radium-223 n = 600 n (%) Placebo n = 301 Hematologic Anemia 187 (31) 92 (31) 77 (13) 39 (13) Neutropenia 30 (5) 3 (1) 13 (2) 2 (1) Thrombocytopenia 69 (12) 17 (6) 38 (6) 6 (2) Non-hematologic Bone pain 300 (50) 187 (62) 125 (21) 77 (26) Diarrhea 151 (25) 45 (15) 9 (2) 5 (2) Nausea 213 (36) 104 (35) 10 (2) Vomiting 111 (19) 41 (14) 7 (2) Constipation 108 (18) 64 (21) 6 (1) 4 (1) At 1.5 years after the final injection, there were no reports of AML, MDS, or primary bone cancer Aplastic anemia was reported in 1 patient in the radium-223 arm (considered treatment-related) Primary cancers in other organs were identified in 2 radium-223 treated patients and 3 placebo-treated patients (deemed not study-drug related by investigators) Parker C, et al. N Engl J Med. 2013;369(3):213-223. Nilsson S, et al. J Clin Oncol. 2014;32(suppl 4). Abstract 9.

Aspects of Ra-223 Therapy Administration Outpatient therapy Every 4 weeks x 6 (~ 6 months total), unless other therapy initiated for PoD Hematologic toxicity comparable to placebo Requires coordinated multidisciplinary care Radium-223 will increase the role of nuclear medicine physicians in prostate cancer care

Future Challenges in the Management of CRPC Sequencing and combination of newer therapies Movement of newer therapies into earlier prostate cancer Integrating novel targeted agents Cost-effective management

What is the optimal sequence of therapy? Practical Considerations for Treatment of Patients With Metastatic CRPC How do we make treatment choices if there are no randomized comparisons? How can we better stratify patients to increase their chances of responding? What is the optimal sequence of therapy?

Practical Considerations: Patient Case Discussion

Metastatic CRPC Case A 65-year-old man with a previous history of CAD presented with a PSA of 97 ng/mL Biopsy showed a Gleason 3+4 adenocarcinoma of the prostate Bone scan showed evidence of osteoblastic metastases He was treated with an LHRH agonist 2 years later he develops castrate-resistant disease His PSA has increased from 10 to 30 ng/mL He complains of fatigue, difficulty urinating, and bone pain Several new osseous metastases are detected

How would you treat this patient? Key Takeaways?

Metastatic CRPC Case Continued The patient was treated with docetaxel chemotherapy After 6 cycles he developed painful peripheral neuropathy and discontinued treatment His PSA increased from 16 to 38 ng/mL His bone pain has worsened

How would you treat this patient now? Key Takeaways?

Case Takeaways Multiple active agents are now available for CRPC Patients have treatment options. The first treatment is generally not the last treatment The optimal sequence of treatments has yet to be determined Data are unclear regarding the safety of radium-223 therapy following chemotherapy

Treatments for CRPC by Symptoms and Presence of Visceral Disease Symptomatic Asymptomatic Visceral Non-Visceral Docetaxel √ Sipuleucel-T √* Abiraterone acetate Enzalutamide Cabazitaxel Mitoxantrone Radium-223 *Mild symptoms. Mohler JL, et al. J Natl Compr Canc Netw. 2013;11:1471-1479.

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