Table 3. Patient Disposition (ITT Population)

Radium-223 n = 614

Placebo n = 307

ALSYMPCA Study

Patients treated with study drug (safety population), n

599 302

Median number of study drug injections, range

6 (1-6) 5 (1-6)

Patients receiving all 6 injections of study drug, n (%)

387 (63) 145 (47)

Chemotherapy After Study Drug

Patients treated with chemotherapy after study drug, n

93 54

Median number of study drug injections, range

6 (2-6) 5.5 (1-6)

Patients receiving all 6 injections of study drug, n (%)

66 (71) 27 (50)

The most common chemotherapeutic agents •administered after study drug treatment were docetaxel (n = 105), mitoxantrone (n = 23), and cyclophosphamide (n = 19)

Median time to chemotherapy after study drug •was 15.5 days longer in the radium-223 group than in the placebo group (80.0 vs 64.5 days, respectively; Table 4)

Median duration of chemotherapy administered •after study drug was 120 days (17.1 weeks) in the radium-223 group vs 112.5 days (16.1 weeks) in the placebo group (Table 4)

Table 4. Median Time to Chemotherapy and Duration of Chemotherapy Administered After Study Drug

ParameterRadium-223

n = 93Placebo n = 54

Patients receiving chemotherapy* after study drug, n

93 54

Median time to chemotherapy, days (range)

80.0 (1-667) 64.5 (2-448)

Median duration of chemotherapy, days (range)

120.0 (1-809) 112.5 (1-863)

*The most common chemotherapeutic agents administered after study drug were docetaxel (n = 105), mitoxantrone (n = 23), and cyclophosphamide (n = 19).

Overall Survival

In the updated ALSYMPCA analysis of all •921 randomized patients prior to placebo crossover, radium-223, compared with placebo, significantly improved OS in patients with CRPC and bone metastases (P = 0.00007; HR = 0.695; 95% CI, 0.581-0.832; Figure 3)

Median OS was 14.9 months in the −radium-223 group vs 11.3 months in the placebo group

Radium-223, 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

578 504 369 274 178 105 60 41 18 7 1 0 0 307 288 228 157 103 67 39 24 14 7 4 2 1 0

%

Radium-223 614Placebo

3027242118151296300

10

20

30

40

50

60

70

80

90

100

33 36 39Month

Figure 3. ALSYMPCA Overall Survival in Patients With CRPC and Bone Metastases

Administering chemotherapy after radium-223 •had no deleterious effect on patient OS

Median OS from start of chemotherapy −was 15.6 months in the radium-223 group and 14.6 months in the placebo group (P = 0.663) for patients treated with chemotherapy after the study drug (n = 147)

Adverse Events

In patients receiving chemotherapy after the •last dose of study drug (n = 147), median values of hemoglobin, neutrophils, and platelets were similar for the radium-223 vs placebo group from baseline to month 12 (Table 5)

Table 5. Hematologic Values in Patients Receiving Chemotherapy After Study Drug

Hematologic Parameter

Radium-223 (n = 93)

Placebo (n = 54)

nMedian

(min-max) nMedian

(min-max)

Hemoglobin, g/dL

Baseline* 9311.2

(7.7-14.6)54

11.4 (7.7-15.1)

Month 2 5110.6

(6.6-14.2)34

10.8 (7.7-14.2)

Month 4 4211.0

(6.4-13.6)20

10.6 (7.1-14.6)

Month 6 2411.1

(8.6-12.4)14

11.1 (8.6-14.0)

Month 8 1310.5

(8.2-12.5)7

10.8 (10.3-12.8)

Month 10 1410.2

(7.9-13.1)9

11.8 (9.9-13.3)

Month 12 810.5

(9.0-13.2)6

10.7 (9.8-13.4)

Neutrophils (Absolute) x 109/L

Baseline* 913.6

(0.9-26.0)49

4.6 (1.9-16.4)

Month 2 474.4

(0.5-24.4)30

5.7 (1.6-13.1)

Month 4 423.9

(1.3-10.8)19

4.6 (1.1-8.9)

Month 6 233.5

(0.5-6.3)12

4.7 (1.5-12.2)

Month 8 123.5

(1.9-9.4)7

3.9 (3.0-6.4)

Month 10 133.6

(1.1-8.9)8

4.6 (3.0-8.5)

Month 12 85.0

(2.5-7.1)6

5.6 (2.8-8.9)

Platelets x 109/L

Baseline* 93214

(67-484)54

241 (80-563)

Month 2 51197

(48-427)34

256 (87-385)

Month 4 42241

(48-437)20

221 (131-411)

Month 6 24216

(85-423)14

217 (99-305)

Month 8 13202

(26-512)7

288 (168-565)

Month 10 14255

(95-370)9

259 (179-512)

Month 12 8305

(164-464)6

264 (89-394)

*Lab value before start of chemotherapy (after end of study treatment); 2 patients in radium-223 group and 5 patients in placebo group were missing neutrophil values at the study visit after end of treatment.

In patients receiving chemotherapy after •study drug, the incidence values for death and causality during and 30 days after chemotherapy were similar between the treatment groups (Table 6)

BACKGROUND

> 90% of patients with metastatic CRPC have •radiologic evidence of bone metastases1

Bone metastases are a major cause of death, •disability, decreased quality of life, skeletal-related events, and increased treatment cost in patients with CRPC2

Current bone-targeted therapies have not been •shown to improve survival

Radium-223 Mechanism of Action

Radium-223 dichloride is a first-in-class alpha-•emitter pharmaceutical with a potent and highly targeted antitumor effect on bone metastases3,4 and a highly tolerable side effect profile5

Acts as a calcium mimetic −

Naturally targets new bone growth in and −around bone metastases

Excreted by the small intestine −

Bone-targeted radium-223 emits alpha-particles •with ultra-short penetration (< 100 µm; 2-10 cell diameters), causing highly localized tumor cell killing with minimal damage to surrounding normal tissue3,4 (Figure 1)

Alpha-particles have a shorter range of action −than beta-particles, permitting more selective cancer cell killing and less bone marrow toxicity compared with beta-particles4

The high linear-energy transfer (LET) −radiation produced by alpha-particles is more effective at killing cancer cells than the low-LET radiation produced by beta-particles4

Bone marrow

Range of Radium-223alpha-

Range of beta-particle

Bone Bone

surface

Tumor

particle

Figure 1. Radium-223 Targets Bone Metastases

ALSYMPCA Trial

Historically, physicians have been reluctant to •give chemotherapy after radiotherapy because of their concern that radiotherapy depletes bone marrow reserves, making chemotherapy less tolerable

In the phase 3, double-blind, randomized, •multinational ALSYMPCA study of radium-223 vs placebo in CRPC patients with bone metastases receiving best standard of care (BSoC),6 147/921 (15.9%) patients received chemotherapy after completing treatment with study drug

In order to better understand the safety •of administering chemotherapy following radium-223 therapy, a post hoc analysis was conducted to evaluate the hematologic safety profile in ALSYMPCA patients receiving chemotherapy after completing treatment with the study drug

ALSYMPCA STUDY DESIGN

In ALSYMPCA, eligible patients had •progressive, symptomatic CRPC with ≥ 2 bone metastases on scintigraphy and no known visceral metastases; were receiving BSoC; and had previously received docetaxel, were docetaxel ineligible, or had refused docetaxel

Patients were randomized 2:1 to receive •6 injections of radium-223 (50 kBq/kg IV) every 4 weeks or matching placebo (Figure 2)

Patients were stratified by prior docetaxel −use, baseline alkaline phosphatase (ALP) level, and current bisphosphonate use

The patient cohort used in the post hoc •analyses consisted of all patients who received any type of chemotherapy after completing treatment with radium-223 or placebo

Chemotherapy agents were identified, and •length of time from last injection of study drug to start of chemotherapy, as well as duration of chemotherapy, was calculated. Available hematology data were reviewed, and a post hoc analysis of survival was conducted

TREATMENT

6 injections at 4-week intervals

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

Placebo (saline)+ Best standard of care

RANDOMIZED

2:1

N = 921

PATIENTS

• ConfirmedsymptomaticCRPC• 2 bone

metastases• No known

visceralmetastases• Post-

docetaxel orunfit fordocetaxel

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

STRATIFICATION

Planned follow-up is 3 years

Figure 2. ALSYMPCA Phase 3 Study Design

RESULTS

Patients

921 patients (radium-223, n = 614; placebo, •n = 307) were randomized in ALSYMPCA from June 2008 to February 2011

Patient demographics and baseline •characteristics were well balanced between the treatment groups (Table 1)

The proportion of patients treated with •chemotherapy after completing study drug was 93/614 (15%) in the radium-223 group and 54/307 (18%) in the placebo group. Patient demographics and baseline characteristics are shown in Table 2

The number of study drug injections patients •received is shown in Table 3

Safety of Cytotoxic Chemotherapy Following Radium-223 Dichloride Therapy in the Phase 3 ALSYMPCA Study in Patients With Castration-Resistant Prostate Cancer (CRPC) With Bone Metastases

O. Sartor,1 R.E. Coleman,2 S. Nilsson,3 N. Vogelzang,4 A. Cross,5 C.G. O’Bryan-Tear,6 K. Staudacher,6 J. Garcia-Vargas,7 J. Zou,7 C. Parker8

1Tulane Cancer Center, New Orleans, LA, USA; 2Weston Park Hospital, Sheffield, UK; 3Karolinska University Hospital, Stockholm, Sweden; 4Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA; 5PharmaNet, Hemel Hempstead, UK; 6Algeta ASA, Oslo, Norway; 7Bayer HealthCare, Montville, NJ, USA; 8The Royal Marsden NHS Foundation Trust, Sutton, UK

Poster 936P

Table 1. ALSYMPCA Patient Demographics and Baseline Characteristics (ITT Population)

ParameterRadium-223

n = 614Placebo n = 307

Mean age, y (SD) 70.2 (8.1) 70.8 (7.9)

Caucasian race, n (%) 575 (94) 290 (95)

Baseline ECOG PS, n (%) ≤ 1 2 3 Missing

536 (87) 76 (12) 1 (< 1) 1 (< 1)

265 (86) 40 (13) 1 (< 1) 1 (< 1)

Extent of disease, n (%) < 6 metastases 6-20 metastases > 20 metastases/superscan Missing

100 (16) 262 (43) 249 (41) 3 (< 1)

38 (12)

147 (48) 121 (40) 1 (< 1)

WHO ladder, cancer pain index ≥ 2, n (%)

345 (56) 168 (55)

Current use of bisphosphonates, n (%) Yes

250 (40.7)

124 (40.4)

Any prior use of docetaxel, n (%) Yes

352 (57)

174 (57)

Hemoglobin, g/dL, median (min-max)

12.2 (8.5-15.7)

12.1 (8.5-16.4)

Albumin, g/L, median (min-max)

40 (24-53)

40 (23-50)

Total ALP, µg/L, median (min-max)

211 (32-6431)

223 (29-4805)

LDH, U/L, median (min-max)315

(76-2171)336

(132-3856)

PSA, µg/L, median (min-max)146

(3.8-6026)173

(1.5-14500)

Table 2. Demographics and Baseline Characteristics for Patients Treated With Chemotherapy After Study Drug (Cohort Population)

ParameterRadium-223

(n = 93)Placebo (n = 54)

Mean age, y 67.2 68.2

Caucasian race, n (%) 86 (93) 50 (93)

Baseline ECOG PS, n (%) ≤ 1 2

88 (95) 5 (5)

47 (87) 7 (13)

WHO ladder, cancer pain index ≥ 2, n (%)

48 (52)

29 (54)

Total ALP, n (%) < 220 U/L ≥ 220 U/L

59 (63) 34 (37)

38 (70) 16 (30)

Current use of bisphosphonates, n (%) Yes No

45 (48) 48 (52)

24 (44) 30 (56)

Any prior use of docetaxel, n (%) Yes No

63 (68) 30 (32)

32 (59) 22 (41)

External beam radiation within 12 weeks of screening Yes No

12 (13) 81 (87)

2 (4) 52 (96)

Hemoglobin, g/dL, median (min-max)

12.4 (9-15.7)

12.2 (8.7-14.7)

Albumin, g/L, median (min-max)

40 (24-49)

40 (28-49)

Total ALP, µg/L, median (min-max)

144.6 (32-2681)

147.5 (36-2166)

LDH, U/L, median (min-max)301

(76-1297)324.5

(132-1022)

PSA, µg/L, median (min-max)87.19

(14-848)79.94

(3.6-2566)

ALP = alkaline phosphatase; ECOG = Eastern Cooperative Oncology Group; ITT = intent to treat; LDH = lactate dehydrogenase; PS = performance status; PSA = prostate specific antigen; SD = standard deviation; WHO = World Health Organization.

Table 6. Number of Deaths and Causality

ParameterRadium-223

(n = 93)Placebo (n = 54)

During Chemotherapy Administration

Deaths on chemotherapy, % Causality: PC and skeletal mets (± other mets) PC with other mets (or mets not specified) Cerebral hemorrhage due to trauma Cardiopulmonary failure

14

10 3 1 0

15

13 0 0 2

30 Days After Chemotherapy Administration

Deaths within 30 days after chemotherapy, n (%) Causality: PC and skeletal mets (± other mets) Bronchopneumonia Respiratory failure + pulmonary edema

6 4 1 0

4 4 1 0

Mets = metastases; PC = prostate cancer.

CONCLUSIONS

Radium-223 significantly prolonged OS •by 3.6 months vs placebo (HR = 0.695; 95% CI, 0.581-0.832; P = 0.00007)

30.5% reduction in risk of death −

Administering chemotherapy after •radium-223 had no deleterious effect on patient OS

Hematologic safety profiles for patients •receiving chemotherapy after radium-223 were similar to those for patients receiving chemotherapy after placebo

Radium-223, a novel alpha-emitter, may •provide a new standard of care for the treatment of patients with CRPC and bone metastases

REFERENCES

Tannock et al. 1. N Engl J Med. 2004;351:1502-1512.Lange and Vasella. 2. Cancer Metastasis Rev. 1999;17:331-336.Henriksen et al. 3. Cancer Res. 2002;62:3120-3125.Henriksen et al. 4. J Nucl Med. 2003;44:252-259.Nilsson et al. 5. Lancet Oncol. 2007;8:587-594.ClinicalTrials.gov Registration Number: NCT00699751http://6. www.clinicaltrials.gov/ct2/show/NCT00699751.

FUNDING

Research support was provided by Algeta ASA and Bayer HealthCare.