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.