At the time of this interim analysis, the median duration of observation of the 583 eligible patients from radium-223 initiation to end of observation was 7 months (range, 0–20 months). Nineteen of these 583 (3%) patients had possible concomitant treatment with chemotherapy and were thus excluded from the exploratory analysis (Online Resource 1). Therefore, analysis according chemotherapy subgroups was performed on 564 patients: 190 (34%) in the prior chemotherapy group and 374 (66%) in the no prior chemotherapy group. Baseline and disease characteristics of these patients are summarised in Table 1. The median age of patients was 73 years (range, 44–94 years), with 78% having an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. A high proportion of patients who had previously received chemotherapy were enrolled in Europe and Israel (74%), and the rest were enrolled in North America (26%). One hundred and twenty-three of 190 patients (65%) who had previously received and completed chemotherapy and 107 of 374 patients (29%) who had not, had also received and completed abiraterone and/or enzalutamide prior to radium-223.
Patients who had been treated with chemotherapy prior to radium-223 appeared to have poorer baseline characteristics than those who had not (Table 1). This included a higher proportion of patients with an ECOG performance status of 2 or 3 (22% vs 11%), a higher proportion with >20 metastatic lesions (not including superscan), as observed on bone scans (26% vs 15%), and higher median levels of prostate-specific antigen (PSA, 132.0 vs 40.2 ng/mL) and alkaline phosphatase (ALP, 162.0 vs 115.0 U/L), in the group who had previously received chemotherapy compared with those who had not. In addition, patients previously treated with chemotherapy had longer median times with castration-resistant disease (23 vs 10 months) and with bone metastases (34 vs 19 months) before study entry.
Eighty-five of 190 patients (45%) who had received chemotherapy prior to radium-223, and 237 of 374 patients (63%) who had not previously received chemotherapy, had completed six radium-223 injections; the median number of radium-223 injections was five and six, respectively, in these groups (Table 2). Fifty-nine (31%) patients who had previously received chemotherapy and 148 (40%) who had not, were treated with concomitant abiraterone and/or enzalutamide.
Overall safety data are summarised in Table 3. In total, 300 of 564 patients (53%) experienced any adverse event. Drug-related TEAEs were reported in 213 patients (38%), the most common of which were gastrointestinal disorders in 118 patients (21%) and haematological toxicities in 73 patients (13%). Drug-related TEAEs were recorded in 78 of 190 (41%) patients who had received prior chemotherapy and 135 of 374 (36%) patients who had not; most of these were gastrointestinal disorders, which occurred in 41 (22%) and 77 (21%) patients, respectively. Haematological toxicities were reported in 39 of 190 (21%) patients who had received prior chemotherapy and 34 of 374 (9%) patients who had not.
Drug-related TEAEs by MedDRA preferred term and worst NCI-CTCAE grade occurring in ≥3% of patients in any treatment group or selected for relevance for chemotherapy are summarized in Table 4. Differences in the observed frequency of drug-related TEAEs by MedDRA preferred term of any grade between patients who had received previous chemotherapy and those who had not, included anaemia (15% vs 7%), leukopenia (3% vs 1%), thrombocytopenia (5% vs 3%), and nausea (13% vs 9%). The most common grade 3 or 4 drug-related TEAE was anaemia, which was reported in 23 of 564 patients (4%), occurring in 15 of 190 patients (8%) who had received prior chemotherapy and 8 of 374 (2%) who had not. Grade 3 or 4 fractures in the prior chemotherapy group included a femoral neck fracture, a hip fracture, and a spinal compression fracture, and in the no prior chemotherapy group included a femur fracture, a hip fracture, and a humerus fracture (Online Resource 2).
The incidence of treatment discontinuation due to treatment-emergent drug-related adverse events was low, occurring in 34 of 564 patients (6%) overall, including 17 of 190 (9%) who had previously been treated with chemotherapy, and 17 of 374 (5%) patients who had not (Table 3).
Drug-related SAEs occurred in 13 of 190 (7%) patients who had previously received chemotherapy and 12 of 374 (3%) who had not, the most common of which were haematological toxicities reported in eight and five patients, respectively.
Post-treatment grade 3 or 4 bone marrow suppression events were reported in 50 of 564 patients (9%), occurring in 24 of 190 (13%) who had received prior chemotherapy and in 26 of 374 (7%) who had not (Online Resource 3). The most common were haematopoietic erythropenia in 11% vs 6% and thrombocytopenia in 4% vs 2% of patients who had or had not previously received chemotherapy.
Blood transfusions were received prior to radium-223 therapy in 46 of 546 patients (8%) and concomitantly with radium-223 in 68 patients (12%), including 21 (4%) who received transfusions both before and during radium-223 therapy. Patients who had received prior chemotherapy were more likely to undergo blood transfusions than those who had not, either prior to radium-223 (17% vs 5%) or concomitantly with radium-223 (21% vs 8%) (Table 5).
There were four reported drug-related SAEs leading to death, all occurring in patients who had received prior chemotherapy. These included one patient each with anaemia, pancytopenia, and monocytic leukaemia, and one patient where the event was not reported.