The data from the first interim analysis of the REASSURE study demonstrated that radium-223 had a good short-term safety profile in patients with mCRPC with bone metastases treated in routine clinical practice across the European Union, Israel, and the United States. These findings are in line with the safety profiles previously reported for radium-223 in patients with bone mCRPC in the clinical trial setting [1, 9, 10]. Compared with the ALSYMPCA study [1], patients in the present analysis tended to have less advanced disease, as evidenced by fewer metastatic lesions (≤20 lesions in 67% vs 59% and superscan in 6% vs 9%) and lower median levels of PSA (61 ng/mL vs 146 ng/mL) and ALP (132 U/L vs 211 U/L).
For many years, docetaxel was the only systemic treatment option with a proven survival benefit for mCRPC [5, 6]. However, more recently, abiraterone, enzalutamide, sipuleucel-T (only in the United States), cabazitaxel, and radium-223 are survival-prolonging treatment options for patients with mCRPC [4, 11]. The optimal patient profile for radium-223, and its best use in sequence with the other approved agents, however, is unclear, with no level 1 evidence reported and few consensus opinions available. In the present analysis, patients who had not previously received chemotherapy appeared to have less advanced disease than patients who had received prior chemotherapy, as suggested by their more favourable baseline disease characteristics, including a shorter time for which tumours had been castration-resistant, fewer patients with an ECOG performance status ≥2, the presence of fewer metastatic lesions, and lower baseline PSA and ALP levels. In addition, patients who had not previously received chemotherapy more often completed six radium-223 injections than those who had received prior chemotherapy. Similarly, completion of radium-223 was reported to be more likely in patients with less advanced disease (as defined by better baseline characteristics) treated in a community-based setting [12, 13]. Furthermore, the better safety profile and lower rates of treatment discontinuation reported in patients who had not previously received chemotherapy compared with those who had, might also suggest that patients with mCRPC and bone metastases may benefit from radium-223 earlier in their treatment course, before administration of chemotherapy. Alternatively, this may simply reflect incomplete recovery from the prior effects of chemotherapy in the previously treated patient group.
Bone marrow function is often compromised in patients with bone metastases [14]; therefore, assessing bone marrow suppression and the need for bone-targeting treatments is of interest in this patient group. In contrast to radiopharmaceuticals that emit long-range beta particles, the short-range alpha particles emitted by radium-223 theoretically result in a more localised effect, with less bone marrow suppression and fewer related adverse events [15, 16]. In the current post hoc analysis, blood transfusions were received by 46 patients (8%) prior to initiation of radium-223 and by 68 patients (12%) during the course of radium-223 therapy; 21 of these patients received transfusions both before and during radium-223 therapy. Notably, patients who had received prior chemotherapy were more likely to have received blood transfusions prior to receiving radium-223, or concomitantly with radium-223. In the ALSYMPCA study, 42% of patients required blood transfusions from randomisation to study end. Post hoc analyses from the ALSYMPCA study identified significant baseline predictors for haematological toxicity related to radium-223 treatment, which included the extent of bone disease, PSA levels, decreased haemoglobin levels and platelet counts, and prior chemotherapy use [17]. The authors recommended that such factors should be considered in the management of patients with mCRPC treated with radium-223.
In this analysis, drug-related haematological SAEs occurred more frequently in patients with a history of prior chemotherapy use; these patients generally had a higher burden of bone disease and more often discontinued treatment, suggesting that the higher haematological adverse event rate was perhaps a consequence of prior treatment and/or disease stage rather than radium-223-related toxicity. Subsequent analyses of the REASSURE study may help clarify the long-term effects of radium-223 on bone marrow. Safety studies such as this play a critical role in helping to determine the optimal treatment approach for patients.
This study provides the opportunity to prospectively collect safety data on radium-223 in routine clinical practice, although caution must be used in interpreting the results due to the observational nature of the study. In particular, the single-arm study design does not allow comparison with a control group. The current analysis is of particular interest, since radium-223 is commonly administered later in the disease course, often after chemotherapy and in patients that are considered not suitable for chemotherapy or where chemotherapy is contraindicated [1, 18, 19]. Some physicians consider that it is important for management of the disease that the opportunity is provided to administer as many of the available life-prolonging therapies as possible. Therefore, it may be the case that radium-223 might be better placed early in the disease course during initial lines of treatment, but must be placed prior to the onset of visceral disease (lung, liver, or other organ metastases) [20].
Although the short follow-up time for this interim analysis precluded data on overall survival, subgroup analyses from the ALSYMPCA trial showed an overall survival benefit for radium-223 irrespective of prior docetaxel use [7]. Exploratory analyses suggested that administration of docetaxel following radium-223 was viable, well tolerated, and did not adversely affect overall survival [8]. Long-term safety and outcomes on all patients in REASSURE will be reported in the next interim analysis, expected in 2019.
In conclusion, the short-term safety profile of radium-223, when used in routine clinical practice settings in patients with mCRPC with bone metastases, was comparable to other clinical studies, regardless of prior chemotherapy use, with no unexpected findings reported. Drug-related SAEs were most often haematological and occurred more frequently in patients with a history of prior chemotherapy use and a higher burden of disease, which could potentially be due to advanced disease or toxicity from prior chemotherapy. Patients who had not previously received chemotherapy appeared to have a lower burden of disease at baseline, experienced a lower incidence of haematological adverse events, and discontinued radium-223 treatment less often. These results may suggest that selected patients with mCRPC with bone metastases may benefit from the use of radium-223 earlier in the course of treatment, before treatment with chemotherapy.