Radium-223 Chloride: Extending Life in Prostate Cancer Patients by Treating Bone Metastases

Radium-223 chloride

²²³RaCl₂ is a water-soluble radium salt. In ionic form, radium accumulates in bones at areas with increased bone turnover because of its chemical similarity to calcium ions; both are alkaline earth metals (18, 19). Radium-223 is an α-emitting radioisotope that decays via 7 daughter nuclides before it stabilizes as lead-207 (Fig. 1). During the decay of each radium-223 isotope, 4 α-particles and 2 electrons (β-particles) are emitted (Table 1). Both α- and β-irradiation can induce local therapy by inducing damage in the surrounding tissue. Because of the size and high energy of α-particles, these particles are highly effective in inducing double-strand breaks in DNA within 100 μm. The half-life of radium-223 is 11.4 days; the half-lives of its daughter nuclides range from seconds to minutes. These daughter nuclides do not have a chemical similarity to calcium ions. Therefore, the half-lives of radon-219 (4.0 seconds), bismuth-211 (2.1 minutes), and thallium-207 (4.8 minutes) seem to be long enough to allow diffusion from the primary accumulation site.

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Figure 1.

Radioactive decay of radium-223. Radium-223 decays via 7 daughter nuclides to lead-207, resulting in the emission of both α-particles (vertical step in diagram) and β-particles (horizontal step in diagram). T_1/2, half-life.

Early preclinical and clinical studies

In a preclinical study, nude rats with MT-1 human breast cancer xenografts were treated with pamidronate, a bisphosphonate used against skeletal complications of cancer, with or without radium-223 (18). Although all rats treated with pamidronate only had to be sacrificed within 21 days, 40% of rats treated with pamidronate and radium-223 at 10 or 30 kBq survived beyond 50 days. Compared with β-emitting particles such as strontium-89, rodents treated with radium-223 showed no signs of bone marrow suppression or other toxicities (20).

In a phase I study, ²²³RaCl₂ was administered to 15 prostate and 10 breast cancer patients with bone metastases (21). Patients received a single i.v. injection of radium-223 with activities up to 250 kBq/kg. More than 50% of patients reported pain relief, although toxicity was low. Grade 3 leukopenia occurred in 3 patients, and the maximum-tolerated dose (MTD) was not established. Radium-223 accumulated in the skeleton, particularly in sites with metastases. In the blood, radioactivity levels diminished quickly: to 6% after 1 hour and to <1% 24 hours after injection. Recently, similar findings were presented from another phase I study (22). In this study, 10 mCRPC patients received radium-223 up to 200 kBq/kg, among which 6 patients received a second dose of 50 kBq/kg. The MTD was again not established, and radium-223 was rapidly cleared from the blood, primarily into the small bowel.

A subsequent phase II study compared treatment of 50 kBq/kg radium-223 with placebo treatment in 64 CRPC patients with painful bone metastases (23, 24). The median time to skeletal-related event was 14 weeks in the radium-223–treated group versus 11 weeks in patients treated with placebo (P = 0.257; ref. 23). Low toxicity of radium-223 was confirmed in this phase II study. None of the 33 radium-223-treated patients discontinued treatment because of adverse events. Grades 3 and 4 adverse events occurred in 3 (9.1%) and 0 (0%) radium-223–treated patients and in 1 (3.3%) and 1 (3.3%) placebo-treated patients, respectively. Severe nonhematologic adverse events occurred in 3 (9.1%) radium-223–treated patients and in 5 (16.7%) placebo-treated patients. In a follow-up report, 24 months after the first injection of study medication, no long-term treatment-related toxicity was noted (24). The median overall survival was 65 weeks in the radium-223–treated group, and 46 weeks in the placebo-treated group (P = 0.056).

ALSYMPCA

The ALSYMPCA phase III study was initiated in 2008, comparing the efficacy and safety of ²²³RaCl₂ with that of placebo (a saline injection) in patients with symptomatic CRPC with bone metastases (25). Patients needed to have at least 2 bone metastases, diagnosed by bone scintigraphy. Patients were eligible if they had previously received docetaxel, if they were unfit for docetaxel, if they declined therapy with docetaxel, or if docetaxel was not available. Patients were excluded if they had visceral metastases. Patients received an i.v. injection (50 kBq/kg) once every 4 weeks for a maximum of 6 cycles.

In total, 921 patients were included at 135 study locations worldwide, primarily in North America, Australia, and Europe (26). Six hundred fourteen patients received radium-223, of whom 352 had received docetaxel before radium-223 treatment (57.3%). In the placebo group, a similar percentage had received prior docetaxel [56.6% (174 patients)]. Other baseline characteristics, such as age, disease stage, and baseline opioid use, were similar between the two treatment groups as well (25).

The primary endpoint of the ALSYMPCA study was overall survival. In general, the median overall survival in patients treated with radium-223 was extended by 3.6 months compared with placebo-treated patients (P < 0.001; ref. 25). For patients who had received docetaxel before participation in the ALSYMPCA trial, the median overall survival was 14.4 months in radium-223–treated patients versus 11.3 months in placebo-treated patients [HR = 0.71; 95% confidence interval (CI), 0.56–0.89]; for patients who had not received prior docetaxel, the median overall survival durations were 16.1 months and 11.5 months, respectively (HR = 0.74; 95% CI, 0.56–0.99; ref. 25).

The key secondary endpoint in the ALSYMPCA trial was time to symptomatic skeletal event (SSE), defined as the time to first use of external-beam radiotherapy to relieve skeletal symptoms, new symptomatic pathologic bone fractures, spinal cord compression, or tumor-related orthopedic surgery. Imaging to assess for skeletal events was only performed when clinically indicated to avoid registration of asymptomatic fractures. Time to SSE was 15.6 months in radium-223–treated patients versus 9.8 months in the placebo-treated group (P < 0.001; HR = 0.66; 95% CI, 0.52–0.83; ref. 25). Time to initial opioid use and time to external beam radiotherapy were both increased in patients treated with radium-223 (HR = 0.670 and 0.621, respectively; ref. 27). Sixteen and 24 weeks after initiation of radium-223 treatment, patients had significantly less pain compared with baseline (P < 0.001 and 0.001, respectively).

Further analysis revealed that an increase in the levels of total alkaline phosphatase was associated with an increased risk for death in the patient population studied in the ALSYMPCA trial (P < 0.0001; ref. 28). In patients treated with radium-223, a ≥30% reduction in total alkaline phosphatase levels compared with the baseline was seen in 47% of patients versus 3% of placebo-treated patients (25).

In general, radium-223 was well tolerated by patients, with grade 3 or 4 adverse events occurring more frequently in the placebo-treated group (62%) than in patients treated with radium-223 (56%). The only reported nonhematologic grade ≥3 adverse events that occurred more frequently in the radium-223–treated patient group were anorexia (2% versus 1%) and a decreased appetite (2 patients vs. 0 patients). Comparing grade ≥3 hematologic adverse events in the radium-223–treated group to the placebo group, anemia occurred in 13% and 13%, neutropenia in 3% and 1%, and thrombocytopenia in 6% and 2%, respectively (25). Analysis of these hematologic adverse events revealed that a baseline total alkaline phosphatase of ≥220 U/L strongly predicted anemia (29). Apart from the use of radium-223 instead of placebo, other baseline predictors for neutropenia and thrombocytopenia were prior docetaxel use and more than 6 bone metastases. However, prior external beam radiotherapy to the bone was associated with a decrease in anemia and neutropenia.

FDA approval

Interim results from the ALSYMPCA phase III clinical trial led to approval of radium-223 by the FDA for the treatment of mCRPC patients who have symptomatic bone metastases and no visceral metastases. It was recommended to be administered at 50 kBq/kg every 4 weeks with a maximum of 6 doses, which is equal to the treatment regimen in the ALSYMPCA trial. This approval makes radium-223 the first agent available for mCRPC patients that significantly increases overall survival by exclusively treating bone metastases.

Despite its decision to approve radium-223, the FDA required four additional studies, besides final analysis of ALSYMPCA study results (30). Noncompliance to this decision, or negative results, could result in the FDA revoking the approval.

As mentioned previously, no MTD for radium-223 has been established (21, 22). Results from phase I studies suggested concentrations higher than 50 kBq/kg could be administered to patients with relatively few changes in the toxicity profile of the agent. Two recent phase II studies confirm that treatment up to 100 kBq/kg has similar toxicities compared with radium-223 at 50 kBq/kg, although the efficacy of radium-223 is increased (31, 32). Therefore, the FDA required a randomized phase II study to further assess the efficacy and safety of radium-223 in CRPC patients with bone metastases at concentrations higher than 50 kBq/kg. If these results suggest a beneficial risk–benefit profile for higher doses, an additional phase III study will be required to confirm the optimal activity level.

The FDA required the company to perform three studies to further assess the safety of radium-223: an observational study in 1,200 CRPC patients with bone metastases, evaluating the long-term safety of radium-223 administered at the recommended dose; a randomized clinical trial in CRPC patients with bone metastases and no visceral metastases to further assess the safety of radium-223, particularly for enhanced assessment of the effect of radium-223 on healthy bone marrow and secondary malignancies, such as acute myeloid lymphoma and myelodysplastic syndrome (33), and finally, an assessment of the short- and long-term safety of a radium-223 rechallenge, for which the company was required to perform a study in which CRPC patients with bone metastases were re-treated with radium-223.