Radium-223 in Metastatic Prostate Cancer
First alpha emitter to undergo phase III testing and receive approval for clinical use
The results of Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA), a phase III, randomised, double-blind, multinational study comparing the efficacy and safety of radium-223 versus placebo in patients with castration-resistant prostate cancer and bone metastases have been reported by Dr Chris Parker and colleagues in July 18, 2013 issue of The New England Journal of Medicine.
More than 90% of patients with metastatic castration-resistant prostate cancer have radiologic evidence of bone metastases, which are not only a major cause of death, but also of disability, decreased quality of life and increased treatment cost. Current bone-targeted therapies have not been shown to improve survival, and the benefits derived from bisphosphonates, denosumab, and existing radioisotope treatments are primarily limited to pain relief and delay of skeletal events.
Radium-223 dichloride (radium-223) is a targeted alpha emitter that selectively binds to areas of increased bone turnover in bone metastases and emits high-energy alpha particles of short range (<100 μm). As a bone-seeking calcium mimetic, radium-223 is bound into newly formed bone stroma, especially within the microenvironment of osteoblastic or sclerotic metastases. The high-energy alpha-particle radiation induces mainly double-stranded DNA breaks that result in a potent and highly localised cytotoxic effect in the target areas. The short path of the alpha particles also means that toxic effects on adjacent healthy tissue and particularly the bone marrow may be minimised.
Radium-223 has been reported to have a favorable safety profile, with minimal myelotoxicity, in phase I and II studies involving patients with bone metastases. Phase II studies have shown that radium-223 reduces pain and improves disease-related biomarkers (e.g., bone alkaline phosphatase and prostate-specific antigen), and they have suggested a survival benefit among patients with castration-resistant prostate cancer and bone metastases.
In this phase III, randomized, double-blind, placebo-controlled study, the researchers randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary endpoint was overall survival. The main secondary efficacy endpoints included time to the first symptomatic skeletal event and various biochemical endpoints. A pre-specified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223.
At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; p = 0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; p < 0.001). Assessments of all main secondary efficacy endpoints also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events.
The authors concluded that in this study, which was terminated for efficacy at the pre-specified interim analysis, radium-223 improved overall survival.
The study was funded by Algeta and Bayer HealthCare Pharmaceuticals. The extensive list of disclosures of conflict of interest is available in the original article, but in this news we report on disclosure from the first study author. Dr Parker reported receiving consulting and lecture fees from Amgen, Astellas, Bayer, and Janssen, consulting fees from Bristol-Myers Squibb, BN ImmunoTherapeutics, and Takeda, and lecture fees from Sanofi-Aventis. The study authors thanked to Heather Nyce, PhD from the SciStrategy Communications for medical writing assistance.
The study was first presented in part at the European Multidisciplinary Cancer Congress organised by ECCO and ESMO in Stockholm, Sweden (September 23–27, 2011); and subsequently at the Genitourinary Cancers Symposium, San Francisco, USA (February 2–4, 2012); 27th Annual Congress of the European Association of Urology, Paris, France (February 24–28, 2012); annual meeting of the American Urological Association, Atlanta, USA (May 19–23, 2012); annual meeting of the American Society of Clinical Oncology, Chicago, USA (June 1–5, 2012); and the European Society for Medical Oncology Congress, Vienna, Austria (September 28–October 2, 2012).
A long-awaited momentum in the research of alpha emitters
In their article, the authors discussed that radium-223 significantly prolonged overall survival in patients who had castration-resistant prostate cancer and bone metastases, with a 30% reduction in the risk of death, as compared with placebo. In the updated analysis, the median survival was longer among patients who received radium-223 than among those who received placebo, by 3.6 months. All main secondary efficacy endpoints were significant and favored treatment with radium-223, including the clinically defined endpoint of the time to the first symptomatic skeletal event, which was significantly prolonged among patients who received radium-223.
Whereas other trials included asymptomatic fractures — detected by means of periodic radiologic review — as skeletal events, in this study, only symptomatic pathologic bone fractures were included as symptomatic skeletal events.
The highly targeted nature of radium-223, with alpha particles of short range, minimizes myelosuppression and has limited effects on normal tissue. The overall incidence of adverse events was consistently lower in the radium-223 group than in the placebo group for adverse events of all grades, grade 3 or 4 adverse events, and serious adverse events. The number of patients who discontinued the study drug because of adverse events was also lower in the radium-223 group. No clinically meaningful differences in the frequency of hematologic adverse events were observed between the study groups.
A distinctive feature of the study was the liberal definition of the best standard of care permitted with both study drugs (radium-223 and placebo); this allowed patients to be treated with standard therapies chosen by the treating physician. Consequently, findings from this study may be generalizable to routine clinical practice, since the control group consisted of patients who received placebo with the best standard of care. The study also has high external validity because it used liberal inclusion criteria that are representative of the general population of patients with castration-resistant prostate cancer. One limitation was the exclusion of patients with visceral metastases, which may occur in up to 25% of patients with castration-resistant prostate cancer.
Many patients with castration-resistant prostate cancer and bone metastases do not receive docetaxel because they are too frail (ECOG performance-status score >2), they have coexisting conditions that preclude its use, or they simply decline treatment. However, this study addressed this important group by including patients who were not thought to be eligible to receive chemotherapy or who chose not to receive it. It is possible that some of these men could have received chemotherapy at other institutions or in other studies, the authors speculated. At least 20 to 40% of patients with castration-resistant prostate cancer and bone metastases never receive chemotherapy, so this study addressed an important unmet need in a population that is not served by current therapies.
The treatment of prostate cancer has evolved since the trial began, with new data on the use of cabazitaxel, abiraterone, and enzalutamide in patients who have received docetaxel. The excellent safety profile of radium-223 and the non-overlapping mechanism of action make radium-223 potentially suitable for use either sequentially or in combination with these other agents. A phase I–II trial of radium-223 combined with docetaxel in patients with castration-resistant prostate cancer and bone metastases is currently ongoing.
The first alpha emitter to reach the clinic
In an accompanied editorial article entitled “Fighting Prostate Cancer with Radium-223 — Not Your Madame's Isotope”, Drs Neha Vapiwala and Eli Glatstein from the Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia (USA) wrote that radium-223, the first alpha emitter to undergo phase III testing and receive approval for clinical use, acts independently of cell cycles, surface markers, and tumor types. The simplicity of the alpha emitter radium-223 lies in its winning combination of a convenient half-life (11.4 days) and its inherent bone-seeking and potent DNA-damaging properties.
No discussion of radium is complete without first acknowledging Madame Marie Curie, who with her husband Pierre first isolated radium-226, the editorialists wrote. Despite the current widespread availability of radiopharmaceutical agents, short-lived alpha emitters that are suitable for intravenous medical therapy have been limited until recent advances in radiochemical separation and cyclotron-based production of alpha emitters made their generation feasible. Yet, obstacles to their use may still exist.
Alpha particles traditionally provoked fear in the lay public and nervousness in the medical community (including some radiation safety officers) because of their enhanced relative biologic effectiveness, which is several times that of traditional x-rays (depending on the tissue type), but it is their most and least attractive feature. Alpha particles are efficient, and they cause cell damage with a single knockout as compared with gamma rays and beta particles. Such killing power is rendered unattractive if it is coupled with an unforgiving half-life.
Historically, safety concerns stemmed from the 1601-year half-life of radium-226 and its decay into volatile radon gas. These concerns were further fueled by horror stories that included lost radium sources that underwent accidental heat sterilization and vaporization and closed down entire hospitals. However, alpha disintegrations are in fact remarkably easy to shield because of the particles' heavy mass and limited penetration — picture a minimal-range heavy missile stopped by a sheet of paper. Universal precautions generally suffice.
Radium-223 is transportable worldwide in shielded, screw-cap vials. Unlike its older cousin, it rapidly decays into stable compounds — meaning that after several half-lives, one can discard any waste with ordinary trash. Logistically, alpha-emitter therapy is feasible for most centers whose staff members are well-trained in radionuclide therapy as long as there is some initial investment to update existing safety procedures and to acquire alpha-tailored assay and survey devices, as well as an ongoing investment in training for radiation safety personnel.
As for patients' safety, Parker et al. reported remarkable tolerability of radium-223 in a population that had a baseline risk of progressive complications from underlying disease. The decay kinetics of radium-223 and its use in patients with metastatic disease also suggest that the legacy of second cancers observed in the female factory workers who had radium poisoning in the early 20th century and the common medical use of thorium dioxide will not be repeated.
In 1996, a workshop sponsored by the USA Department of Energy on the development of alpha emitters for medical use identified multiple priority areas for future clinical research, including applications for non-malignant conditions. Astatine-211 and bismuth-213 were deemed the most promising agents at the time. Yet in 2013, barriers to their adoption remain. Few alpha emitters are actively being tested in the clinic, and these tests are limited to cancer trials.
Radionuclide therapy is not a new concept in oncology. Radioimmunotherapy is a successful approach in cancer therapy that marries a homing antibody of choice to a lethal radioisotope. As newer targeting molecules emerge, the editorialists envisioned alpha emitters as a potent partner to further enhance radioimmunotherapy. But some questions certainly remain.
Bone-seeking beta emitters such as phosphorus-32, strontium-89, and samarium-153 lexidronam have been tested, yet the alpha emitter is the only one to show a survival advantage. Is the higher relative biologic effectiveness of alpha particles the sole cause, or did differences in study design, patient selection, or isotope localization contribute the authors have questioned. Established and validated methods to quantify the dose delivered to the body and to each lesion are lacking. As compared with non–alpha emitters, alpha particles, which have high linear energy transfers and limited-range paths, necessitate a greater emphasis on elucidating their biodistribution and microdosimetry.
Nonetheless, this study imparts some long-awaited momentum to research on the use of alpha emitters and shows an overall survival advantage with a compound that is safe and manageable for both patients and providers. While the most appropriate treatment approach with radium-223 is actively investigated, the first-line role of taxanes in metastatic castration-resistant prostate cancer may be reexamined and the viability of alpha particles in medicine may be newly explored 115 years after their discovery, the authors concluded.
Parker C, Nilsson S, Heinrich D, et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. N Engl J Med 2013; 369: 213-223
Read the full article in the New England Journal of Medicine