Radium-223 in Advanced Prostate Cancer

Saby George, MD, FACP

Corresponding Author:

Assistant Professor of Medicine and Oncology,

Roswell Park Cancer Institute,

Elm and Carlton Streets, Buffalo, NY

saby.george@roswellpark.org

Abstract

The progression of prostate cancer to castration-resistant prostate cancer (CRPC) is a crucial change in the behavior of this cancer. As CRPC progresses in the face of androgen-deprivation therapy, bony metastasis is a common finding that may cause symptoms such as pain. Until recently, symptomatic metastatic disease has been commonly treated by the initiation of docetaxel plus prednisone-based therapy. Recently approved novel agents in the CRPC setting include immunotherapy (sipuleucel-T), a CYP- 17 inhibitor (abiraterone), an androgen receptor (AR) signaling blocker (enzalutamide), and a semi-synthetic taxane (cabazitaxel), all of which have shown survival advantages in large, randomized phase III trials. The most recent addition to this list of approved agents is the radiopharmaceutical Xofigo (previously named Alpharadin), or radium-223 dichloride. Radium is an alkali earth metal (such as calcium) that has the tendency to seek areas of new bone formation. Intravenous injection of radium-223 emits alpha particles, which are distinct from beta particles in terms of mass, energy, distance travelled by the particles in tissues, and lethal hits per cell. Recently, the ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial demonstrated improved survival in patients with CRPC with predominant bony metastatic disease who were treated with radium-223 as compared with placebo.

Significance of Bone Metastasis and Bone-Targeted Therapies in Metastatic CRPC

Prostate cancer is the most common cancer in men.¹Castration-resistant prostate cancer (CRPC) is a part of the natural history of metastatic prostate cancer and remains a lethal malignancy, despite the recent introduction of new treatments over the past 10 to15 years that include docetaxel, cabazitaxel, abiraterone, enzalutamide, and sipuleucel-T, all of which have been shown to prolong overall survival (OS) significantly versus their respective comparators.^2-6Anticancer drugs to treat prostate cancer also have been complemented by the development of clinically effective bone-modifying agents such as denosumab and zoledronic acid^7,8since it is well known that the majority of the metastatic prostate cancer burden is located in bones. Sclerotic bone lesions are a hallmark of metastatic prostate cancer, and these sites are usually associated with new bone formation and rapid bone turnover. Radium-223 is an alkali earth metal that has bone-seeking properties that allow for its accumulation in areas of new bone formation.Bone is the most common site of metastasis from prostate cancer, and bone metastases cause significant morbidity and are associated with increased costs for cancer care. Effects of bone metastases from prostate cancer include skeletal-related events (SREs; defined as pathological fracture, spinal cord compression, need for therapeutic radiation to bone, or surgery to bone), myelosuppression/myelophthisis, and the need for transfusions. Bone is a highly vascular structure with a complex microenvironment. Bone-modifying agents such as zoledronic acid and denosumab are specifically used to prevent SREs.^7,8

Radium-223: Unique Radiobiological Characteristics

Early Clinical Trials of Radium-223

TABLE. Main Differences Between Alpha and Beta Particles¹⁴

Feature

Beta

Alpha

Mass (atomic mass unit/ amu)

1

7300

Energy per emission (MeV)

0.01-2.5

3-8

Equivalent to

1 electron

2 protons and 2 neutrons (or a helium nucleus)

Distance range in tissues(mm)

50-5000

40-100

Lethal hits per cell

100-1000

1-10

Phase III ALSYMPCA Trial

Strontium-89 and samarium-153 are two radiopharmaceuticals that emit beta particles, causing an anticancer effect/cell kill. Both have been used mainly for pain palliation related to bone metastases in a variety of cancers.^9-11Even though these agents have not been shown to prolong survival in patients with CRPC, they are effective in relieving pain associated with bone metastasis. Radium-223 is a similar radiopharmaceutical agent developed for its anticancer effects.^12,13Radium-223 is an injectable radiopharmaceutical compound that has the ability to seek and deposit in new bone-forming areas,^12,13which correspond to sclerotic/ osteoblastic bony metastatic sites. Radium-223 has a half-life of 11.4 days and decays via the emission of four alpha particles. Alpha particles are heavier than beta particles and travel over a shorter distance when they are deposited in tissues. The main differences between alpha particles and beta particles are summarized in the Table.^14,15The alpha particles travel to the adjacent areas of radium deposition in the sclerotic lesions, which logically correspond to malignant cells in the bone. Alpha particles are high-energy particles that can damage the cancer cells as well as the adjacent normal marrow/stromal cells.¹⁶Thus, an anticancer effect is accompanied by adverse events such as cytopenias, which in turn are secondary to damage to noncancer cells such as hematopoietic precursor cells.Early proof-of-concept studies using gamma-scintigrams to localize the isotope in the body demonstrated that radium-223 accumulates in skeletal metastatic lesions in comparison with techniteum-99m methylene diphosphonate (^99mTc-MDP).¹²These studies also demonstrated rapid clearance of radium-223 from blood, as well as clinical effects that included reductions in bone pain and serum alkaline phosphatase levels.¹²These observations led to a series of phase II clinical trials.^17,18The large randomized, double-blind, placebocontrolled ALpharadin in SYMptomatic Prostate CAncer (ALSYMPCA) trial randomized patients with symptomatic CRPC with bone metastasis and good organ function with no metastasis to the liver, brain, or lung to receive either radium-223 or placebo.¹⁹The treatment arms included six intravenous injections of radium-223 at a dosage of 50 kBq/kg every 4 weeks plus best supportive care (BSC). The control arm included intravenous placebo (saline infusions every 4 weeks) plus BSC. All patients continued androgen-deprivation therapy. A total of 921 patients were randomized in a 2:1 manner to radium-223 (n = 614) and placebo (n = 307). The randomization was stratified by the alkaline phosphatase level, current use of bisphosphonates, or prior docetaxel treatment. No other radioisotope-based treatments were allowed during the study. The primary endpoint of the trial was OS.

Demographic characteristics were well balanced between the two groups. The majority of patients had an ECOG performance status of <1 and had more than six bony metastatic sites. The percentage of patients who experienced adverse events (AEs; all AEs, grade 3 or 4 AEs, and serious AEs) was lower in the radium-223 arm. Cytopenias (anemia, neutropenia, lymphocytopenia, and thrombocytopenia) were more frequent in the radium-223 arm. Most of the cytopenias were low grade, and the proportion of grade 3 or 4 AEs was relatively low and comparable between the arms. Gastrointestinal AEs included nausea, diarrhea, and vomiting, and were comparable between the groups. Bone pain at baseline was assessed using the World Health Organization (WHO) analgesic ladder, and the pain assessment on the study was performed using patientreported Functional Assessment of Cancer TherapyProstate (FACT-P). Bone pain was significantly lower in the radium-223 arm.²⁰This included a reduction in the need for external-beam radiation therapy (EBRT) for pain control, need for opioids, and lower pain scores, all favoring the radium arm.

Clinical Pearls

• Radium-223 has been shown to prolong survival and delay SREs in metastatic CRPC.
• The ideal patient for radium-223 should have metastatic CRPC with predominant disease in bones and should have bone pain.
• Patients with metastatic CRPC considered for radium-223 should ideally be on ADT and bone-modifying agents.

Approval and Availability of Radium-223

Conclusions and Future Considerations

Overall survival significantly favored the radium-223 arm compared with placebo (14.9 months vs 11.3 months, respectively; hazard ratio [HR] = 0.695; 95% CI, 0.58-0.832;P=.00007). The median time to first SRE was significantly prolonged in the radium-223 group compared with placebo (15.6 months vs 9.8 months, respectively; HR = 0.658; 95% CI, 0.522-0.830;P=.00037). A subgroup analysis of patients with alkaline phosphatase of > 220 U/L suggested a significant improvement in survival in the radium-223 arm compared with placebo (P=.00009).Radium-223 was approved by the FDA on May 15, 2013, based on the ALSYMPCA trial meeting its primary efficacy endpoint. The therapy is expected to be commercially available soon at select centers.²¹Administration of this radiopharmaceutical must be performed by nuclear medicine specialists. Therefore, medical oncologists will need to identify and refer appropriate patients for radium-223 treatment at qualified centers. Adverse-event management will be similar to that of strontium and samarium, and incorporation of best supportive care is key with this treatment.Radium-223 is a first-in-class alpha-emitting radiopharmaceutical that is now approved for use in patients with advanced prostate cancer with symptomatic bone metastases. The drug has been shown to prolong survival in this group of patients compared with placebo, and its approval is a major milestone in prostate cancer research. How one should sequence radium-223 with other approved drugs in the CRPC setting needs to be evaluated through systematic study in clinical trials and emerging clinical experience. Insights from ongoing and planned trials integrating radium-223 in the care of patients with CRPC will optimize the maximum use of all approved agents in metastatic CRPC.

Thus, a number of critical clinical trials are needed in order to refine the use of this new agent. Radium-223 is being combined in a clinical trial with docetaxel in metastatic CRPC (Clinicaltrials.gov identifier: NCT01106352). The safety of combining marrow-suppressing chemotherapy with radium-223 needs to be well understood before this treatment approach can be endorsed. In addition, long-term effects of radium-223 and alpha particles on the bone marrow are yet to be determined. This is an important aspect of alpha particle therapy that needs to be evaluated prior to using radium-223 in earlier settings of prostate cancer compared with its current approval for use late in the natural history of the disease.

Author Disclosure

Dr. George has no conflicts of interest to disclose.

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