Alpha Particles as Radiopharmaceuticals in the Treatment of Bone Metastases: Mechanism of Action of Radium-223 Chloride (Alpharadin) and Radiation

Approximately 85% to 90% of men with castration-resistant prostate cancer (CRPC) have radiological evidence of bone metastases. To date, however, therapies to manage bone metastases have been primarily palliative. Among CRPC patients with bone metastases, there is a significant unmet need for active antitumor treatment options that are highly efficacious and have a favorable safety profile. This article will present current information about alpha-pharmaceuticals, a new class of targeted cancer therapy for the treatment of patients with CRPC and bone metastases. It will review preclinical and clinical studies of the experimental radiopharmaceutical radium-223 chloride (Alpharadin), a first-in-class, highly targeted and well-tolerated alpha-pharmaceutical under development to improve survival in patients with bone metastases from advanced prostate cancer. Alpharadin kills cancer cells via alpha radiation from the decay of radium-223, a calcium mimetic that naturally self-targets to bone metastases. The mechanism of action of Alpharadin and specifics of administration, radiation protection, and patient management will be discussed.

Introduction

Prostate cancer is the most common cancer among men living in the United States and Europe.[1,2] An estimated 240,890 new cases of prostate cancer occurred in the US in 2011-making it the most frequently diagnosed of all new cancers (25%), and about 33,720 men died from the disease.[3] Currently, approximately 2 million American men are living with prostate cancer.[4] Management considerations include individualizing therapy with clearly defined goals that focus on specific treatments, adverse events (AEs), and quality of life (QoL).

FIGURE 1

Radium-223 Physical Properties

Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer characterized by disease progression following surgical or pharmaceutical (androgen deprivation) castration. The process by which prostate cancer cells become castrate-resistant is unclear, but it has been proposed that androgen ablation provides a selective advantage to androgen-independent cells, which grow and eventually repopulate the tumor.[5] Compared with castration-sensitive prostate cancer, the prognosis for patients with CRPC is poor, and survival is reduced. Treatment options for metastases to bone have, until very recently, been limited mainly to symptomatic relief of pain, which occurs more frequently in progressive CRPC than in castration-sensitive disease.[6,7]

Bone metastases in CRPC

Bone metastases cause morbidity and mortality in a wide range of cancers, including CRPC, breast, renal, lung, thyroid, and others. Approximately 85% to 90% of men with CRPC have radiological evidence of bone metastases.[8-10]

FIGURE 2

Radium-223 Decay Chain

Bone metastases occur in almost all prostate cancer patients during the natural course of the disease, typically appearing in the lumbar spine, vertebrae, and pelvis. Bone metastases have several clinical consequences in patients with CRPC. In particular, metastatic bone may be more susceptible to pathologic fractures and spinal cord compression, and patients may require surgery or radiation therapy. Skeletal-related events (SREs), including pathologic fracture, spinal cord compression, and the need for bone surgery and/or radiation therapy to the bone, also present a significant challenge in the management of prostate cancer.

Kaplan-Meier survival analyses of patients with prostate cancer who have no bone metastases vs one or more bone metastases confirm that the development of bone metastases (and subsequent SREs) negatively impacts the overall survival (OS) of these patients, compared with patients who do not develop bone metastases.[11] Indeed, fewer than 50% of patients with CRPC and bone metastases are alive 5 years after diagnosis.[12] Furthermore, bone metastases and SREs often result in bone pain that is a main cause of disability, and these can have a significant impact on QoL[13,14] and result in increased treatment costs.[15]

The underlying mechanisms of bone metastases in patients with prostate cancer[16-19] include (1) factors released by tumor cells that stimulate both osteoclast and osteoblast activity; (2) excessive new bone formation occurring around tumor cell deposits, resulting in low bone strength and potential vertebral collapse; and (3) osteoclastic and osteoblastic activity, releasing growth factors that stimulate tumor cell growth, perpetuating the cycle of bone resorption and abnormal bone growth.

Current therapies for bone metastases

Currently, other therapies for bone metastases are considered to be primarily palliative and are mainly used for symptom relief or to prevent serious complications, such as those caused by fractures, hypercalcemia, and spinal cord compression.

Despite pain palliation, external beam radiation therapy (EBRT) and beta-emitting radiopharmaceuticals have not demonstrated improved OS in patients with advanced prostate cancer. With EBRT, normal cells and cancer cells receive the same amount of radiation within the target field. Beta-emitting radiopharmaceuticals palliate pain, but they have not demonstrated a survival benefit. Agents such as ⁹⁰Sr have been associated with significant thrombocytopenia.[20] Bisphosphonates are used to reduce the incidence of bone fractures and other SREs, but they do not have much effect on pain and do not affect survival.[21,22] The new agent denosumab (Xgeva),[23] targeted to treat pain and SREs, has been demonstrated to delay development of the first skeletal metastases by 4 months in initially nonmetastatic patients.[24]

Chemotherapy in CRPC with bone metastases

Chemotherapy with docetaxel and prednisone improves survival in metastatic CPRC, compared with mitoxantrone and prednisone. Cabazitaxel (Jevtana), a new chemotherapy agent, was recently approved for second-line use in men with advanced hormone-refractory prostate cancer already treated with docetaxel. Sipuleucel-T (Provenge), an autologous cellular immunotherapy, is now also approved by the US Food and Drug Administration (FDA) for the treatment of metastatic CRPC.

Pain relief has been demonstrated in patients treated with docetaxel-based chemotherapy, and a pain response has been correlated with an improved survival.[25] However, docetaxel chemotherapy may not be appropriate for all patients, and it can be associated with significant neutropenia and asthenia. Thus, a significant unmet medical need in the treatment of patients with CRPC and bone metastases is for active antitumor treatment options that are highly efficacious and have a favorable safety profile.[10]

Alpha-Pharmaceuticals

The rationale for use of alpha-pharmaceuticals in metastastic CRPC

Alpha-pharmaceuticals, radionuclides that emit alpha particles, are of increasing interest in CRPC.[26] They represent a new class of targeted cancer therapy for patients with bone metastases. Targeted alpha therapy has the potential to inhibit the growth of micrometastases by selectively killing cancer cells.[27-29]

Alpha particles differ from beta particles in energy (MeV), tissue range, linear-energy transfer (LET), and number of DNA hits needed to kill a cell.[30] Radionuclides of interest in alpha-radionuclide therapy[31,32] include ²²⁵Ac, ²¹³Bi, ²¹¹At, and ²²³Ra, or Alpharadin. Radium-223 is one of the most promising candidates for high- LET alpha-particle irradiation of cancer cells on bone surfaces. Unlike beta-emitting radiopharmaceuticals, alpha-pharmaceuticals deliver an intense and highly localized radiation dose (with a range of 2 to 10 cell diameters) to bone surfaces.[30] Radium-223 and its daughter radionuclides are thus much more potent, causing double-stranded DNA breaks leading to cell death,[33] but with substantially less irradiation of healthy bone marrow than standard bone-seeking beta-emitters. Thus, ²²³Ra does not require cells to cycle in order to achieve its antitumor effect. This distinct advantage is of particular benefit in the treatment of prostate cancer, which has a low proliferative rate.

Radium-223 is a first-in-class, highly targeted, alpha-pharmaceutical under clinical development to improve survival in patients with bone metastases from advanced prostate cancer. Phase I and II efficacy and safety trials are now complete for ²²³Ra, and a phase III trial in patients with CRPC and bone metastases is under way. ²¹³Bi and ²²⁵Ac are both in preclinical development for use in prostate cancer.[34-37]

Radionuclide selection criteria

Treatment success depends on matching the physiologic characteristics of the target tissue to a specific pharmaceutical carrier and optimal radionuclide.[38] Radium-223 is a natural bone-seeking radionuclide. Using an alpha-pharmaceutical like ²²³Ra to treat bone metastases has the potential to spare surrounding healthy bone tissue[30,39] and result in a highly tolerable side effect profile.[40] Furthermore, any ²²³Ra not taken up by the bone metastases is rapidly cleared to the gut and excreted. Alpha-pharmaceuticals are easy to handle and do not require complex shielding during shipping or administration.[39]

Alpharadin Mechanism of Action

FIGURE 3

Bone-Targeted Localized Mechanism of Action of α-Pharmaceuticals

Alpharadin, radium-223 chloride (²²³RaCl₂) in solution, is classified as an alpha-pharmaceutical or alpha-particle–emitting nuclide.[39,41,42] Radium-223, an alkaline earth metal (Figure 1), is a calcium mimetic and thus a natural bone-seeking agent.[41] Bone mineral hydroxyapatite, which forms 50% of the bone matrix, is its target. Alpharadin has preferential uptake in areas of new bone formation, targeting tumor cells in close proximity to areas of new bone growth in and around metastases.[39,43] Alpharadin forms complexes with hydroxyapatite, thus it subsequently gets incorporated into the bony matrix. Alpharadin has a half-life of 11.4 days (Figure 2).[39]

The localized action of Alpharadin’s alpha emission (with a short path length only in the 40- to 100-μm range in tissue) helps to preserve the surrounding healthy bone tissue and bone marrow[39] and limits distribution of the agent to soft tissue, thus also minimizing the risk of systemic side effects (Figure 3). Alpharadin thus has potentially better efficacy and tolerability when compared with beta-emitters.

Preclinical Studies of Alpharadin

Three key preclinical studies[30,39,44] with Alpharadin reveal its targeted mechanism of action in bone and provide the efficacy and safety rationales for proceeding to clinical development and trials in patients with CRPC and bone metastases.

The becquerel (Bq) is the International System of Units (SI)-derived unit of radioactivity. One Bq is defined as the activity of a quantity of radioactive material in which one nucleus decays per second. A measurement in becquerels is proportional to activity, so a more dangerous source of radiation gives a higher reading.

FIGURE 4

Effect of

²²³

Ra in Prolonging Symptom-Free Survival of Rats

Henriksen et al addressed the therapeutic efficacy of alpharadin in the treatment of experimental skeletal (human breast cancer) metastases in nude rats (Figure 4).[39] All of the tumor-bearing control animals had to be sacrificed because of tumor-induced paralysis 20 to 30 days after injection with tumor cells, whereas the rats treated with a dose of 10 kBq or higher of ²²³Ra had a significantly increased rate of symptom-free survival (P < .05). A total of 36% of rats (5 of 14) treated with 11 kBq and 20% of rats (1 of 5) treated with 6 kBq were alive beyond the 50-day follow-up period.

Biodistribution studies, involving measurement of ²²³Ra in rat bone marrow samples after IV injection, were also performed in this study. The investigators demonstrated that ²²³Ra was selectively concentrated in bone as compared with soft tissues, after analysis of ²²³Ra levels in the femur vs in the kidney, spleen, and bone marrow. No signs of bone marrow toxicity or body weight loss were observed in the groups of treated animals.

The authors concluded that the significant antitumor effect of ²²³Ra at doses that do not induce significant neutropenia or thrombocytopenia were linked to the intense and highly localized radiation dose from alpha particles at the bone surfaces. The results of this study indicated that ²²³Ra should be investigated further as a potential bone marrow–sparing treatment of skeletal metastases.

In a later study, Henriksen et al compared the bone-seeking properties of, and potential exposure of red marrow to, ²²³Ra vs the beta-emitter 89Sr.[30] In this study, the biodistribution of both agents was assessed in mice. Tissue uptake was determined at various time intervals after IV administration of each agent. Both ²²³Ra and ⁸⁹Sr were found to be selectively concentrated on bone surfaces relative to soft tissues. However, the measured bone uptake of ²²³Ra was higher than that of 89Sr. After 24 hours, the percentage of injected dose of ²²³Ra per gram of femur tissue was 40.1 ± 7.7. For ⁸⁹Sr, the corresponding value was 17.7 ± 2.8. At 14 days, the values for ²²³Ra and ⁸⁹Sr were 31.1 ± 2.6 and 21.1 ± 2.7, respectively.

Furthermore, estimates of the dose to marrow cavities showed that the ²²³Ra alpha-emitter might have a marrow-sparing advantage, with substantially less irradiation of healthy bone marrow compared with standard bone-seeking beta-emitters for targeting osteoid surfaces. This effect was substantiated from data obtained from marrow-cavity spheres. For ²²³Ra, the estimated absorbed dose in a 250-µm marrow-cavity sphere decreased steeply from approximately 65 Gy at 5 µm from the surface to 0 Gy at about 70 µm, the energy-range cutoff distance. For a 150-µm sphere, the absorbed dose decreased steeply with distance from 75 Gy at 3 µm to 0 Gy at 69 µm. For a 50-µm sphere, the absorbed dose decreased from 97 Gy near the bone surface to about 60 Gy in the least exposed volume.

By comparison, only small changes in the absorbed dose from ⁸⁹Sr, with increasing distance from the surface, were observed from the dose calculations. The implications of this dosimetry are clearly important to understanding the potential differences between ²²³Ra and ⁸⁹Sr with respect to marrow toxicity, with short-range alpha-particles of ²²³Ra irradiating a significantly lower fraction of the marrow volumes. At the same time, the bone surfaces received a therapeutically effective radiation dose. The results of this study thus indicated that ²²³Ra was a promising candidate for high-LET alpha-particle irradiation of cancer cells on bone surfaces, and together with its daughter radionuclides, ²²³Ra delivered an intense and highly localized radiation dose to the bone surfaces. That ²²³Ra has a mar row-sparing advantage theoretically makes it a better isotope to combine with other cytotoxic agents.

The third preclinical study, by Larsen et al, investigated adverse effects in mice receiving IV doses of either 1250, 2500, or 3750 kBq/kg of dissolved ²²³Ra who were followed in the initial toxicity phase.[44] This resulted in a dose-related minimal-to-moderate depletion of osteocytes and osteoblasts in the bones. Furthermore, the investigators observed a dose-related minimal-to-marked depletion of the bone marrow hematopoietic cells, and a minimal-to-slight extramedullary hematopoiesis in the spleen and in the mandibular and mesenteric lymph nodes.

The LD50 (lethal dose that kills 50% of study animals) for acute toxicity, defined as death within 4 weeks of receiving the substance, was not reached. This study demonstrated that high doses of ²²³Ra did not completely inactivate the blood-producing cells. The relatively high tolerance to skeletal alpha doses was probably caused by the surviving pockets of red bone marrow cells beyond the range of alpha particles from the bone surfaces, and the recruitment of peripheral stem cells.

Administration and Radiation Protection

Administration

Alpharadin can be prepared and shipped ready for use anywhere in the world. The half-life of ²²³Ra provides sufficient time for its preparation, distribution (including long-distance shipment),[39] and administration to patients. In clinical trials, treatment is on an outpatient basis, administered by IV injection once a month for 4 or 6 months.[40,43,45] No imaging dose or premedications are required. No comparative effectiveness trials have been conducted comparing the cost of treatment with Alpharadin to that of other therapies.

Handling of alpharadin and radiation protection

The ultra-short penetration of alpha particles, the fact that alpha radiation is readily blocked (eg, by a sheet of paper) along with the favorably low γ-irradiation, allow for ease of handling of alpharadin and administration through simple plastic tubing. There is no requirement for complex shielding or handling during shipping or administration, and no radiation protection procedures are required. Alpharadin requires no additional specialized detection equipment. Standard equipment for contamination monitoring can be used; no specialized alpha-monitoring equipment is required. For Alpharadin waste disposal, radioactive waste should be stored for 4 months, then discarded as normal clinical waste.

In contrast, alpha-emitters are more toxic and mutagenic than beta-emitters in terms of effects on single cells. The high-LET of alpha particles does, therefore, have the potential to induce development of secondary hematologic or solid malignancies. It is possible to compensate for these adverse properties in targeted therapy because of the potential to irradiate much smaller volumes of normal cells when alpha-emitters are targeted against tumor cells. Furthermore, it is unlikely that isotope therapy will result in significant increased rates of hematologic malignancies. This is because development of secondary hematologic and solid cancers takes approximately 10 and 20 or more years, respectively, yet the median survival time of patients with CRPC is short, ranging from 18 to 24 months.

Clinical Development of Alpharadin

Phase I studies

ATI-BC-1. The main goals of this phase I study, results of which were published in Clinical Cancer Research in 2005, were to assess the safety and tolerability of ²²³Ra in patients with CRPC and patients with breast cancer who had skeletal metastases.[45] In addition, pain palliation was evaluated. A total of 15 prostate cancer and 10 breast cancer patients were enrolled, each receiving a single IV injection of ²²³Ra. Groups of five patients were included at each of the dosages (46, 93, 163, 213, or 250 kBq/kg) and followed for 8 weeks. Palliative response was evaluated according to the pain scale of the European Organisation for Research and Treatment of Cancer (EORTC)QLQ C30 questionnaire at baseline and at 1, 4, and 8 weeks after injection. Weekly blood sampling during follow-up revealed mild and reversible myelosuppression, with the nadir occurring 2 to 4 weeks after the injection. Importantly, for thrombocytes only grade 1 toxicity was reported. Grade 3 neutropenia and leukopenia occurred in two and three patients, respectively. Mild, transient diarrhea was observed in 10 of the 25 patients. Nausea and vomiting were more frequently observed in the highest dosage group, due to nonspecific uptake of ²²³Ra by the gut. Serum alkaline phosphatase decreased, with nadir averages of 29.5% in females and 52.1% in males. Pain relief (defined as a decrease in pain score of > 10 on the EORTC QLQ-C 30 questionnaire) was reported by 52%, 60%, and 56% of the patients after 7 days, 4 weeks, and 8 weeks, respectively. Radium-223 cleared rapidly from blood and was below 1% of initial level at 24 hours. Post-treatment bone scans, which imaged the small gamma component in Alpharadin, showed accumulation of ²²³Ra in the skeletal metastases. Elimination was mainly intestinal. Median survival time was 20 months. The investigators concluded that ²²³Ra was well tolerated at therapeutically relevant dosages. As a result of the findings in this study, phase II studies were initiated.

BC1-05. This open-label, phase I, dosimetry, biodistribution, and pharmacokinetics (PK) study assessed Alpharadin in six patients with CRPC and bone metastases. Patients received two infusions of ²²³Ra at a dose of 100 kBq/kg, 6 weeks apart. The trial revealed that ²²³Ra was rapidly eliminated from blood and sequestered to bone/bone metastases (about 60% at 4 hr) and excreted into the small intestine. The kidneys were spared, receiving only a low radiation dose with less than 5% urinary excretion and no hepatobiliary excretion. The highest calculated absorbed doses were to osteogenic cells, red marrow, and lower large intestine wall. Because of the very short range of alpha particles (2 to 10 cell diameters), however, only a small volume of red marrow would have received a significant radiation dose, possibly accounting for the favorable hematologic safety profile.

BC1-08. This open-label, phase I, dose-escalation study recruited 10 patients with progressive CRPC and more than two bone metastases to assess safety, pharmacokinetics, biodistribution, radiation dosimetry, and toxicity of Alpharadin. Patients received one treatment at the cohort-defined dose (50, 100, or 200 kBq/kg), followed by one optional treatment 6 weeks later at 50 kBq/kg. Total body clearance was largely determined by transit through the gut. Radium-223 was seen in small bowel within 10 minutes of dosing, with subsequent fecal transit to the colon. Six patients received a second injection. Four patients did not receive a second dose due to disease progression (two patients), grade 3 anemia (one patient) and an unrelated AE (one patient). Drug-related AEs reported were one patient with grade 3 anemia; one with grade 3 thrombocytopenia (> 7 days); and one with grade 3/4 neutropenia (> 14 days), grade 3 diarrhea, and grade 3 nausea.

Phase II studies

BC1-02. This randomized, placebo-controlled, multicenter, phase II study of Alpharadin in patients with CRPC and symptomatic bone metastases was published in Lancet Oncology in 2007.[40] Patients with CRPC and bone pain needing EBRT were assigned to four IV injections of ²²³Ra at 50 kBq/kg (33 patients) or placebo (31 patients), given every 4 weeks. Primary endpoints were change in bone alkaline phosphatase (ALP) concentration and time to SREs. Secondary endpoints included toxic effects, time to prostate-specific antigen (PSA) progression, and OS.

Median relative change in bone ALP during treatment was −65.6% and 9.3% in the ²²³Ra group and placebo group, respectively (P < .0001). Hematologic toxic effects did not differ significantly between the treatment and placebo groups. No patient discontinued ²²³Ra because of treatment toxicity. Median time to PSA progression was 26 weeks (16 to 39) vs 8 weeks (4 to 12; P = .048) for ²²³Ra vs placebo, respectively. Median OS was 65.3 weeks for ²²³Ra and 46.4 weeks for placebo (P = .066, log rank). The investigators concluded that ²²³Ra was well tolerated with minimum myelotoxicity, and had a significant effect on bone ALP concentrations. There are, however, no data that evaluate long-term administration of Alpharadin beyond what is demonstrated in the phase I studies.

BC1-03. This double-blind, dose-response, phase II, multicenter study (n = 100) of ²²³Ra reported on the palliation of painful bone metastases in CRPC patients. It showed no evidence of a dose effect following evaluation of median change in baseline from diary pain ratings (using visual analogue scores) at ²²³Ra doses of 5, 25, 50, and 100 kBq/kg. Most AEs were gastrointestinal, including nausea, vomiting, diarrhea, and constipation. Minor decreases in platelet counts, white blood cell (WBC) counts, and neutrophils were reported in the 50 and 100 kBq/kg groups.

BC1-04. This double-blind, randomized, dose-finding, phase II study of Alpharadin for the treatment of patients with CRPC and painful bone metastases randomized 75 patients (25 in each group) to receive a dose of 25, 50, or 80 kBq/kg. Bone markers, PSA levels, safety, and survival data were assessed. Change in PSA level over a 24-week period was found to be dose-dependent. The most common AEs reported were gastrointestinal and musculoskeletal. Patients were not treated with antiemetics in this study. Grade 3 or 4 thrombocytopenia occurred in two patients. No patients discontinued due to an AE. Grade 3 or 4 neutropenia was not observed. These hematologic results could be based on disease burden, as patients with marrow invasion may be at higher risk for thrombocytopenia. The difference in disease stage (typically very advanced in patients who have received strontium) is an important difference between patients treated with Alpharadin and patients treated with strontium, and it may account for some of the increased thrombocytopenia seen in the strontium patients. It is difficult to quantify these differences when comparing studies, however, since they were separated by many years.

Summary of phase I and II clinical trials

REFERENCE GUIDE

Therapeutic Agents
Mentioned in This Article

Abiraterone (Zytiga)
Actinium-225 (

²²⁵

Ac)
Astatine-211 (

²¹¹

At)
Bismuth-213 (

²¹³

Bi)
Cabazitaxel (Jevtana)
Denosumab (Xgeva)
Docetaxel
MDV3100
Mitoxantrone
Prednisone
Radium-223 Cl (

²²³

Ra, Alpharadin)
Samarium-153 (

¹⁵³

Sm, Quadramet)
Sipuleucel-T (Provenge)
Strontium-89 (

⁸⁹

Sr, Metastron)
Strontium-90 (

⁹⁰

Sr)

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

Overall safety and tolerability were evaluated in 292 patients across all phase I and II trials. Five trials were assessed: two phase I trials (Alpharadin n = 37) and three phase II trials (Alpharadin, n = 255; placebo, n = 31). Alpharadin was administered (single or repeated injections) at doses of 5 kBq/kg to 250 kBq/kg. Efficacy results were shown to confer an OS benefit in patients with CRPC and bone-predominant disease, as well as improvement in disease-related biomarkers (bone and PSA), and in pain. Alpharadin was also found to be safe and well tolerated. Of note, none of these studies demonstrated a dose-limiting toxicity, implying that further dose escalation is possible.

Alpharadin also showed promising preliminary results in a phase IIa trial in patients with bone metastases from breast cancer no longer responding to endocrine therapy. The data showed that Alpharadin reduced the levels of bone alkaline phosphatase (bALP) and urine N-telopeptide (uNTX), key markers of bone turnover associated with bone metastases in breast cancer.

Phase III: the ALSYMPCA trial

Alpharadin successfully met the primary endpoint of OS in ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients), a double-blind, randomized, multicenter, phase III study of Alpharadin in the treatment of bone metastases resulting from CRPC.

The 922-patient ALSYMPCA study was stopped early after a preplanned efficacy interim analysis, following a recommendation from an Independent Data Monitoring Committee, on the basis of achieving a statistically significant improvement in OS (two-sided P value = .0022, hazard ratio [HR] = 0.699; median OS, 14.0 months for Alpharadin vs 11.2 months for placebo). Earlier phase II results of the trial showed an increased survival time of 4.5 months. The lower figure of 2.8 months increased survival in phase III is probably a result of too short follow-up, because of the early termination of the study. Survival time for patients who were still alive could not be calculated. Algeta SAS of Norway and its partner Bayer Healthcare are preparing to file regulatory submissions for Alpharadin in the US and Europe in mid 2012.

It is difficult to compare the results of phase III studies that have evaluated samarium, strontium, and Alpharadin, due to the different eras in which these trials were performed. Although the entry hematologic parameters are similar in all studies, extent of disease in the bone marrow is difficult to quantitate. The ⁸⁹Sr studies by Porter et al[46] and the ¹⁵³Sm studies by Sartor[47] were performed before docetaxel-based chemotherapy was approved by the FDA for treatment of CRPC in 2004. A total of 12% of patients in the ¹⁵³Sm study had received prior chemotherapy.[47]

At the time of the initial strontium studies, chemotherapy was not standard treatment, and the number of patients treated with chemotherapy in the Porter et al study[46] was not reported. Entry criteria for hematologic function in Porter et al study were a WBC count greater than 3.5 × 10⁹ per liter and a platelet count greater than 150 × 10⁹ per liter.[46] There is no way to quantitate the amount of bone marrow involvement in the strontium study or the ALSYMPCA study.

Ongoing trial NCT00699751

Other ongoing studies include Alpharadin in combination with docetaxel in patients with CRPC and bone metastases as well as single-agent Alpharadin in patients with metastatic breast cancer and bone metastases. Outcomes from clinical trials will provide insight into the effect of Alpharadin on OS, and will reveal important biodistribution, dosimetry, and safety data.

Data from ongoing trials will continue to add to our knowledge about the efficacy and safety of Alpharadin in treating patients with CRPC and bone metastases. Currently in development are studies to improve survival in patients with bone metastases from advanced prostate cancer and breast cancer. Studies are also underway evaluating the potential for Alpharadin to be used in patients with other cancers that have a propensity to metastasize to the bone (eg, lung).

Patient Management

A multidisciplinary team approach is used to administer Alpharadin to patients with CRPC and bone metastases. The goal is for the urologist and medical oncologist to collaborate in determining patient eligibility to receive Alpharadin, as well as in post-treatment follow-up. Once the patient is deemed suitable for treatment, a radiation oncologist or nuclear medicine physician would administer the Alpharadin infusion with careful assessment and monitoring for minimal expected toxicities. The ability to administer concomitant or subsequent therapies is a crucial question that remains to be addressed, particularly with recent approval of agents such as abiraterone (Zytiga), cabazitaxel, sipuleucel-T, and the probable approval of MDV3100.

Summary and Conclusion

Alpha-pharmaceuticals deliver high-LET radiation to the target, with large amounts of energy per unit track length and short ranges (< 100 μm). Using alpha-pharmaceuticals to treat patients with CRPC and bone metastases allows highly targeted, localized delivery of the radiation to the metastases.

Alpharadin is an alpha-emitter with a mechanism of action that has a potent and highly targeted antitumor effect on bone metastases. It is a calcium mimetic that targets new bone growth in and around metastases. It emits high-energy alpha particles that induce primarily nonreparable, double-stranded DNA breaks in target cells. The short path length of the alpha particles keeps toxicity to adjacent healthy tissue (particularly the bone marrow) at a minimum.

Preclinical studies with Alpharadin revealed important efficacy and safety data related to the compound and provided the rationale for proceeding to clinical trials.

Clinical studies indicate that Alpharadin has a favorable safety profile and is efficacious in patients with CRPC and bone metastases. The phase II BC1-02 (placebo-controlled) study[40] showed it had statistically significant effects on bone markers, was associated with a decrease in PSA levels and improvement of OS, had a highly tolerable safety profile (with fewer AEs/ serious AEs when compared to placebo), and had no significant hematologic safety issues. Hematologic AEs were typically mild (Common Toxicity Criteria toxicity grades 1 and 2) and transient; no patient withdrew due to hematologic toxicity. Treatment with Alpharadin up to 12 weeks is thus deemed safe and highly efficacious.

Data from ongoing trials will continue to add to our knowledge regarding the efficacy and safety of Alpharadin in treating patients with bone metastases. These include the ALSYMPCA double-blind, randomized, multicenter, phase III study, which has a primary endpoint of OS; a trial of Alpharadin in combination with docetaxel, which will assess safety and tolerability, as well as preliminary efficacy; and a study of Alpharadin (as a single agent) in patients with breast cancer and bone metastases, which is focusing on its effect on bone markers.

Financial Disclosure:Dr. Petrylak receives grant support from Dendreon, Sanofi, Pfizer, AstraZeneca, GlaxoSmithKline, Rogensen Institute, and Boehringer Ingelheim. He is a paid consultant for Bayer, Pfizer, Ferring, Millennium, Novartis, Dendreon, Johnson & Johnson, and GlaxoSmithKline, and serves on the scientific advisory boards of Bellicum and Egenix. Dr. Cheetham has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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