Radium-223 Dichloride: A Novel Treatment for CRPC and Symptomatic Bone Metastases

Abstract

Bone metastases are a major cause of death, disability, and decreased quality of life in patients with castration-resistant prostate cancer (CRPC). Radium 223 dichloride (radium-223) is a novel alpha-emitting radiopharmaceutical that selectively targets bone metastases with high-energy, short-range (<100 μm; 2-10 cell diameters) alpha particles and represents a unique treatment option for men with CRPC and symptomatic bone metastases. In early clinical studies, radium-223 had a positive impact on cancer-related as well as bone-related outcomes, and this was confirmed in the phase III Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) study. This randomized, double-blind, placebo-controlled study, which was prematurely stopped because of the positive effect of radium-223 on survival, showed that radium-223 significantly prolonged overall survival and time to first symptomatic skeletal event, along with reducing levels of alkaline phosphatase (ALP), a marker of bone turnover. Radium-223 was safe and well tolerated. Myelosuppression rates were low, and the most common nonhematologic adverse events were bone pain, nausea, diarrhea, fatigue, vomiting, and constipation. On the basis of these data, radium-223 has been approved by 34 countries so far for the treatment of patients with CRPC with symptomatic bone metastases and no known visceral metastatic disease. In conclusion, radium-223 is a highly effective and well-tolerated treatment for patients with CRPC and symptomatic bone metastases.

Nicholas J. Vogelzang, MD

The recent approval of several new agents for the treatment of prostate cancer has heralded a new era for managing this condition. “We’re right in the middle of a complete paradigm shift,” said Matthew Cooperberg, MD, MPH, in an interview published online on OncLive in December 2013.¹ One of the most intriguing of these new agents is radium-223 dichloride (radium-223; Xofigo; Bayer HealthCare Pharmaceuticals and Algeta ASA), the first alpha emitter shown to confer a survival advantage and to be approved for the treatment of patients with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease.²

Advantages of Alpha-Emitting Radium-223

Radium-223 is a calcium mimetic that forms complexes with hydroxyapatite at areas of increased bone turnover, such as osteoblastic lesions.^3,4 In preclinical studies, radium-223 showed marked accumulation in areas of high osteoblastic activity.⁵ Radium-223 begins to decay almost instantaneously, reaching a final product of stable lead over a 6-stage decay process. For each atom of radium-223, 4 alpha particles (each composed of 2 protons and 2 neutrons) are released, representing 94% of the total radiation energy emitted.⁵ Nanomolar quantities of radium are needed to achieve high localized radiation doses, given the high linear energy transfer (LET) of alpha radiation.

Unlike beta-emitting radiopharmaceuticals (such as strontium-89 and samarium-153), which are associated with significant myelotoxicity (particularly thrombocytopenia), the extremely short range of alpha particles allows for highly targeted tumor cell killing and may spare hematopoietic bone marrow cells from damage.^3-5 Moreover, the high-LET radiation produced by alpha particles induces double-stranded DNA breaks in adjacent tumor cells and is more effective at killing cancer cells than the low-LET radiation produced by beta particles.^3-5

Early Clinical Experience With Radium-223

Early studies with radium-223 showed a promising clinical profile in patients with bone metastases, including no dose-limiting hematologic toxicity⁶; the most common adverse events (AEs) were transient diarrhea, bone pain, fatigue, nausea, and vomiting.⁶ In a phase I study in men and women with bone metastases, all patients showed a reduction in alkaline phosphatase (ALP) levels, but the effect was more marked in men than in women,⁶ suggesting that radium-223 may target osteoblastic lesions more effectively than osteolytic lesions.⁷

Therefore, the phase II studies focused on patients with metastatic CRPC. In phase II, single doses of radium-223 were associated with a dose-dependent reduction in pain response across the dose range of 5 to 100 kBq/kg.⁸ In a separate study, 66% to 67% of patients receiving repeated doses of radium-223 25, 50, or 80 kBq/kg every 6 weeks showed a ≥ 50% decline in ALP levels in a dose-dependent manner.⁹ In addition, 6% of patients receiving radium-223 50 kBq/kg and 13% of those receiving 80 kBq/kg had a ≥ 50% reduction in prostate-specific antigen (PSA) levels,⁹ suggesting that radium-223 may have a positive impact on cancer-related, as well as bone-related, outcomes. Indeed, this proved to be the case in another phase II study in which 64 patients with CRPC and bone pain were randomized to radium-223 50 kBq/kg or placebo every 4 weeks.¹⁰ Not only did radium-223 significantly reduce ALP levels relative to placebo (P <.0001), but it significantly delayed the time to PSA progression (median 26 vs 8 wk with radium-223 vs placebo; P = .048) and significantly increased the odds of survival (hazard ratio [HR] = 2.12; 95% confidence interval [CI], 1.13-3.98; P = .02 after adjustment for baseline covariates).¹⁰ These positive clinical results, coupled with the favorable tolerability profile,^6,8-10 led to further clinical development of radium-223.

Phase III ALSYMPCA Study

The pivotal phase III trial was the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) study, a multicenter, randomized, double-blind study comparing the efficacy and safety of radium-223 and placebo in patients with CRPC and symptomatic bone metastases. 2 A total of 921 men with progressive CRPC and ≥2 bone metastases were randomized 2:1 to receive radium-223 50 kBq/kg plus best standard of care (BSOC), or placebo plus BSOC, every 4 weeks. BSOC could include, inter alia, corticosteroids, ketoconazole, external beam radiation therapy, and analgesia. The primary endpoint was overall survival (OS), with planned follow-up for 3 years, but the interim analysis showed a statistically significant benefit in favor of radium-223, so the study was prematurely stopped and placebo recipients were offered radium-223.²

In the final analysis, median OS was 14.9 months with radium-223 versus 11.3 months with placebo.² There was a 30% reduction in the risk of death with radium-223 (HR = 0.70; 95% CI, 0.58-0.83; P <.001), which was seen in all subgroups of patients.2 The significant clinical benefit of radium-223 relative to placebo was also seen in all the major secondary endpoints, including time to first symptomatic skeletal event (median, 15.6 mo vs 9.8 mo; HR = 0.66; 95% CI, 0.52-0.83; P <.001) and time to an increase in ALP or PSA level (ALP: HR = 0.17; 95% CI, 0.13-0.22; P <.001; PSA: HR = 0.64; 95% CI, 0.54-0.77; P <.001).² More radium-223 patients experienced a meaningful improvement in overall quality of life (based on the Functional Assessment of Cancer Therapy—Prostate [FACT-P] questionnaire) when compared with placebo patients (25% vs 16%; P = .02).²

Importantly, radium-223 was well tolerated in ALSYMPCA.² The overall incidence of AEs was lower in the radium-223 than in the placebo group (Table).² Fewer grade 3/4 or serious AEs occurred in the radium-223 group than the placebo group. Consistent with earlier studies, the most common nonhematologic AEs were bone pain, nausea, diarrhea, fatigue, vomiting, and constipation (Table).² In radium-223 compared with placebo patients, grade 3 or 4 neutropenia occurred in 2% versus 1%, grade 3 or 4 thrombocytopenia in 6% versus 2%, and grade 3 or 4 anemia in 13% versus 13%, respectively. Grade 3 febrile neutropenia occurred in one patient in each group.²

Practical Implications

Prostate cancer is the most common cancer in US men,¹¹ and 90% of men with advanced disease have radiologic evidence of bone metastases.¹² Not only are bone metastases a major cause of death, but they are a major cause of pain, disability, and reduced quality of life in men with prostate cancer.¹³

Radium-223 is the first alpha-emitting radiopharmaceutical shown to improve survival in metastatic CRPC,² and has been recommended by the National Comprehensive Cancer Network (NCCN) as an option in first-line and post-docetaxel settings for patients with CRPC and symptomatic bone metastases (category 1), providing them with a novel treatment option.¹⁴ Radium-223 is provided as a ready-to-use solution for intravenous administration and requires universal radiopharmaceutical precautions during handling and administration.

Patients are treated on an outpatient basis, with few limitations on personal contact; patient contact with others (eg, family members and caregivers) is not restricted, although precautions should be taken to prevent contact with patients’ bodily fluids. Whenever possible, patients should dispose of bodily waste in a toilet and flush the toilet several times after each use. Clothes soiled with bodily fluids should be washed promptly and separately from other clothing, and caregivers should wear gloves and wash their hands after handling patients’ bodily fluids or soiled clothing.

Additionally, patients should wear condoms if sexually active during treatment, and because of potential effects on spermatogenesis, should continue to use a highly effective contraceptive method for 6 months after completing treatment.¹⁵ Because of the risk for hematologic toxicity and myelosuppression, it is important to advise patients to be compliant with blood cell count monitoring appointments while receiving radium-223 and to report any signs of low blood cell counts, such as shortness of breath, tiredness, bleeding, and infection. Additionally, patients with evidence of compromised bone marrow should be monitored closely for hematologic AEs.¹⁵

Given the potential for additive myelosuppression, radium-223 should not be administered during treatment with chemotherapy, other systemic radioisotopes, or hemibody external radiation therapy; patients should know that if any of these agents are administered during the treatment period, then radium-223 should be discontinued.¹⁴ The use of docetaxel prior to radium-223, however, while associated with slightly higher rates of myelosuppression on radium-223, has not been shown to affect the safety or efficacy of radium-223¹⁶ and therefore should not affect the decision to receive radium- 223. In addition to myelosuppression, patients may experience gastrointestinal AEs, most notably diarrhea and vomiting, although these usually resolve with weekly hydration and antidiarrheal medications.¹⁵ In conclusion, the results from the ALSYMPCA study show that radium-223 is a highly effective, safe, and welltolerated treatment for patients with CRPC and symptomatic bone metastases.

Table. Incidence of Adverse Events in the ALSYMPCA Study²

ABOUT THE AUTHORAffiliation: Nicholas J. Vogelzang, MD, is Vice Chair of the SWOG GU Committee and Research Medical Director, US Oncology Research, Comprehensive Cancer Centers of Nevada.

Disclosures: Dr Vogelzang serves as a consultant to Bayer HealthCare and Algeta ASA, and his practice has received research funding from both.

Source of funding: Funding for this article was provided by Bayer HealthCare.

Address correspondence to: Nicholas J. Vogelzang, MD, US Oncology Research, Comprehensive Cancer Centers of Nevada, 3730 S. Eastern Avenue, Las Vegas, NV 89169; phone: (702) 952-3400; email: nicholas.vogelzang@usoncology. com

ACKNOWLEDGMENTS

Medical writing support was provided by Heather Nyce, PhD, and Julia D’Ambrosio, PhD, of SciStrategy Communications, funded by Bayer HealthCare Pharmaceuticals, Inc.

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