In this issue of ONCOLOGY, Cheetham and Petrylak deliver an in-depth review of radium-223 (223Ra, Alpharadin) for the treatment of bone metastases in patients with castrate-resistant prostate cancer. This article emphasizes that 223Ra, the first-in-class agent of alpha-emitting radiopharmaceuticals, is a potent agent that delivers highly targeted radiation to sites of bony metastases. A calcium mimetic, 223Ra is preferentially taken up in areas of new bone formation in close proximity to regions of metastases. With the alpha-emitting properties of 223Ra, a highly localized density of ionizing radiation is delivered to nearby tumor cells, causing a significant amount of irreparable double-stranded DNA damage. This DNA damage triggers tumor cell death. Because of the short range of penetration of alpha particles, the bone marrow is relatively spared, resulting in a high therapeutic index.
The authors discuss the preliminary results of a recent phase III ALSYMPCA trial that demonstrated a 30% reduction in the risk of death with 223Ra treatment. This trial was stopped early after a preplanned interim analysis demonstrated a statistically significant improvement in overall survival, even though some 40% of these patients had 20 or more bone metastases. This exciting finding also confirms the findings of a small phase II randomized trial of biologic agents and radiopharmaceuticals targeting bone, which suggested that such an approach might result in a survival benefit.[2,3] These preliminary results of the ALSYMPCA study suggest that 223Ra will be a powerful weapon in our armamentarium for treatment of bone metastases in castrate-resistant prostate cancer.
Prostate cancer is a bone-trophic disease. Approximately 25% of patients with prostate cancer develop bone metastases, which can cause severe morbidity from pain, fracture, cord compression, and marrow suppression. The associated morbidity affects the quality of life and is the primary cause of death in most patients. While many therapies for prostate cancer are designed to target and treat all sites of disease, their effectiveness may be suboptimal for bone disease. Docetaxel(Drug information on docetaxel) has been established as first-line therapy for treatment of castrate-resistant prostate cancer. However, only half of patients respond to docetaxel treatment, with the majority dying of metastatic prostate cancer (median survival, 19 months).[5-7] Moreover, patients receiving docetaxel therapy need to have a high performance status; toxicity is significant, with a high incidence of grade 3/4 neutropenia, fatigue, nausea, diarrhea, and neuropathy.[5,7]
Radiopharmaceuticals targeting bony sites of disease are effective treatments for bone metastases and have fewer side effects than conventional cytotoxic therapies such as docetaxel. The US Food and Drug Administration (FDA)-approved beta-emitters, samarium-153 EDTMP (153Sm, Quadramet) and strontium-89 (89Sr, Metastron), palliate metastatic bone pain with responses ranging from 55% to 80%.[8-10] However, the durability of response is limited (2 to 17 weeks). Also, bone marrow suppression, primarily in the form of thrombocytopenia and leukopenia, is a common side effect, due to the long range of beta emission. Although a recent study demonstrated that repeat administration of 153Sm may be feasible, platelet and white blood cell counts dropped progressively with each treatment and did not return to baseline. In contrast, the range of alpha decay with 223Ra therapy is much shorter (100 μm), resulting in minimal myelotoxicity. In a phase II study and in the phase III ALSYMPCA trial, no significant difference in myelosuppression was observed compared with the placebo-control arm, while treatment of bony metastases was effective. Because 223Ra has a minimal effect on bone marrow suppression, serial administrations of 223Ra are likely to be feasible and may improve the durability of response.
The limited toxicity of 223Ra potentially allows it to be used with other treatment modalities to provide an additive or even synergistic effect. In patients with metastatic prostate cancer, approximately 25% to 30% develop disease outside the bone. Because 223Ra is selectively taken up in bone, its use for treatment of soft tissue lesions is limited. In patients with both soft tissue and bony disease, a combination approach of cytotoxic chemotherapy and 223Ra will likely be more effective than either therapy alone. Cytotoxic chemotherapies such as cisplatin(Drug information on cisplatin) and docetaxel may be utilized to treat the soft tissue metastases, while 223Ra is used to target bony sites of disease. In addition, these cytotoxic agents may radiosensitize bony lesions to make 223Ra therapy more effective. Already, phase II studies evaluating the combination of cytotoxic agents with 89Sr and 153Sm have suggested feasibility and efficacy.[2,3] The feasibility efficacy of combination therapy with 223Ra and cytotoxic agents will need to be evaluated in future studies.
Patients with metastatic prostate cancer often present with a large, dominant lesion affecting weight-bearing bones or causing significant cord compression, along with multiple small metastatic bony lesions. A limitation of 223Ra for treatment of large lesions is the limited range of the alpha particle emission. An effective treatment for this population of patients may be the combination of external beam therapy to eradicate the dominant lesion(s), while the smaller bony lesions and micrometastatic disease can be targeted with 223Ra. Interestingly, patients who receive a single dose of external beam fractionation often require retreatment for recurrent or residual pain.[13-15] The radiation from 223Ra can also act as a “boost” treatment to supplement the external beam radiotherapy.
With the currently available therapies, resistance often develops. For systemic agents, this may occur due to continued signaling from the androgen receptor, repair mechanisms, activation of growth and survival pathways, or interactions with the microenvironment. With external beam radiotherapy and the beta-emitters, single-strand DNA breaks are produced. Decreased radiation sensitivity can occur if cells adapt to repair these breaks efficiently. Radium-223 is potentially less prone to the development of resistance than the conventional systemic agents or beta-emitting radionuclides. As mentioned previously, the mechanism of action of 223Ra is through alpha emission, which leads to dense, localized packets of ionizing radiation resulting in irreparable DNA double-strand breaks.
Radium-223 is a promising agent that represents a new class of alpha pharmaceuticals that gets down to the site of bony metastases. The limited side-effect profile potentially allows for repeat administration of 223Ra to increase durability of pain control, and for its use in combination with novel biologic and chemotherapeutic agents. It will be interesting to see how these combination therapies with 223Ra can be tailored for specific disease presentations and for targeting the pathways involved in disease progression. As the authors point out, only time and more studies will clarify its role compared with other exciting agents such as MDV3100, abiraterone (Zytiga), cabazitaxel (Jevtana), and sipuleucel-T (Provenge).
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.