Radium-223 and concomitant therapies: prospects and prudence

tau.amegroups.com © Translational Andrology and Urology. All rights reserved. Most patients with relapsed prostate cancer develop metastatic disease and eventually become castration-resistant. Skeletal metastasis is common in castrate resistant prostate cancer and is an independent poor prognostic factor (1). Furthermore, skeletal related events (SRE) such as spinal cord compression, pathologic fractures and requirement for external beam radiation for pain palliation continue to represent a significant cause of morbidity for patients with bone metastasis (2). Over the last decade, significant strides have been made in the development of therapies for patients with castrate resistant metastatic prostate cancer (CRPC). Abiraterone (Zytiga) (3), and Enzalutamide (Xtandi) (4) were approved based on data supporting improved overall survival compared to placebo and in addition, both agents decreased time to SRE and increased rates of pain palliation in the case of Abiraterone. More recently, Radium-223 (Xofigo) became the first approved radiopharmaceutical which decreased SRE’s, palliated pain, and showed improved overall survival in symptomatic or minimally symptomatic patients with CRPC and bone metastasis only (5). As such, both the American Society of Clinical Oncologists and the American Urologic Association have recommended incorporation of Radium-223 into the treatment algorithm (6,7). Ongoing debate has focused on the initiation of Radium-223 earlier in the disease course and the question of safety and efficacy of combining Radium-223 with other AR-directed therapies (8). In a recently published article, Saad et al. (9) conducted a single-arm, phase 3b, international multicenter clinical trial investigating the safety and efficacy of radium-223 and concomitant therapies in 696 patients with CRPC. The trial involved a majority of Caucasian men aged 65 years and older with bone-predominant disease with at least two or more skeletal metastases. Although, men with nodal disease were permitted, patients with visceral metastases were excluded from the study. Patients could receive concomitant administration of abiraterone, enzalutamide, or denosumab. The primary endpoints for the study were safety and overall survival. After a median followup of 7.5 months, the authors reported improved overall survival in patients who received concomitant radium-223 and either abiraterone, enzalutamide, abiraterone and enzalutamide or denosumab. The same benefit did not extend to patients undergoing treatment with radium-223 and bisphosphonates. Combination treatment was reported to be well-tolerated. Discontinuation of radium-223 due to adverse effects occurred in 21% patients. Grade 1–2 adverse effects occurred in 32% of patients and 37% of patients experienced any grade 3–4 toxicity. The most common adverse effect was grade 3 anemia (12%) and combined grade 3–4 cytopenia (anemia, thrombocytopenia, leucopenia and neutropenia) occurred in 20% of patients. This study raises the potential of radium-233 and ARdirected therapy to synergize and modulate the bonetumor microenvironment. The cellular and molecular mechanisms of prostate cancer dissemination and survival in the bone microenvironment have been well-described. For instance, prostate cancer cells have been shown to have Editorial