Bone-targeting radiopharmaceuticals for the treatment of prostate cancer with bone metastases

Abstract

Patients with castration-resistant prostate cancer (CRPC) frequently have metastases to the bone, which may cause pain and lead to a deterioration in quality-of-life. Bone-seeking radiopharmaceuticals are agents which, when administered systemically, localize to the site of bone metastases and deliver focal radiation there. In this review, we will summarize the current literature on bone-targeting radiopharmaceuticals for CRPC, focusing on strontium-89, samarium-153, rhenium-186 and radium-223. We will discuss their indications, clinical efficacy, and toxicities and highlight some of the challenges in optimizing treatment with these agents. Historically, clinical trials with these drugs have failed to demonstrate survival improvements, restricting their use for palliative purposes only. Radium-223 is the first agent in this class to show an overall survival advantage in CRPC patients with bone metastases. This landmark finding will likely have a considerable impact on the treatment paradigm of bone-metastatic CRPC, and will pave the way for further developments in the future.

Introduction

An estimated 241,740 men will be diagnosed with prostate cancer in the United States this year [1], contributing to an estimated 28,170 cancer-related deaths. In patients with recurrent or advanced prostate cancer, use of androgen deprivation therapy (which acts by depleting or blocking the effects of androgens) is the standard-of-care [2], [3], [4]. Androgen deprivation usually results in initial tumor regressions with declines in prostate-specific antigen (PSA) levels and relief of symptoms in many patients, but the disease eventually progresses to a castration-resistant state [5]. Many mechanisms for castration-resistance have been postulated, including persistent androgen receptor (AR) signaling, ectopic androgen synthesis, and activation of AR-independent pathways [6]. In patients with castration-resistant prostate cancer (CRPC), treatment options are expanding [7] and four modalities have been FDA-approved to date based on evidence of survival prolongation in men with metastatic CRPC: docetaxel is approved as first-line chemotherapy [8], cabazitaxel is approved as second-line chemotherapy [9], the immunotherapy product sipuleucel-T is approved for asymptomatic patients [10], and the androgen biosynthesis inhibitor abiraterone is approved for docetaxel-pretreated men [11].

CRPC metastasizes frequently to the bone, an event occurring in the majority of advanced prostate cancer patients [8], [12], [13]. Osseous metastases are most commonly found in the axial skeleton (vertebral bodies, pelvis, ribs and skull), but may also occur in long bones (femurs, humeri). Bone scintigraphy using ⁹⁹technetium-methylene diphosphonate (⁹⁹Tc-MDP) remains the standard method for detection of osseous metastases, and is an essential component of the staging of the disease [14]. Newer modalities for the identification of bone metastases are also being investigated, and have shown encouraging results when compared with ⁹⁹Tc-MDP bone scans [15], [16].

The extent of osseous involvement in metastatic prostate cancer has been found to be associated with patient survival [17]. Clinically, bone lesions may manifest as pain or as skeletal-related events (SREs). SREs include bone complications such as spinal-cord compression, pathological fractures, hypercalcemia of malignancy, need for bone surgery, and need for bone radiation, some of which could have devastating consequences. Additionally, patients receiving chronic androgen deprivation are especially vulnerable to fragility fractures from reduced bone-mineral density [18]. These effects can result in diminished mobility and a considerable deterioration in quality-of-life [19].

In patients with advanced CRPC, PSA elevations usually precede detectable bone lesions which in turn usually precede bone pain [20]. The development of bone metastases is thought to involve multiple cytokines and growth factors including transforming growth-factor (TGF-β), bone-morphogenic proteins (BMPs), and epidermal growth-factor (EGF) that engage in processes involving migration of prostate cells to bone tissue and cellular adhesion to bone matrix [21], [22], [23], [24]. In patients with bone metastases, there is increased bone turnover with activation of both osteoblastic and osteoclastic activity [25], [26]. Bone pain manifests in multiple forms and the exact mechanism of this pain is poorly understood. Studies have suggested the role of tumor-induced cytokines, tumor infiltration of bone matrix causing osteolysis, direct nerve injury, and stimulation of peripheral nerve endings by various substances leading to nerve sensitization causing allodynia and hyperalgesia [27]. One of the roles of radiopharmaceuticals is the reduction of these growth factors and cytokines at the interface of tumor metastases and normal bone.

Adequate treatment of metastatic bone pain is impeded by underestimation of pain by physicians, patient reluctance to report pain, and poor knowledge of treatment options [28]. Approximately 80–90% of patients with cancer pain report effective pain relief with the WHO-recommended “three-step ladder” approach [29], [30]. Acetaminophen and non-steroidal anti-inflammatory drugs constitute first-line agents for pain control, although these may provide insufficient relief requiring escalation to low-potency opioids. Subsequently, stronger opioids are added in a step-wise fashion as the disease progresses. Optimal management of bone pain requires a multi-disciplinary approach including chemotherapeutic options, osteoclast-inhibitory agents, corticosteroids, external-beam radiotherapy, or even surgery [31]. Radiopharmaceutical agents have emerged as another viable option in patients with multiple osseous metastases. These compounds are systemically-administered radioactive agents that localize to sites of bone metastases and deliver focal radiation through β-emission (strontium-89, samarium-153, rhenium-186) or α-particles (radium-223). Bone-seeking radiopharmaceuticals have considerable advantages including easy administration, ability to treat multiple metastatic lesions simultaneously, and the possibility of combination with chemo-/radiotherapeutic agents for enhanced efficacy.

Agents comprising the current radiopharmaceutical armamentarium against prostate cancer include strontium-89, samarium-153, rhenium-186, and the novel α-emitter radium-223. These compounds have been the subject of multiple randomized controlled trials exploring their efficacy in prostate cancer patients with bone metastases [28], [32], [33], [34], [35]. Historically, outcomes of interest in radiopharmaceutical trials included pain response, analgesic consumption, and quality-of-life. Notably, radium-223 is the first radiopharmaceutical agent to demonstrate improved survival among patients with symptomatic bone-metastatic CRPC. This is a landmark development in the current treatment paradigm of metastatic prostate cancer, and places us at the cusp of an exciting period in the development of successful treatments against CRPC.

This review will summarize the role of traditional bone-targeting radiopharmaceuticals in the management of prostate cancer with osseous metastases, and will also highlight the impact that the novel agent radium-223 could potentially have on the treatment landscape of bone-metastatic CRPC.