ABSTRACT: Metastasis to bone represents an all-too-frequent complication of advanced-stage prostate cancer (PCa): 50% to 70% of these patients will ultimately develop this devastating complication. PCa preferentially metastasizes to bone, and the skeletal complications increase mortality and decrease quality of life. The clinical consequences of skeletal metastasis also include pain, skeletal-related events (SREs), and increased costs of therapy. Recent advances in our understanding of the mechanisms of metastasis and the physiologic changes that occur with it, together with the introduction of new treatments, are furthering our ability to combat this problem. In this review, we examine bone-targeted palliative agents, nontargeted systemic cytotoxic therapies, and bone-targeted agents that go beyond palliation to also potentially improve progression-free and overall survival. We specifically focus on post-treatment outcomes—including pain relief, decreased opioid use, improvement in quality of life, freedom from SREs or new bony metastases, and increases in overall survival—in men with symptomatic, metastatic PCa. Treatments discussed include varied drug classes, such as bisphosphonates and human monoclonal antibodies; beta-emitting radiopharmaceuticals; external beam radiotherapy; systemic chemotherapies; Src inhibitors; endothelin-A receptor antagonists; clusterin inhibitors; and alpha-emitting radiopharmaceuticals.
Introduction
Metastasis to bone represents a frequent complication of advanced-stage prostate cancer (PCa). The exact prevalence of bony metastasis is generally unknown, but some estimate that 50% to 70% of patients with advanced-stage PCa will ultimately develop this devastating complication.[1,2] PCa preferentially metastasizes to the axial skeleton, including the vertebrae, pelvis, proximal ends of long bones, and skull.[3] The resulting skeletal complications are widely recognized to increase mortality and decrease quality of life, since affected patients suffer loss of independence, mobility, and social functioning (Figure 1). The clinical consequences of skeletal metastasis also include pain, skeletal-related events (SREs), and increased costs of therapy. Recent advances in our understanding of the mechanisms of metastasis and of the physiologic changes that occur along with it, along with the introduction of new treatments, are improving our ability to combat this problem.
The Negative Impact of Bone Complications
There are several important characteristics of bone that implicate it as the preferential site for metastasis of visceral cancers. In 1889, Stephen Paget first noted in his “seed and soil” hypothesis that the complementary characteristics of target organs and circulating tumor cells would determine where tumors metastasize.[4] Bone has high blood flow to marrow, where many important growth factors and cytokines reside and are involved in the constant remodeling of bone; these factors include transforming growth factor β, endothelin-1, interleukin (IL)-1 and IL-6, prostaglandins, insulin-like growth factors, fibroblast growth factors, and platelet-derived growth factors.[5] The final necessary step in metastasis involves tumor cell expression of adhesive molecules. The bone microenvironment milieu provides the perfect environment for tumor cell deposition and clonal expansion.
Skeletal pain from metastasis manifests as a deep nonspecific ache that worsens with movement and that can be quite severe; it progresses as metastatic disease progresses. Patients usually start on nonsteroidal anti-inflammatory drugs (NSAIDs), move to opioids, and then require more advanced, systemic palliation therapies, which will be reviewed here. Some early studies mentioned in the sections below measured the palliative effects of an intervention using pain scale questionnaires or diaries, opioid usage (either prescribed or patient-reported usage), patient-reported sleep patterns, or even doctor-reported pain scores. As the reader may realize, some of these measures are highly subjective and vary from patient to patient, making the comparison of different studies more difficult.
Trials of Treatments for Castration-Resistant Prostrate Cancer Mentioned in This ReviewUnfortunately, few treatments specifically target tumor cells that reside in bone, and those that are available have drawbacks related to dose-limiting toxicities and may have only small therapeutic benefit. Further, patients who have exhausted chemotherapeutic options or who do not tolerate their side effects find themselves with a limited number of treatment options after the diagnosis of skeletal metastasis. This review will examine agents with potential activity in the palliation and treatment of skeletal metastases of PCa, and will weigh the clinical-outcomes evidence for and against their broad use (Table).
Targeted Treatments for Symptom Palliation
Bisphosphonates
Bisphosphonates target the osteoclastic feedback loop that develops between a metastatic lesion and bone, thereby preventing or delaying the onset of SREs.[6,7] These drugs bind to the active site of bone resorption and turnover, enter osteoclasts, disrupt cellular signaling pathways, induce apoptosis, and prevent further resorption.[8] The goals of bisphosphonate therapy include increasing bone mineral density (BMD), preventing new and recurrent SREs, palliating bone pain, reducing the need for other therapies, and mitigating further morbidity. The efficacy of this class of drug in attaining these clinical goals has been investigated in multiple placebo-controlled randomized trials, which have shown significant improvements in clinical outcomes with these agents.[9-11] Zoledronic acid(Drug information on zoledronic acid) (Zometa) is a bisphosphonate approved for the prevention of SREs in men with metastatic castration-resistant prostate cancer (CRPC). Its role was established by a study of men with metastatic CRPC by Saad et al, in which 4 mg of zoledronic acid was given every 3 weeks; the incidence of SREs was reduced from 44% in the placebo arm to 33% in the zoledronic acid arm.[12] Follow-up phase II trials have examined other dosing regimens, such as 4 mg every 3 months—or even yearly—and have demonstrated preservation of BMD in men receiving androgen-deprivation therapy (ADT), but these studies did not specifically examine outcomes involving SREs.[13,14]
Bisphosphonates, when used for the treatment of debilitating bone pain, reduce the need for NSAIDs and opioid analgesics, which can have unintended consequences for patients with advanced cancer. Zoledronic acid is administered intravenously. Despite its systemic activity, it lacks the myelosuppressive side effects of chemotherapy or radiation, and it can be used as an adjunct to such therapies. Bisphosphonates have never been shown to prevent metastasis, but they do offer prevention of their deleterious effects and mitigation of SREs and bone pain. Some studies have demonstrated in vitro synergistic cytotoxic effects between bisphosphonates and chemotherapies, but these have never been borne out in clinical studies.[15,16]
The Vicious Cycle of Bone Destruction From Metastases: the Role of RANK Ligand—
Human monoclonal antibodies
Denosumab (Xgeva) is a fully human monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL); it disrupts the normal homeostatic messaging that occurs between osteoblasts and osteoclasts in bone, and its administration causes a decrease in bone turnover and resorption (Figure 2). Denosumab has been well studied in several clinical areas that involve bone loss, including in postmenopausal women and in men with CRPC. It is currently FDA-approved for use in both postmenopausal women and men with advanced prostate cancer and bone metastase, to prevent bone loss and subsequent fracture.[17,18] The latter group presents a particular challenge with respect to potential loss in BMD and subsequent SREs for several reasons, including prolonged use of ADT and/or development of skeletal metastasis. Below we highlight several of the key studies of denosumab that have been published to date.
In a phase II trial of denosumab in patients with bone metastases from prostate, breast, and other cancers who were noted to have persistently elevated bone turnover markers (urinary N-telopeptide [uNTx]) while receiving intravenous (IV) bisphosphonate treatment, patients were randomly assigned to receive subcutaneous denosumab or continuation of the IV bisphosphonate. This study noted that more patients achieved normal levels of urinary bone turnover markers (about 64% vs 37%; P = .01) and that patients experienced fewer SREs (8% vs 17%; odds ratio [OR], 0.31; 95% confidence interval [CI], 0.08-1.18) with denosumab than with bisphosphonate treatment. Similar numbers of patients suffered adverse events in the two arms.[19]
In 2009, Smith et al published the results of a phase III randomized controlled trial comparing denosumab to placebo in patients with nonmetastatic PCa who were receiving ADT. The key endpoints were percent change in BMD in the lumbar spine, total hip, and femoral neck at 24 and 36 months, and incidence of new vertebral fractures.[20] Lumbar spine BMD increased by 5.6% in the treatment group as opposed to a BMD decrease of 1.0% in the placebo arm (P < .001). Patients who received denosumab also experienced a decreased incidence of new vertebral fractures at 36 months (1.5% vs 3.9% with placebo) (relative risk, 0.38; 95% CI, 0.19 to 0.78; P = .006). Subsequent analyses noted that patients with high baseline levels of turnover markers (serum C-telopeptide and tartrate-resistant alkaline phosphatase 5b) had the greatest increases in BMD.[21]
Phase III studies comparing denosumab to the bisphosphonate zoledronic acid with respect to time to development of a first SRE in patients with CRPC and at least one bone metastasis were published in 2010.[22,23] Denosumab improved the median time to development of a first SRE (20.7 months vs 17.1 months for zoledronic acid, a difference of 3.6 months). Rates of osteonecrosis of the jaw were not significantly different between the two study arms, at 2.3% and 1.3%, respectively (P = .09), but hypocalcemia was observed more frequently with denosumab than with zoledronic acid (13% vs 6%). This report showed no difference in overall survival between the two groups.
Recently, results were presented regarding the ability of denosumab to prevent the development of bone metastasis.[24] Some have hypothesized that, by limiting bone turnover and resorption, denosumab may make bone an environment that is less amenable to circulating tumor cells remaining and clonally expanding. In this report by Saad et al, denosumab increased the time to development of first bone metastasis by a median of 4.2 months compared with placebo, in a population of men deemed to be at high risk for development of metastatic disease. No difference in overall survival was noted, however.
In summary, denosumab is a fully human monoclonal antibody against RANKL; it inhibits osteoclast activity, limiting bone turnover and resorption. It is approved for the prevention of SREs in high-risk postmenopausal women and men with advanced prostate cancer and bone metastasis. Denosumab does not have any direct antitumor activity, and while there is some recent evidence that denosumab prevents development of bone metastasis, it has not yet been approved for this use. Studies published to date have demonstrated its ability to help prevent and reduce SREs in men with and without bone metastasis, compared with bisphosphonates and placebo, to increase BMD over placebo, and to improve the time to development of a first SRE compared with zoledronic acid. Clinicians will ultimately have to grapple with cost-benefit issues, since denosumab is more expensive than zoledronic acid. Clinicians will also have to weigh the convenience of a subcutaneous injection of denosumab against the intravenous administration of zoledronic acid and fewer cases of renal toxicity with denosumab. As mentioned, in a head-to-head study, denosumab delayed SREs by 3.6 months compared with zoledronic acid.
