Efficacy of Ibandronate in Metastatic Bone Disease: Review of Clinical Data

Efficacy of Ibandronate in Metastatic Bone Disease: Review of Clinical Data Richard Bell The Andrew Love Cancer Centre Cancer Services, Medical Oncology, Geelong, Victoria, Australia Key Words. Bisphosphonate Ibandronate Intravenous Oral Bone metastases Abstract Metastatic bone disease affects many cancer patients and has a significant disease burden because of complications such as pathologic fractures and severe pain, which affect patient mobility and quality of life. Bisphosphonates are the current standard of care for treating metastatic bone disease. Available agents have shown varying degrees of efficacy in clinical trials, and treatment potential can be limited by efficacy, tolerance, or toxicity issues. Ibandronate (Bondronat ; F. Hoffman-La Roche Ltd., Basel, Switzerland, http://www.roche.com) is a highly potent, single-nitrogen bisphosphonate that is available in i.v. and oral formulations. In phase III trials in breast cancer patients, both formulations reduced the incidence of skeletal complications associated with metastatic bone disease and had significant and sustained effects on bone pain and patient quality of life. Open-label studies of loading-dose ibandronate administered over consecutive days suggest it also may be useful for relieving severe or opioid-resistant metastatic bone pain. New trials have been designed or are in progress that may extend the clinical indications of ibandronate for patients with metastatic bone disease. The Oncologist 2005;10(suppl 1):8 13 Introduction Bone involvement is a significant complication of metastatic cancer that occurs in up to 95% of multiple myeloma patients, up to 75% of breast and prostate cancer patients, and 15% 40% of patients with primary lung, colon, or kidney tumors [1, 2]. Bone metastases cause considerable morbidity, including severe pain, immobility and disability, pathologic fractures, life-threatening hypercalcemia, and spinal cord compression. These problems have a major impact on patient quality of life. The spread of tumor cells to bone normally signifies that the cancer is incurable with, for example, only 20% of breast cancer patients alive at 5 years after the initial diagnosis [1]. The primary treatment goal for metastatic bone disease is therefore to alleviate symptoms and enable patients to continue with a normal life for as long as possible. Bisphosphonates are the standard of care for treating metastatic bone disease. These agents inhibit the function of osteoclasts, which are bone-resorbing cells essential for bone remodeling [3]. The presence of tumor metastasis in bone tissue results in excessive osteoclast activity with consequent destruction of bone architecture and loss of structural integrity. Bisphosphonates have the potential to prevent bone complications, and current recommendations suggest that all Correspondence: Richard Bell, MBBS, FRACP, FRCPA, FAChPM, MRACMA, The Andrew Love Cancer Centre Cancer Services, Medical Oncology, 70 Swanston Street, Geelong, Victoria 3220, Australia. Telephone: 61-35226-7855; Fax: 61-35226- 7290; e-mail: richardb@barwonhealth.org.au Received August 1, 2005; accepted for publication August 29, 2005. AlphaMed Press 1083-7159/2005/$12.00/0 The Oncologist 2005;10(suppl 1):8 13 www.theoncologist.com

Bell 9 breast cancer patients with bone metastases receive continuous bisphosphonate treatment initiated following diagnosis [4] to reduce skeletal-related events (SREs). Several bisphosphonates are available for treating metastatic bone disease. The efficacy of the agents has traditionally been judged mainly on their ability to reduce SREs such as pathologic fracture, surgery, or radiotherapy for bone metastases, spinal cord compression, and hypercalcemia. The first agent in this class shown to deliver a clinical benefit for metastatic bone disease was clodronate (Bonefos ; Schering AG, Berlin, http://www.schering.de; and Ostac, Loron, F. Hoffmann-La Roche Ltd., Basel, Switzerland, http://www.roche.com), which is approved in Europe in an oral form. Although several studies demonstrated clodronate efficacy in patients with breast cancer, recent randomized, placebo-controlled studies failed to demonstrate significant or durable clinical benefits for patients with advanced prostate cancer [5]. There are important compliance and tolerability concerns associated with clodronate because of a high incidence of gastrointestinal side effects and problems with swallowing the large clodronate tablets [6 8]. Pamidronate (Aredia ; Novartis Pharmaceuticals Corporation, East Hanover, NJ, http://www.pharma.us.novartis.com), a second-generation bisphosphonate that is administered i.v., has demonstrated clinical benefits across different SRE end points in several trials [9]. As a result, it was approved in the U.S. and quickly became established as the international standard of care for metastatic breast cancer patients [5]. Pamidronate administration is difficult because of its long (2-hour) infusion time and limited efficacy for metastatic bone pain, particularly in prostate cancer patients [10]. More recently, the third-generation bisphosphonate zoledronic acid (Zometa ; Novartis Pharmaceuticals Corporation), which can be administered via a 15-minute infusion, was found to be at least as effective as pamidronate in breast cancer and myeloma patients in a head-to-head trial for preventing SREs [11, 12]. Zoledronic acid has some effects against bone pain in breast and prostate cancer patients [5, 13 15]. However, the potential for renal toxicity with zoledronic acid can sometimes limit its usefulness in terms of flexibility of dosage or treatment regimen [16 20]. Bone pain is a particularly debilitating and distressing symptom of bone metastases and may respond poorly to conventional treatment with radiotherapy or opioids. In a recently conducted survey, more than 20% of patients with skeletal involvement were experiencing bone pain that was resistant to treatment [21]. In a separate study, clinicians in Europe and North America (n = 900) stated that more than 20% of their patients still experienced severe bone pain despite optimal analgesic treatment [22, 23]. Forty percent of radiation oncologists were dissatisfied with their ability to relieve pain [24]. For these reasons, pain palliation remains an area in which there is scope for more effective treatments. This article reviews efficacy data from clinical trials of ibandronate (Bondronat ; F. Hoffmann-La Roche Ltd., Basel, Switzerland, http://www.roche.com), a third-generation, single-nitrogen bisphosphonate available in i.v. and oral formulations that was recently approved in the European Union for breast cancer patients with metastatic bone disease. Effects on SREs and bone pain are considered. Clinical Trials in Metastatic Breast Cancer Recommended doses of ibandronate are 6 mg i.v. ibandronate every 3 4 weeks and 50 mg oral ibandronate daily. The efficacy of these doses in the treatment of metastatic breast cancer patients was demonstrated in randomized, double-blind, placebo-controlled, multicenter phase III trials [25 28]. The primary end point used was the skeletal morbidity period rate (SMPR), which measures the number of 12-week periods in which each patient experienced an SRE. This end point avoids multiple counting of SREs that cluster close together in time and are likely to arise from a single event (e.g., a pathologic fracture) leading to surgery and radiotherapy. In these trials, SREs were defined as pathologic fractures and radiotherapy or surgery for bone complications. Other end points included bone pain, analgesic use and quality-of-life scores, and urinary CTx, or cross-linked C-terminal telopeptide of type I collagen (a marker of bone resorption). Results from the trials showed that treatment with either formulation of ibandronate was associated with a significantly lower SMPR than placebo (p =.004 for i.v. and p =.041 for oral ibandronate) (Table 1) [25, 26]. Poisson multipleevent regression analyses showed that i.v. and oral ibandronate were associated with 40% and 38% risk reductions for an SRE, respectively [27, 29]. Both formulations also caused significant reductions in bone-pain scores to below baseline that were maintained throughout 2 years of treatment, whereas a gradual increase in bone-pain scores was observed for placebo-treated patients (p.001 for ibandronate versus placebo at study end) (Fig. 1 and Fig. 2) [26, 27, 30]. Both i.v. and oral ibandronate were associated with a statistically significant preservation of quality-of-life scores compared with placebo (p.05) [27, 30]. The efficacy of 6 mg i.v. ibandronate for metastatic breast cancer was further evaluated in a placebo-controlled trial of 102 patients treated every 4 weeks for 24 months. In that study, a significantly lower proportion of patients in the ibandronate group experienced SREs compared with the placebo group (36% versus 48%; p =.027) [31]. Ibandronate also was associated with an extended time to first SRE (mean number of days, 457 versus 304

10 Ibandronate for Metastatic Bone Disease Table 1. Mean SMPR and individual components of the SMPR following treatment with i.v. or oral ibandronate versus placebo for metastatic breast cancer [25, 26] i.v. trial Pooled oral trials Ibandronate Ibandronate 6 mg Placebo 50 mg Placebo (n = 154) (n = 158) p value (n = 287) (n = 277) p value All new bone events (SMPR) 1.19 1.48.004 0.95 1.18.004 Vertebral fractures 0.71 0.82.023 0.58 0.63.093 Nonvertebral fractures 0.72 0.81.396 0.60 0.61.246 Events requiring radiotherapy 0.91 1.09.011 0.73 0.98 <.001 Events needing surgery 0.56 0.62.075 0.47 0.53.037 Abbreviation: SMPR, skeletal morbidity period rate. for placebo; p =.007), and a multiple-event analysis calculated an SRE risk reduction of 32% (p =.003). More recently, at the 41st Annual Meeting of the American Society of Clinical Oncology, Body et al. [32] presented results from a comparative study of oral ibandronate and i.v. zoledronic acid. In that 12-week study, markers of bone Figure 1. Long-term effects of 6 mg i.v. ibandronate on bone pain scores compared with placebo in the pivotal phase III trial [25, 28]. *p <.001. Figure 2. Long-term effects of 50 mg oral ibandronate on bone pain scores compared with placebo in phase III trials [27]. *p =.001. turnover were used to determine drug efficacy. The results showed that oral ibandronate suppressed tumor-induced bone damage as effectively as i.v.-administered zoledronic acid. Clinical Studies of Ibandronate in Other Tumor Types Intravenous ibandronate, 4 mg administered monthly, was compared with 90 mg pamidronate over a 10-month period in multiple myeloma patients [33]. Although both bisphosphonates decreased levels of bone resorption and disease activity markers from baseline, superior scores were observed in the pamidronate group. However, the dose of ibandronate used in that study was nonstandard [34]. In the phase III trials of breast cancer patients, in contrast to data from the recommended 6-mg dose, a 2-mg dose of i.v. ibandronate was not associated with a significantly lower SMPR compared with placebo. Further studies are needed to assess 6 mg i.v. ibandronate for treating multiple myeloma patients. The efficacy of daily oral ibandronate is also being investigated in this setting. All phase IV trials of i.v. ibandronate will use monthly 6-mg infusions. A recently performed trial included a subset of 15 patients with colorectal cancer metastatic to bone treated with 6 mg i.v. ibandronate for 9 months [31]. Treatment with ibandronate resulted in a significantly lower proportion of patients with an SRE (39% versus 78% for placebo; p =.019) and prolonged the time to first event by 6 months (median > 279 days for ibandronate and 93 days for placebo; p =.009). The mean skeletal morbidity rate was also lower (2.36 versus 3.14 for placebo; p =.018). Studies of Intensive Ibandronate Dosing The phase III trials demonstrated that regular administration of ibandronate has analgesic effects in breast cancer patients with metastatic bone pain. Several open-label trials suggest that i.v. ibandronate administered on consecutive days can provide rapid relief from severe or opioid-resistant metastatic

Bell 11 bone pain. In a trial of 18 patients with opioid-resistant bone pain resulting from various primary tumors, 4 mg i.v. ibandronate was administered on 4 consecutive days (total dose, 16 mg), leading to significantly reduced bone-pain scores from baseline within 7 days (p <.001) [35]. The reductions were sustained throughout the 6-week study period. Ibandronate also significantly improved scores for quality of life, patient functioning, and performance status (p <.05 for each). Two trials have studied patients treated with 6 mg i.v. ibandronate administered on 3 consecutive days (total dose, 18 mg), followed by standard dosing of 6 mg ibandronate every 4 weeks. In a study of 53 patients with urologic malignancies, bone-pain scores were improved in 83% of patients (mean score p <.001 versus baseline on day 3), with 25% of patients becoming pain-free [36]. Mean bone-pain scores remained below baseline for 20 weeks and were accompanied by improved patient functioning. In a separate study of 45 patients with hormone-refractory prostate cancer, ibandronate significantly relieved pain in 89% of patients by day 3 of treatment (p <.001) [37, 38]. Pain relief was accompanied by a 50% reduction in daily analgesic requirement in 20 of 45 patients and a significant improvement in performance status (p =.01). Conclusions The clinical data described clearly demonstrate the efficacy of ibandronate in treating metastatic bone disease from breast cancer. Preliminary evidence from a small placebocontrolled study suggests that ibandronate may be effective in patients with metastatic colorectal cancer [31]. Clinical trials are currently ongoing or planned to assess the activity of ibandronate in other tumor types. Since other bisphosphonates, such as pamidronate and zoledronic acid, are effective in patients with bone metastases regardless of tumor type, ibandronate may also have broad spectrum activity. The evidence from these trials is awaited. The newer, more potent bisphosphonates have significant clinical benefits in reducing SREs in cancer-induced bone disease seen in various trials. There do not appear to be differences in efficacy among the various modern bisphosphonates, and their ability to suppress SREs would appear to have reached a plateau. For example, phase I dose-ranging studies of zoledronic acid showed that effects on levels of bone resorption markers, which can be used to predict skeletal complications [39], were maximal at doses below the recommended 4-mg dose [40, 41]. In the first comparative study of newer bisphosphonates, oral ibandronate was shown to be at least as effective as i.v. zoledronic acid in suppressing markers of bone turnover [32]. To choose the most effective and suitable treatment for their patients, physicians might therefore Figure 3. Phase III trials of i.v. (Bon-I-Pain) and oral (Bon- O-Pain) ibandronate compared with zoledronic acid for metastatic bone pain. Abbreviation: VAS, visual analogue scale. need to consider other attributes of bisphosphonates, such as metastatic bone pain relief, safety, and convenience. Ibandronate is unique among bisphosphonates because data show that it has proven efficacy in reducing SREs as well as reducing metastatic bone-pain scores below baseline for up to 2 years [25 28], a benefit that has not been reported for zoledronic acid and other agents. Open-label studies have demonstrated that loading-dose ibandronate effectively relieves severe or opioid-resistant bone pain. Two randomized, doubleblind, phase III trials have been designed to compare either i.v. ibandronate (administered over a shorter 15-minute infusion time) or oral ibandronate with an i.v. zoledronic acid comparator in groups of 450 patients over 24 weeks with an end point of effect on bone pain scores (Fig. 3). The clinical efficacies of zoledronic acid and ibandronate represent important treatment advances for patients with metastatic bone disease. The availability of head-to-head efficacy data will help clinicians make better-informed treatment decisions for patients with metastatic bone disease. Acknowledgments I thank Thomson Gardiner-Caldwell US for their editorial assistance. Disclosure of Potential Conflicts of Interest Dr. Bell has acted as a consultant for Roche, AstraZeneca, Novartis, and Amgen.

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