A Step in the Journey of Denosumab From Bone-Targeted Therapy to Seed- and Soil-Targeted Therapy
Authors: Stéphane Vignot, David Khayat
Journal: Journal of Clinical Oncology (2009)

Oral or intravenous bisphosphonates are largely used in oncology and can be considered as bone-targeted therapies. Denosumab represents a new therapeutic opportunity by targeting the receptor activator of nuclear factor B ligand (RANKL) system, which has been has been linked to osteoclast formation, activity, and survival. Clinical activity of this compound on bone density in the setting of adjuvant aromatase inhibitor therapy for early breast cancer has recently been reported in Journal of Clinical Oncology. In this issue, Fizazi et al present another aspect of denosumab development through a randomized phase II study of 111 patients with bone metastases or myeloma, evaluating two schedules of denosumab compared with placebo. In this study, tumor types were mainly prostate or breast cancer (45% and 41%, respectively); 8% of patients had myeloma. Denosumab activity has been reported previously in another phase II study of women with bone metastases from breast cancer who were naive to bisphosphonates. As in this previous publication, the present study evaluates several schedules of administration for denosumab (two schedules were selected: 180 mg subcutaneously every 4 weeks or every 12 weeks) and a biologic end point was chosen. Elevated levels of bone turnover markers such as elevated urinary N-telopeptide (uNTx) represent excessive bone resorption activity and have been linked to skeletal-related events. Levels of uNTx are therefore considered as a convenient biomarker for the early evaluation of bonetargeted therapies and are commonly used in this setting. The originality of the present phase II study is the focus on patients who present with bone metastases and persistent elevated uNTx levels despite ongoing intravenous bisphosphonates. This situation could represent a major concern, given that one fifth of patients treated with bisphosphonates have been shown to have moderate or high uNTx levels (defined as 50 to 99 and 100 nmol/L/mM creatinine, respectively) during treatment. Recent retrospective analyses with bisphosphonates, particularly with zoledronic acid, have shown significant correlations between persistent elevated bone resorption markers levels such as uNTx and clinical outcomes. Interestingly, a control arm with continuation of intravenous bisphosphonates was included in the study. Twenty-nine percent of patients in this treatment arm achieved uNTx levels less than 50 nmol/L/mM creatinine. This observation could be interpreted as a late biologic response to standard treatment. The experimental arm with denosumab resulted in better efficacy in this parameter, with a biologic response rate of 71% (P .001 compared with bisphosphonates), which reached the primary end point of the study. Normalized uNTx levels with denosumab were observed early and the response was sustained, regardless of tumor types. As previously reported in bisphosphonate-naive patients, the 4-week schedule appears to provide more sustained response in bone turnover markers than the 12-week schedule. The clinical activity of denosumab compared with bisphosphonates was evaluated by the incidence of skeletalrelated events: 8% in the denosumab arms compared with 17% in the bisphosphonates arm, which was not statistically significant. Finally, the safety profile of denosumab was acceptable, with no osteonecrosis of the jaw reported (a feared toxicity in bone-targeted therapies). In summary, this study demonstrates activity of denosumab in the setting of biologic failure of intravenous bisphosphonates. Phase III trials are now awaited to define the efficacy of denosumab compared with bisphosphonates using clinical primary end points such as time to skeletal-related event in first-line therapy for patients with bone metastases. Bone-targeted therapy development is nevertheless wider than the meaningful but restricted setting of bone metastases. Both bisphosphonates and denosumab are currently being evaluated in other settings (summarized in Table 1). First, several bisphosphonates are approved for the treatment of osteoporosis, and the most efficacious modes of administration (oral v intravenous) are currently being investigated. Denosumab has also been evaluated for osteoporosis treatment for postmenopausal women in a phase II study. Raloxifene is the third agent proposed in this setting in relation to selective estrogen receptor modulator activity. The second aspect of bonetargeted therapy development is represented by prevention of bone loss, mainly for women receiving aromatase inhibitors for breast cancer treatment and also for men receiving hormonal therapy for prostate cancer. Bisphosphonates and denosumab are both currently evaluated in this indication, and we suggest that you read the recent editorial in Journal of Clinical Oncology for a clear focus on this subject. Not surprisingly, future evaluation of these agents should certainly be based on efficacy but also on schedule and routes of administration, on toxicity profiles, and on cost. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 10 APRIL 1 2009