| | Denosumab Treatment of Prostate Cancer With Bone Metastases and Increased Urine N-Telopeptide Levels After Therapy With Intravenous Bisphosphonates: Results of a Randomized Phase II TrialReceived 22 December 2008 published online 15 June 2009. PurposePatients with bone metastases have high rates of RANKL driven bone resorption and an increased risk of skeletal morbidity. Osteoclast mediated bone resorption can be assessed by measuring urine N-telopeptide and can be inhibited by denosumab, a fully human antibody against RANKL. Materials and MethodsEligible patients (111) had bone metastases from prostate cancer, other solid tumors or multiple myeloma, 1 or more bone lesions and urine N-telopeptide greater than 50 nM bone collagen equivalents per mM creatinine (urine N-telopeptide greater than 50) despite the use of intravenous bisphosphonates. Patients were stratified by cancer type and screening urine N-telopeptide, and randomized to continue intravenous bisphosphonates every 4 weeks or receive 180 mg subcutaneous denosumab every 4 weeks or 180 mg every 12 weeks. The primary end point was the proportion of patients with urine N-telopeptide less than 50 at week 13. We report the efficacy results for the subset of patients with prostate cancer. ResultsPatients with prostate cancer represented 45% (50 of 111) of the study population. At week 13, 22 of 32 (69%) patients in the denosumab arms had urine N-telopeptide less than 50 vs 3 of 16 (19%) in the intravenous bisphosphonates cohort. At week 25, 22 of 32 (69%) denosumab treated patients continued to have urine N-telopeptide less than 50 vs 5 of 16 (31%) treated with intravenous bisphosphonates. Grade 4, asymptomatic, reversible hypophosphatemia, possibly related to denosumab, was reported in 1 patient. ConclusionsIn patients with prostate cancer related bone metastases and increased urine N-telopeptide despite intravenous bisphosphonate treatment, denosumab normalized urine N-telopeptide levels more frequently than ongoing intravenous bisphosphonates. Abbreviations and Acronyms: AE, adverse event, BCE, bone collagen equivalents, BP, bisphosphonates, Cr, creatinine, ECOG, Eastern Cooperative Oncology Group, IV, intravenous, Q4W, every 4 weeks, Q12W, every 12 weeks, RANKL, receptor activator of nuclear factor κB ligand, SC, subcutaneous, SRE, skeletal related event, uNTx, urine N-telopeptide Prostate cancer was diagnosed in more than a half-million men worldwide in 2002 and was the cause of death for more than a quarter-million men.1 In up to 75% of patients with advanced disease prostate cancer metastasizes to bone, which may result in skeletal complications including pathological skeletal fractures, spinal cord compression, or radiation therapy or surgery to bone, collectively known as skeletal related events.2 In patients with bone metastases tumor cells in the bone disrupt the local balance between bone resorption (mediated by osteoclasts) and bone formation (mediated by osteoblasts) in the affected region.3 The result is increased, unbalanced bone turnover that contributes to a loss of structural integrity in the bone. This process creates a vicious cycle of tumor growth and bone destruction at sites of metastatic cells. Within the bone microenvironment growth factors secreted by tumor cells induce stromal cells and osteoblasts to secrete the receptor activator of NF-κB ligand (RANKL), an essential mediator of osteoclast formation, function and survival.4 Binding of RANKL to its receptor, RANK, on osteoclasts and osteoclast precursors promotes increased osteoclast formation and bone resorption. Growth factors released from the bone matrix promote further tumor growth and perpetuate the vicious cycle. The key role of the RANKL/osteoprotegerin axis in the cycle of bone metastases from prostate cancer was shown in in vitro models.5 The favorable effect of RANKL inhibition was subsequently demonstrated in animal models of bone metastases.6 Although prostate cancer related bone metastases often appear osteoblastic on radiographs, osteolysis and poor mineralization can be seen microscopically.5, 7, 8 Prostate cancer bone metastases are characterized by increased deposition of quickly formed, immature, woven bone,9 which is more brittle and weaker than normal bone tissue,10 potentially increasing the risk of fracture and other skeletal complications. Cytotoxic, glucocorticoid and androgen deprivation therapies for cancer may also decrease bone mineral density, accelerating bone loss and increasing fracture risk.11 Markers of bone turnover such as urine N-telopeptide, used in research, are indicators of clinical prognosis in patients with prostate cancer related bone metastases. In these patients increased levels of uNTx (greater than 50 nM BCE/mM creatinine [uNTx greater than 50]) represent excess bone resorption, and are associated with increased risk of SREs, disease progression and death.12 Current treatments for reducing skeletal complications of bone metastases in prostate cancer include localized radiation to bone and the intravenous bisphosphonate zoledronic acid.13 Other IV BPs (pamidronate and ibandronate), which are effective in bone metastases with other tumor types, failed to show significant activity in prostate cancer in randomized trials. More effective, safer treatments that are convenient and well tolerated are needed. Denosumab is an investigational fully human monoclonal antibody, administered subcutaneously, that inhibits osteoclast mediated bone resorption in bone metastases from solid tumors and multiple myeloma.14 We recently reported results from a phase II, randomized, active controlled, open label trial that evaluated the effects of denosumab on bone turnover markers and SREs in patients with bone metastases and increased uNTx levels despite previous treatment with zoledronic acid.15 This report focuses on the subset of patients with prostate cancer from that study, describing the effects of denosumab on bone resorption markers, the incidence of skeletal complications and safety in these patients. Materials and Methods  Patients Eligible patients were 18 years old or older, with prostate cancer, other solid carcinomas (except lung cancer) or multiple myeloma with radiographic evidence of 1 or more bone lesions and an ECOG performance status of 2 or less. All patients had received 8 or more weeks of treatment with IV BP for treatment of bone metastases, yet continued to have evidence of excessive bone resorption (uNTx levels greater than 50). Patients were excluded from study if they had more than 2 prior SREs, osteonecrosis or osteomyelitis of the jaw (current or past), planned oral surgery, radiotherapy to bone less than 2 weeks before randomization or evidence of impending fracture in weight bearing bones. The study was approved by the institutional review board or ethics committee for each site. All patients provided written informed consent. Study Design and Procedures This multicenter, phase II, randomized, open label, active controlled study, conducted at 26 centers in Europe and North America from December 2, 2004 through January 20, 2008, compared 2 different doses of subcutaneous denosumab and IV BP. Patients were randomly assigned in a 1:1:1 ratio to continue IV BP therapy every 4 weeks or to discontinue IV BP therapy and receive subcutaneous injections of denosumab 180 mg Q4W or Q12W (fig. 1). Randomization was stratified by cancer type (prostate, breast, or other solid tumors and multiple myeloma) and baseline uNTx (50 to 100 or greater than 100). All patients were instructed to take daily supplements of calcium (500 mg) and vitamin D (400 or more IU). The treatment period was 25 weeks, after which patients were eligible to enroll in a separate 2-year extension study. Those who did not participate in the extension study were followed in posttreatment visits at weeks 33, 45 and 57. We describe final results of the 25-week treatment phase of the study and 32 weeks of off treatment followup (a total of up to 57 weeks) for the patients with prostate cancer (50) at study entry. This subset of patients with prostate cancer had prior treatment with zoledronic acid. Most patients with prostate cancer had evidence of bone metastases despite ongoing androgen deprivation therapy/antiandrogens (78%) so that the disease was considered castration resistant in the majority of patients. Initial and periodic study assessments included a medical history and physical examination, vital signs, electrocardiograms, radiographic evaluations of the spine, and laboratory assessments including hematology, serum chemistry and bone resorption markers. Prostate specific antigen levels were not collected in this study. Concurrent antineoplastic or hormonal therapy was permitted during study treatment at investigator discretion as long as no changes in regimens or agents were planned within 4 weeks of randomization. End Points Efficacy end points included changes in bone resorption markers and the incidence of SREs. The primary efficacy end point was the proportion of patients with uNTx less than 50 at week 13. Secondary end points included the proportion of patients achieving uNTx less than 50 at week 25, time to reduction of uNTx to less than 50 and duration of uNTx level less than 50. The study also evaluated the patient incidence of SREs, defined as a pathological bone fracture, spinal cord compression, or surgery or radiation therapy to bone; the time from enrollment to first on-study SRE; and the incidence of hypercalcemia. Safety end points were assessed at regular intervals, and included AEs graded using the Common Terminology Criteria for Adverse Events version 3, changes from baseline in laboratory assessments and the incidence of anti-denosumab antibody formation. Statistical Analysis The statistical analysis plan for this study has been described previously.15 The 2 denosumab arms were pooled for analysis. The primary analysis was conducted on all patients who were randomized, received at least 1 dose of investigational product, and had uNTx measurements at baseline and at least 1 other time after baseline. Safety analyses were performed on randomized patients who received at least 1 dose of investigational drug. Results Patients Of 111 enrolled patients 50 (45%) had prostate cancer at baseline. The median time to randomization from the diagnosis of bone metastases was 0.6 years, but ranged up to 4 years (table 1). Other patients enrolled in the study had breast cancer (46 of 111, 41%), multiple myeloma (9 of 111, 8%) and other solid tumors (6 of 111, 5%). One patient with prostate cancer assigned to the IV BP group was ineligible after enrollment while 49 patients received treatment (fig. 1). In the prostate cancer subset 27 of 33 patients (82%) in the denosumab groups and 10 of 17 (59%) in the IV BP group completed the full 25 weeks of treatment. The most common reasons for study discontinuation were death from underlying disease and disease progression. | | |  | | IV BP Q4W | Denosumab | |
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| Q12W | Q4W | All | |
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| No. men (%) | 17 (100) | 16 (100.0) | 17 (100.0) | 33 (100.0) | | | Mean ± SD age | 69.5±9.5 | 67.4±12.3 | 64.5±8.7 | 65.9±10.5 | | | No. ECOG status (%): | | | | | | | 0 or 1 | 13 (76) | 11 (69) | 11 (65) | 22 (67) | | | 2 | 4 (24) | 5 (31) | 6 (35) | 11 (33) | | | Median yrs since original diagnosis (min, max) | 2.6 (0.2,13.2) | 3.8 (0.1,8.7) | 3.8 (0.3,11.1) | 3.8 (0.1,11.1) | | | No. treatment received (%): | | | | | | | Chemotherapy | 7 (41) | 5 (31) | 10 (59) | 15 (46) | | | Androgen deprivation/antiandrogens | 14 (82) | 11 (69) | 14 (82) | 25 (76) | | | Median mos on BP (min, max) | 3.7 (1.6,28.7) | 6.8 (2.1,29.1) | 6.60 (1.8,30.2) | 6.60 (1.8,30.2) | | | Median yrs since bone metastases diagnosis (min, max) | 0.5 (0.1,2.7) | 0.6 (0.0,4.1) | 0.7 (0.1,4.1) | 0.6 (0.0,4.1) | | | No. bone metastases (%): | | | | | | | 2 or Less | 0 (0.0) | 1 (6.3) | 1 (5.9) | 2 (6.1) | | | Greater than 2 | 17 (100.0) | 15 (93.8) | 16 (94.1) | 31 (93.9) | | | No. previous SREs (%): | | | | | | | 0 | 13 (76) | 8 (50.0) | 8 (47) | 16 (48) | | | 1 or More | 4 (24) | 8 (50.0) | 9 (53) | 17 (52) | | | Median ml/min/1.73 m2 estimated glomerular filtration rate (min, max) | 102 (49,183) | 97 (39,141) | 81 (38,164) | 86 (38,164) | | | Median nM BCE mM/Cr baseline uNTx corrected for Cr (Q1, Q3) | 103.4 (62.5,212.5) | 149.3 (48.8,346.8) | 129.9 (64.6,278.7) | 129.9 (50.8,285.6) | | | No. less than 50 nM BCE mM/Cr (%) | 2 (12) | 5 (31) | 3 (18) | 8 (24) | | | No. 50–100 nM BCE mM/Cr (%) | 5 (29) | 1 (6) | 2 (12) | 3 (9) | | | No. greater than 100 nM BCE mM/Cr (%) | 10 (59) | 10 (63) | 12 (71) | 22 (67) | | | | |
While baseline demographics and disease characteristics were generally balanced among treatment groups, more patients in the denosumab groups than the IV BP group (33% vs 24%) had an ECOG status of 2. The median age of patients with prostate cancer was 68 years. At baseline the extent of bone resorption was greater in more patients randomized to denosumab compared to those randomized to IV BP, as indicated by uNTx levels (table 1). All patients had prior treatment with zoledronic acid with a median of 6 months treatment before randomization (IV BP 4 months, denosumab 7 months). No other IV BPs were used by patients in the prostate cancer subset. Approximately half (17 of 33, 52%) of the patients randomized to the denosumab groups and a quarter (4 of 17, 24%) of those randomized to the IV BP group experienced SREs before entering the study (a strong predictor of subsequent SREs).16 Efficacy Bone resorption After 13 weeks suppression of bone resorption was observed in a greater proportion of patients in the denosumab groups than in the IV BP group as demonstrated by the proportion of patients with uNTx levels less than 50 (22 of 32, 69% vs 3 of 16, 19%; primary end point, fig. 2, A) and the median percentage reduction in uNTx levels from baseline (84% vs 32%, fig. 2, B). Denosumab induced reduction in bone resorption was sustained at week 25, with 22 of 32 (69%) patients in the denosumab groups and 5 of 16 (31%) in the IV BP group continuing to have uNTx less than 50 (fig. 2, C). Denosumab induced suppression of bone resorption was rapid, observed as early as 2 weeks (the first point at which uNTx was evaluated on-study, fig. 2, B). Median time to reduction of uNTx less than 50 was 10 days in the denosumab arms and 88 days in IV BP treated patients (stratified Cox model p <0.001). Normalization of uNTx levels occurred more frequently in the pooled denosumab groups than the IV BP group at weeks 13 and 25 regardless of screening uNTx levels (fig. 2, A and C). The effects of denosumab were sustained throughout the treatment period. For most patients receiving denosumab, uNTx never increased above less than 50 nm/mmol after suppression. The estimated 25th percentile of duration of maintaining uNTx less than 50 was 160 days (95% CI 56–,) in the denosumab groups and only 28 days (95% CI 21–78) in the IV BP group (p = 0.016). The 25th percentile was evaluated for this comparison because 50% (median) of the patients in the denosumab group never had their uNTx levels revert to a level above 50 nm. Skeletal complications A lower proportion of patients with prostate cancer in the denosumab groups than in the IV BP group experienced an on-study SRE (1 of 33 [3%] treated with denosumab and 3 of 16 [19%] treated with IV BP). This difference was similar to that seen in the overall study population (fig. 3).15 No cases of hypercalcemia were reported. Safety Safety results were as expected in a population with advanced cancer receiving systemic chemotherapy and androgen deprivation therapy. The incidence and types of AEs were similar in both treatment groups and similar to those for the entire population (table 2). In the prostate cancer subset, AEs were reported in 31 of 33 patients (94%) in the pooled denosumab group and 16 of 16 patients (100%) in the IV BP group. AEs considered potentially treatment related were reported in 9 of 33 patients (27%) receiving denosumab and 2 of 16 patients (12%) receiving IV BP. Similar low rates of serious AEs considered potentially treatment related were reported in both treatment groups. Expected, slight decreases in serum calcium levels were observed based on laboratory values (median change [Q1, Q3]) at study week 2 after treatment with IV BP (−0.13 mM/l [−0.21, −0.02]) or denosumab (−0.23 mM/l [−0.30, −0.07]). Serum calcium levels remained relatively unchanged compared with baseline levels in the IV BP arm and the pooled denosumab arm through week 25. Median (Q1, Q3) changes in alkaline phosphatase levels were comparable between the IV BP arm and the denosumab arm after week 2 (−12.5 [−59.0, 39.5] and −14.0 [−84.0, 18.0], respectively) and after week 25 (−167.0 [−325.0, 110.0] and −72.0 [−211.5, −38.0], respectively). Only 1 AE of grade 3 or greater that was considered possibly treatment related was reported among the patients with prostate cancer. This patient received 180 mg denosumab Q4W and experienced asymptomatic transient hypophosphatemia (grade 4), which accompanied rapid underlying cancer progression and biological evidence of hyperparathyroidism (resolved after 5 weeks). Two patients in the prostate cancer subset experienced grade 3 hypocalcemia. In 1 patient treated with denosumab Q4W the hypocalcemia was considered serious but not treatment related. Another patient received IV BP and also experienced grade 3 hypocalcemia that was not considered serious but was deemed treatment related by the investigator. Expected, transient decreases in serum calcium levels were observed in both treatment groups. The rates and nature of deaths on the study were as expected, and none were considered treatment related. Denosumab treatment had no marked effect on renal or hepatic function and no patient experienced neutralizing anti-denosumab antibodies or osteonecrosis of the jaw. Discussion The population described in this study may represent the most difficult patients in whom to treat bone metastases and to normalize bone resorption. They had poor prognoses as well as an increased risk of SREs and death as indicated by increased levels of uNTx despite at least 8 weeks of IV BP treatment before study entry. In these patients regardless of baseline uNTx levels denosumab induced suppression of bone resorption occurred rapidly and continued during the course of treatment. The incidence of SREs in the prostate cancer subgroups was similar to the SRE rate in the overall population and lower in the denosumab treated group (3%) than in the IV BP group (19%), although the small population size does not allow a statistical comparison. The adverse event profiles in both groups were similar and denosumab appeared to be well tolerated overall. In this population more patients randomized to denosumab had an ECOG status of 2 and a higher median uNTx (129.9 vs 103.4) at baseline than those randomized to IV BP. This study demonstrates that denosumab decreased bone resorption markers even in patients with increased uNTx levels despite treatment with IV BP. The results seen in this population of patients with prostate cancer were consistent with those observed in the overall study population, as well as those reported in another phase II study of denosumab in patients with bone metastases from breast cancer who were previously naïve to IV BP.17 In these 2 studies denosumab suppressed bone resorption in patients with bone metastases regardless of whether patients had previous exposure to IV BP. Because the majority of patients with prostate cancer will eventually experience bone metastases,2 multiple bone targeting therapies are in development. Therapeutic approaches in addition to RANKL inhibition include bone seeking radiopharmaceuticals like samarium, strontium or radium,18 targeting of Src family kinases19 and targeting of the endothelin-1 receptor A.20 Denosumab induced inhibition of RANKL in this study reduced markers of bone resorption, even in patients with increased uNTx despite treatment with IV BP. These results support additional studies with denosumab as a new approach to the treatment of bone metastases in prostate cancer. Two global phase III studies of denosumab are in process, with a total planned enrollment of approximately 3,000 patients with prostate cancer who have not been previously treated with bisphosphonates. Study 20050103 (NCT00321620) is an evaluation of denosumab in patients with castration resistant prostate cancer and bone metastases. The primary end point is the time to occurrence of the first on-study SRE. Study 20050147 (NCT00286091) is an evaluation of denosumab in patients with castration resistant prostate cancer without bone metastases and the primary end point is bone metastasis-free survival or death from any cause. Outcomes of these studies will provide further insights into the ability of denosumab to prevent and treat bone metastases for patients with prostate cancer. Conclusions In patients with prostate cancer related bone metastases and increased uNTx despite IV BP treatment, denosumab normalized uNTx levels and reduced the incidence of SREs. This evidence suggests that denosumab may provide a new alternative for the prevention of bone resorption and resulting skeletal complications in patients with prostate cancer. Acknowledgments Ting Chang, PhD and Sue Hudson from Amgen Inc. provided writing assistance. 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a Institut Gustave Roussy and University of Paris XI, Villejuif, France b Wilshire Oncology Medical Group, La Verne, California c Amgen Inc., San Francisco, California d Amgen Inc., Thousand Oaks, California e Amgen (Europe) GmbH, Zug, Switzerland  Correspondence: Department of Medicine, Institut Gustave Roussy and University of Paris XI, 39 Rue Camille Desmoulins, 94800 Villejuif, France (telephone: 33 1 42 11 43 17; FAX: 33 1 42 11 52 11)
Study received institutional review board/ethics committee approval. PII: S0022-5347(09)00932-X doi:10.1016/j.juro.2009.04.023 © 2009 American Urological Association. Published by Elsevier Inc. All rights reserved. | |
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