On-study Skeletal-related Events Research Articles

Abstract OT2-6-02: Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer at high risk of disease recurrence (D-CARE): A global, placebo-controlled, randomized, double-blind, phase 3 clinical trial

Abstract Background: In women with early-stage breast cancer, the skeleton represents one of the most common sites for metastases and represents approximately 40% of all first recurrences. Preclinical studies demonstrated that inhibition of RANKL significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab, a human IgG2 monoclonal antibody, binds RANKL with high specificity and affinity thus inhibiting RANKL activity. Denosumab has been approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumors. Purpose: The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS; primary endpoint) in the adjuvant breast cancer setting. Secondary endpoints include disease-free survival (DFS) and overall survival. Additional endpoints include safety, patient reported outcomes (pain, health utilities), as well as exploratory including breast density, time to first on-study SRE following the development of bone metastasis and biomarkers. Methods: In this global, randomized, double-blind, and placebo-controlled phase 3 trial, approximately 4500 women with stage II or III breast cancer at high risk for recurrence were randomized. High risk is defined as biopsy evidence of breast cancer in regional lymph nodes, tumor size > 5 cm (T3), or locally advanced disease (T4). Patients must be receiving or planned to receive standard-of-care adjuvant/neoadjuvant therapy (chemo-, endocrine, or HER-2 targeted), alone or in combination. Patients with a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, were not eligible. Patients were randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU) and calcium (≥ 500 mg) are required. The primary efficacy and two interim efficacy analyses are planned and will be event-driven. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010 and completed enrollment in late 2012. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-02.

Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors

Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma. Patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg, adjusted for creatinine clearance, with calcium and vitamin D supplementation recommended. Endpoints included times to first on-study SRE, first-and-subsequent SREs, and pain worsening. Denosumab significantly delayed time to first on-study SRE compared with ZA (HR, 0.81; 95 % CI, 0.68-0.96) and time to first-and-subsequent SREs (RR, 0.85; 95 % CI, 0.72-1.00). Denosumab also significantly delayed time to development of moderate or severe pain (HR, 0.81; 95 % CI, 0.66-1.00), pain worsening (HR, 0.83; 95 % CI, 0.71-0.97), and worsening pain interference in patients with no/mild baseline pain (HR, 0.77; 95 % CI, 0.61-0.96). Adverse event rates were 96 % in both groups. Grade 3 or 4 hypocalcemia, mostly without clinical sequelae, was more frequent in denosumab-treated patients (denosumab 4 %, ZA 2 %). Osteonecrosis of the jaw occurred infrequently (denosumab 0.8 %, ZA 1.1 %). Denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and also prevented pain progression compared to ZA in this ad hoc analysis.

Efficacy and Safety of Denosumab Versus Zoledronic Acid in Patients With Bone Metastases

Zoledronic acid (ZA) has been used as the standard treatment for patients with solid cancer or myeloma that has metastasized into bone. A new potential therapeutic strategy, denosumab, is being investigated in a variety of tumors. We conducted a systematic review with meta-analysis of randomized clinical trials assessing the efficacy and safety of denosumab in comparison with ZA in patients with bone metastases secondary to malignancy. A systematic literature search of several electronic databases till July 2011 and a review of reference lists of relevant articles was conducted. Summary relative estimates and 95% confidence intervals (CIs) were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies. Seven reports from 3 randomized controlled trials involving 5723 patients were identified. The pooled analysis showed that denosumab significantly delayed time to first on-study skeletal-related event [hazard ratio (HR) = 0.83; 95% CI, 0.76-0.90, P < 0.001], time to multiple skeletal-related events (HR = 0.83; 95% CI, 0.76-0.90, P < 0.001), and pain worsening (HR = 0.92; 95% CI, 0.86-0.99, P = 0.026) for patients with bone metastases compared with ZA. Similar results of the 2 groups were obtained with respect to overall survival (HR = 0.98; 95% CI, 0.91-1.06), disease progression (HR = 1.02; 95% CI, 0.96-1.09), and pain improvement. Summary of the adverse effects revealed similar safety profiles for the 2 drugs. Denosumab is superior to ZA in preventing complications for patients with bone metastases. However, further studies are still needed to assess longer-term safety and efficacy of denosumab.

Efficacy, Patient-Reported Outcomes (PROs), and Tolerability of the Changing Therapeutic Landscape in Patients with Metastatic Prostate Cancer (MPC): A Systematic Literature Review

ObjectiveNew therapies have attempted to improve on efficacy outcomes observed with docetaxel in patients with metastatic prostate cancer (MPC) who are hormone-therapy refractory or castration-resistant. In addition to the efficacy, patient-reported outcomes (PROs) and tolerability need to be assessed to define treatment benefit, as PROs measure the patient’s subjective experience and can be correlated with hard outcomes. The main objective of this study was to evaluate the survival benefit of new therapies and secondary efficacy-related outcomes. Assessment of the number of studies reporting PROs and tolerability was also conducted. MethodsA predefined search strategy was conducted on major academic/governmental databases and conference proceedings (2007–2011). Exclusion criteria were applied. ResultsOf 77 studies identified, 26 (34%) evaluated survival as an end point; 14 (18%) assessed PROs/tolerability. In chemotherapy-naive patients (no/minimal symptoms), median overall survival (OS) was 26 months for sipuleucel-T. In relapsed patients, the survival benefit of cabazitaxel/abiraterone was 15 months and that of enzalutamide was 18 months. Denosumab prolonged time to first on-study skeletal-related event (20.7 months denosumab, 17.1 months zoledronic acid; P = 0.0002, noninferiority; P = 0.008, superiority). Similar benefit was documented with radium-223, a new bone-targeted α-particle–emitting radiopharmaceutical. Radium-223 also significantly improved the OS (two-sided P = 0.00185). Specific to PROs, they were incorporated primarily as secondary end points, and improvements in pain response (most commonly evaluated) were variable among the agents. Last, the therapies were associated with unique toxicities requiring careful consideration. ConclusionsThe results of this review demonstrate that the therapeutic landscape of MPC has changed dramatically and many therapies in MPC now show OS improvements of about 4 months in the postdocetaxel setting.

Impact of skeletal-related events on pain and analgesic use in patients with solid tumors and bone metastases.

e20514 Background: Skeletal-related events (SREs) including pathological fracture (PF), surgery (SB) or radiotherapy to bone (RB), or spinal cord compression (SCC) occur frequently in patients (pts) with advanced cancer and bone metastases and may cause debilitating clinical sequelae for pts. Pooled results from 3 clinical trials showed denosumab was superior to zoledronic acid (ZA) for prevention of SREs. We now evaluate the burden of SREs through pt-reported pain and analgesic use. Methods: Randomized (1:1) pts in the phase III, double-blind, placebo-controlled trials received denosumab (120 mg SC) or ZA (4 mg IV, adjusted for renal function) monthly. In this posthoc analysis, data from pts with solid tumors in the 2 treatment arms were pooled. At baseline (BL) and each monthly visit, pain was assessed via the Brief Pain Inventory (BPI; 0 no pain to 10 severe pain), and pts’ analgesic use with the Analgesic Quantification Algorithm (AQA; 0 no analgesics to 7 &gt; 600 mg oral morphine equivalent/day). Pain and analgesic use for pts with SREs were assessed from 6 months before to 6 months after the 1st on-study SRE. A control group was comprised of all pts without SREs; the index time was defined as the median time to each SRE type. SRE impact was assessed using a stratified Cox proportional hazards model adjusting for SREs, as time-dependent covariates, and other baseline characteristics, and reported as HR and 95% CI. Results: 1,925 pts had an on-study SRE (first SRE type: 923 PF; 829 RB, 119 SCC, 54 SB), and 3,618 pts did not. A greater proportion of pts with SREs had a BPI worst pain score &gt; 4 (moderate/severe pain) or an AQA score ≥ 3 (strong opioid use) than did pts with no SREs. The development of SRE was associated with significantly greater risk of pain progression from no/mild pain at BL to moderate/severe pain on study (PF 1.29 [1.07, 1.57], P = 0.009; RB 2.51 [2.03, 3.10], P &lt; 0.001; SCC 3.07 [1.83, 5.13], P &lt; 0.001; and SB 2.75 [1.19, 6.33], P = 0.018). Conclusions: Pts who experienced on-study SREs had increased pain severity requiring stronger analgesic use. Effective treatments that delay or prevent SREs can reduce pain and the need for palliation with opioids. Clinical trial information: NCT00321464, NCT00321620, and NCT00330759.

Denosumab and zoledronic acid treatment in patients with genitourinary cancers and bone metastases.

5079 Background: Phase III trial results showed that denosumab is superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) in patients with cancer and metastatic bone disease (Lipton et al; 2012, Eur J Cancer). Genitourinary (GU) cancers are some of the most commonly diagnosed cancers worldwide. We now compare the efficacy and safety of denosumab (DMAb) or ZA in a subgroup analysis of patients with GU cancers enrolled in the pivotal phase III trials. Methods: Patients were randomized 1:1 to receive DMAb (120 mg, SC) or ZA (4 mg, IV, adjusted for renal function) every 4 weeks. Daily calcium and vitamin D supplements were strongly recommended. Time to 1st on-study SRE, using a Cox proportional hazards model, time to 1st and subsequent on-study SRE, using the Anderson-Gill model, and safety were evaluated for the GU subgroup in an ad hoc analysis. Results: 2,128 patients (1,052 DMAb; 1,076 ZA) had GU cancers (prostate = 1,901, renal = 155, bladder = 63, and transitional cell = 9). DMAb significantly delayed the time to 1st on-study SRE by 4.0 months compared with ZA (20.7 months vs 16.7 months) in patients with GU cancers (Table). DMAb also significantly delayed the time to 1st and subsequent on-study SRE. Time to disease progression and overall survival were similar between treatment groups. Adverse events (AEs) and serious AEs were reported by similar percentages of patients in both groups (AEs: 96.9% denosumab, 96.8% ZA; serious AEs: 62.8% denosumab, 60.2% ZA). 14.6% of DMAb pts and 15.9% of ZA pts had a renal AE. Hypocalcemia was reported for 12.9% of DMAb patients and 6.2% of ZA patients. There was no significant difference in the incidence of positively adjudicated osteonecrosis of the jaw between the DMAb (2.2%) and ZA (1.6%) groups (p=0.34). Conclusions: Among patients with GU cancers and metastatic bone disease, DMAb was superior to ZA in preventing SREs. Clinical trial information: NCT00330759 and NCT00321620. [Table: see text]

Evaluating results from the multiple myeloma subset of patients treated with denosumab or zoledronic acid (ZA) in a randomized phase III study.

8589 Background: Denosumab (dmab) is a fully human monoclonal antibody against RANKL and is superior to ZA in preventing skeletal-related events (SREs) as shown in 3 identically designed phase 3 trials (N=5723). Overall survival (OS) was balanced between treatment groups in the overall study populations of these trials. In the trial of patients (pts) with solid tumors (excluding breast and prostate) and multiple myeloma (MM), OS was longer for dmab pts with lung cancer, shorter for pts with MM, and balanced for pts with other solid tumors. This analysis further characterizes the results from the MM subset of this trial. Methods: Pts with solid tumors or MM were randomized (1:1) to receive 120 mg of SC dmab or 4 mg of IV ZA Q4W. Daily calcium and vit D supplements were strongly recommended. The primary endpoint was the time to first on-study SRE; results from the primary endpoint and lung cancer subset were previously reported. Results: Of 1776 randomized pts, 10% had MM (93 ZA, 87 dmab). OS favored ZA (hazard ratio: 2.26; 10 subject difference in deaths). 1-year OS was 83% dmab, 97% ZA. Imbalances in baseline prognostic characteristics were observed. More pts in the dmab arm had low baseline renal function (CrCl &lt; 40 mL/min) (ZA 2 [2%], dmab 9 [10%]) and more ZA pts underwent stem cell transplant (ZA 23 [25%], dmab 15 [17%]). Additionally, more ZA pts had stage I tumors at diagnosis (ZA 13 [14%], dmab 9 [10%]) and better performance status (ECOG = 0; ZA 30 [32%], dmab 21 [24%]). Study discontinuations due to consent withdrawal or lost to follow-up were also higher in the ZA group (ZA 17 [18%], dmab 11 [13%]) and occurred earlier in the ZA arm (ZA 59%, dmab 45% within 9 months of randomization). Conclusions: In this SRE study of dmab vs ZA, pts were stratified by baseline characteristics known to affect SRE outcomes, but not by prognostic factors or concurrent anticancer therapy that may impact survival in MM. OS results in the MM cohort are difficult to interpret due to small sample size and imbalances in baseline disease characteristics, stem cell transplant therapy, and consent withdrawal or loss of follow-up that favored ZA. A phase 3 trial is currently underway, which controls for these factors in pts with MM. Clinical trial information: NCT00330759.

Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer at high risk of disease recurrence (D-CARE): An international, placebo-controlled, randomized, double-blind phase III clinical trial.

TPS662 Background: In women with early-stage breast cancer, bone is a common site of distant recurrence and represents approximately 40% of all first recurrences. Preclinical studies demonstrated that inhibition of RANKL significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab is approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumors. The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS) and disease-free survival (DFS) in the adjuvant breast cancer setting. The primary endpoint of this event-driven trial is BMFS. Secondary endpoints include DFS and overall survival. Additional endpoints include safety, breast density, time to first on-study SRE (following the development of bone metastasis), patient reported outcomes, and biomarkers. Methods: In this international, randomized, double-blind, and placebo-controlled phase 3 trial, 4509 women with stage II or III breast cancer at high risk for recurrence and with known hormone and HERE2 receptor status were randomized. High risk was defined as biopsy evidence of breast cancer in regional lymph nodes, tumor size &gt; 5 cm (T3), or locally advanced disease (T4). Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination, must be planned. Patients with a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, were not eligible. Patients were randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU) and calcium (≥ 500 mg) were required. The trial, sponsored by Amgen Inc., began enrolling patients in June 2010 and completed enrollment in late 2012. Clinical trial information: NCT01077154.

Trends in use of intravenous bisphosphonates in patients with prostate cancer and newly diagnosed metastases to bone in two large U.S. integrated health systems.

192 Background: Bone is a common site of metastatic involvement in patients (pts) with prostate cancer (PC). Bony metastases (mets) are associated with skeletal complications, which can cause significant morbidity and mortality. Intravenous bisphosphonates (IV BPs) have been proven to reduce the incidence and onset of skeletal complications. Patterns of use of IV BPs in clinical practice in pts with bone mets due to PC are largely unknown. Methods: Using the tumor registries and electronic data stores at two large US integrated health systems that serve a total of approximately 1.3 million persons, we retrospectively identified all pts aged ≥18 yrs with primary PC and newly diagnosed bone mets between 1/1/95 and 12/31/09. Information on all administrations of IV BPs between date of diagnosis of bone mets and death, loss to follow-up, or end of study was extracted from administrative data stores and electronic medical records, which also were reviewed by trained medical abstractors for evidence of skeletal-related events (SREs) (spinal cord compression, pathologic fracture, surgery to bone, radiation to bone). Results: We identified a total of 461 pts with primary PC and newly diagnosed bone mets. Mean (SD) age was 72.8 yrs (10.7 yrs); 75% were Caucasian, and 21% were African-American. Median duration of follow-up after diagnosis of bone mets was 1.3 yrs. One-fifth (20.2%) of study subjects received IV BPs (92% zoledronic acid, 8% pamidronate) during follow-up--10.8% prior to, and 9.3% after, first on-study SRE. Median time from diagnosis of bone mets to first administration of IV BPs was 1.7 yrs, and the median number of administrations was 3. The percentage of study subjects receiving IV BPs increased steadily over the 15-yr study period--from 7.5% among those newly diagnosed with bone mets in 1995-1999, to 19.8% among those newly diagnosed with bone mets in 2000-2004, to 27.5% among those newly diagnosed with bone mets in 2005-2009. Conclusions: Despite a high risk of SREs in pts with PC and bone mets, most such pts still do not receive IV BPs.

Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: A combined analysis of 3 pivotal, randomised, phase 3 trials

BackgroundPatients with bone metastases from advanced cancer often experience skeletal-related events (SRE), which cause substantial pain and morbidity. Denosumab, a fully human monoclonal antibody that inhibits RANK Ligand (RANKL), is a novel bone-targeted agent with a distinct mechanism of action relative to the bisphosphonate zoledronic acid, for prevention of SRE. This pre-planned analysis evaluates the efficacy and safety of denosumab versus zoledronic acid across three pivotal studies. MethodsPatient-level data from three identically designed, randomised, double-blind, active-controlled, phase 3 trials of patients with breast cancer, prostate cancer, other solid tumours or multiple myeloma were combined. End-points included time to first SRE, time to first and subsequent (multiple) SRE, adverse events, time to disease progression and overall survival. FindingsDenosumab was superior to zoledronic acid in delaying time to first on-study SRE by a median 8.21months, reducing the risk of a first SRE by 17% (hazard ratio, 0.83 [95% confidence interval (CI): 0.76–0.90]; P<0.001). Efficacy was demonstrated for first and multiple events and across patient subgroups (prior SRE status; age). Disease progression and overall survival were similar between the treatments. In contrast to zoledronic acid, denosumab did not require monitoring or dose modification/withholding based on renal status, and was not associated with acute-phase reactions. Hypocalcaemia was more common for denosumab. Osteonecrosis of the jaw occurred at a similar rate (P=0.13). ConclusionDenosumab was superior to zoledronic acid in preventing SRE with favourable safety and convenience in patients with bone metastases from advanced cancer.

Denosumab: a new option in the treatment of bone metastases from urological cancers.

Bone metastases often create serious clinical problems: they lead to poor performance status due to pathologic fractures, spinal cord compression and intractable pain, commonly referred to as skeletal-related events. The receptor activator of nuclear factor-κB (RANK), the RANK ligand (RANKL), and osteoprotegerin, a decoy receptor for RANK, regulate osteoclastogenesis and may play a key role in bone metastasis. Denosumab (XGEVA; Amgen, Thousand Oaks, CA), a fully human monoclonal antibody that binds to and neutralizes RANKL, inhibits osteoclast function, prevents generalized bone resorption and local bone destruction, and has become a therapeutic option for preventing or delaying first on-study skeletal-related events in various malignancies. In the context of urological cancer, three main Phase III clinical studies have been published in prostate cancer. This article provides a brief overview of the characteristics of bone metastasis in urological cancers, reviews the mechanisms of bone metastasis, including the RANK/RANKL/osteoprotegerin axis, the current standard of care, zoledronic acid, and describes the efficacy of the novel bone-targeted agent denosumab in bone metastasis. Denosumab is emerging as a key therapeutic option in the treatment of bone metastases from urological cancers.

Bone-Related Complications and Quality of Life in Advanced Breast Cancer: Results from a Randomized Phase III Trial of Denosumab versus Zoledronic Acid

Denosumab was shown to be superior to zoledronic acid in preventing skeletal related events (SRE) in patients with breast cancer and bone metastases in a randomized, double-blind phase III study. We evaluated further results from this study related to skeletal complications and health-related quality of life (HRQoL). Patients were randomized 1:1 to receive subcutaneous denosumab 120 mg (n = 1,026) and intravenous placebo, or intravenous zoledronic acid 4 mg (n = 1,020) and subcutaneous placebo every 4 weeks. Analyses reported here include the proportion of patients with one or multiple on-study SREs, time to first radiation to bone, time to first SRE or hypercalcemia of malignancy, and change in HRQoL (functional assessment of cancer therapy-general). Fewer patients receiving denosumab than zoledronic acid had an on-study SRE (31% vs. 36%, P = 0.006). The incidence of first radiation to bone was 12% (n = 123) with denosumab versus 16% (n = 162) with zoledronic acid. Denosumab prolonged the time to first radiation to bone by 26% versus zoledronic acid (HR, 0.74; 95% confidence interval [CI], 0.59-0.94, P = 0.012) and prolonged the time to first SRE or hypercalcemia of malignancy by 18% (HR, 0.82; 95% CI, 0.70-0.95; P = 0.007). Ten percent more patients had a clinically meaningful improvement in HRQoL with denosumab relative to zoledronic acid, regardless of baseline pain levels. Denosumab was superior to zoledronic acid in reducing bone-related complications of metastatic breast cancer and maintained HRQoL, providing an efficacious, well-tolerated treatment option for patients with bone metastases from breast cancer.

Health resource utilization and patient burden associated with SREs in a randomized controlled trial setting.

e19514 Background: Bone metastases (BM) are common in patients (pts) with solid tumors and may result in skeletal related events (SREs) such as spinal cord compression (SCC), pathologic fracture (PF), surgery to bone (SB), and radiation to bone (RT). SREs result in significant morbidity, debilitating pain, decreased health-related quality of life and increased health resource utilization (HRU). Data from 3 registrational phase 3 trials that showed superiority of denosumab over zoledronic acid in patients with solid tumors and BM were combined to assess HRU associated with different SRE types. Methods: Data through 41 weeks for pts with solid tumors and ≥ 1 BM enrolled in these randomized, active-controlled trials were included in this posthoc analysis. HRU were evaluated by SRE type and data were compared between pts with ≥ 1 on-study SRE and those not experiencing an on-study SRE. The index date for pts with on-study SREs was defined as the date that the first SRE was reported. The median time from randomization to incidence of first SRE for each SRE type was used to establish an index date for the control (no SRE) group. The HRU window encompassed a 3-month period (i.e.1 month before and 2 months after the index date) and was assessed by mean number of various types of medical visits during this window. Results: Data from 5,543 pts were included. PF was the most common type of first SRE (n=1,017), followed by RT (n=940), SCC (n=156), and SB (n=74). 3,618 pts did not have an on-study SRE. For all types of medical visits, HRU was higher for pts with an on-study SRE than those without (Table). Conclusions: SREs are associated with increased health resource utilization, reflecting an increased burden for patients with solid tumors and bone metastases. [Table: see text]

AOS13 Denosumab versus zoledronic acid for the prevention of skeletal-related events in patients with bone metastases secondary to solid tumours: An integrated analysis of three phase 3 studies

Background Skeletal-related events (SREs) cause significant morbidity in patients with solid tumours and bone metastases (BMs). An ad hoc analysis was undertaken to compare the effect of denosumab with zoledronic acid (ZA) in the prevention of SREs in patients with BMs secondary to solid tumours who participated in the denosumab pivotal phase 3 studies. Methods Patients with breast cancer ( N = 2046), prostate cancer ( N = 1901), or other solid tumours ( N = 1597) and BMs were randomly assigned in a 1:1 ratio to receive subcutaneous denosumab 120 mg or IV ZA 4 mg (adjusted for renal function) every 4 weeks. Patient-level data from three identically designed, double-blind, double-dummy studies were combined. Time to first on-study SRE and time to first and subsequent SREs were analysed using the Cox proportional hazards model and Anderson–Gill method, respectively. Findings Patients received denosumab ( N = 2776) or ZA ( N = 2768). Denosumab was superior to ZA in delaying time to first on-study SRE and time to first and subsequent SREs. Denosumab reduced the risk of a first SRE by 18% compared with ZA (HR 0.82 [95% confidence interval (CI): 0.75, 0.89], p p p = 0.18) were similar in both groups. Hypocalcaemia was more frequent with denosumab (9.5% versus 4.8% for ZA) and acute phase reactions (first 3 days) were more common with ZA (20.4% versus 8.7% for denosumab). Interpretation This integrated analysis confirmed results from the individual studies; denosumab was superior to ZA in reducing the risk of both first and multiple SREs among patients with solid tumours and BMs. Funding Amgen Inc. A.T. Stopeck is a consultant for Amgen and Novartis; G. Richardson has received honoraria and research funding from Amgen; S. Siena has no conflicts of interest to declare; A. Lipton is a member of the speakers’ bureau, is a consultant, has received research support from Amgen and Novartis, and has provided expert testimony for Novartis; J. Brown has received consultancy fees from Amgen and Novartis, and payment for lectures from Amgen, Novartis, and Bayer; K. Fizazi has participated in Advisory Boards for Amgen and Novartis; D. Henry is a member of the speakers’ bureau, has participated in research and advisory boards for Amgen and Johnson and Johnson; F. Saad is a consultant and has carried out research for Amgen and Novartis; C. Ke and A. Braun are employed by Amgen and own stock.

AOSOP6 Results from the 2-year open-label extension treatment phase of a pivotal phase 3 study of denosumab in patients with breast cancer and bone metastases previously treated with zoledronic acid or denosumab

Background Denosumab was superior to zoledronic acid (ZA) in reducing the risk of a first on-study skeletal-related event (SRE; HR, 0.82; 95% confidence interval (CI) 0.71, 0.95; p = 0.01) in patients with breast cancer and bone metastases (BMs; Stopeck et al., 2010). All patients who remained on treatment after the primary analysis were offered open-label (OL) denosumab for a pre-specified 2-year extension phase. Methods Women with BMs secondary to breast cancer ( N = 2046) were randomly assigned to subcutaneous denosumab 120 mg or IV ZA 4 mg (adjusted for renal function) Q4W. Patients who completed this double-blind, double-dummy treatment phase were offered OL denosumab Q4W. Patients who did not participate in the OL phase were followed up for survival every 12 weeks for up to 2 years after their last dose of investigational drug. Findings Of the 752 patients who completed the double-blind phase, 667 (89%) chose to receive OL denosumab: 325 initially randomly assigned to denosumab (DD) and 342 to ZA (ZD). Total median (Q1, Q3) cumulative denosumab exposure in DD patients was 19.3 months (9.2, 32.2) (range 0.9–59.8 months). Adverse events (AEs) were comparable between groups ( n = 283/318 [89%] for DD; n = 303/334 [91%] ZD) during the OL phase; 20 and 18 patients, respectively, reported osteonecrosis of the jaw; cumulative incidence was 4.7% in DD patients and 3.5% in ZD patients for the entire study duration of 5 years. Hypocalcaemia was comparable between groups ( n = 12 DD; n = 9 ZD). Serious AEs were reported in 126 (39.6%) DD patients and 133 (39.8%) ZD patients. Overall survival was similar between the groups for the entire study: median 34.4 months (95% CI 31.5, 39.3) and 34.2 months (95% CI 31.0, 37.6), respectively. Interpretation This OL extension treatment phase confirmed the safety profile of denosumab in patients with breast cancer with BMs receiving up to 5 years of monthly denosumab therapy or switching to denosumab after up to 3 years of ZA. Funding Funding was provided by Amgen Inc. A.T. Stopeck is a consultant for Amgen and Novartis; A. Lipton is a member of the speakers’ bureau, is a consultant, has received research support from Amgen and Novartis, and has provided expert testimony for Novartis; M. Martin is a consultant for Amgen; J-J. Body is a consultant for and has received lecture fees from both Amgen and Novartis; A. Paterson has received honoraria for speaking from Amgen, Roche, and Novartis; G.G. Steger has received travel grants and attended advisory boards for Amgen and Novartis; K. Tonkin has no disclosures; R.H. de Boer has no disclosures; Y. Fujiwara, Chugai Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma KK, Janssen Pharmaceutical KK, and Takeda Bio Development Center Limited; D. Yardley has no disclosures; J. Jassem has no disclosures; T. Takano is a medical consultant for Daiichi Sankyo; P. Solal-Celigny has no disclosures; and M. Fan and A. Braun are employed by Amgen and own stock.

P4-13-01: Pain Severity and Analgesic Use Associated with Skeletal-Related Events in Patients with Advanced Breast Cancer and Bone Metastases.

Abstract Background: Skeletal-related events (SREs), which include pathologic fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC), occur frequently in patients with bone metastases and can lead to debilitating clinical consequences such as functional impairment and bone pain. Denosumab (XGEVA®) is a fully human monoclonal antibody against RANKL, shown to be superior to zoledronic acid (ZA; Zometa®) for the prevention of SREs in patients with solid tumors. Denosumab also delayed the onset of moderate or severe pain compared with ZA. The pain severity and analgesic use associated with each type of SRE were assessed in patients with advanced breast cancer and bone metastases. Methods: Eligible patients received denosumab 120 mg SC or ZA 4 mg (adjusted for renal function) IV every 4 weeks in a randomized, multinational, double-blind, double-dummy trial. Patient-reported pain was assessed with the Brief Pain Inventory (BPI; 0 no pain to 10 severe pain) at baseline (BL) and at each monthly visit. Opioid and non-opioid analgesic use was recorded and scored using the Analgesic Quantification Algorithm (AQA; 0 no analgesic use to 7 &amp;gt; 600mg oral morphine equivalent/day). Data from the two treatment arms were pooled for this analysis. Pain and analgesic use were evaluated from 6 months prior to and 6 months after the first on-study SRE for each patient. The comparator group included patients without an SRE and was centered at the median time from randomization to first SRE by SRE type, with corresponding 12 month assessments. The proportion of patients with moderate/severe pain (BPI worst pain score &amp;gt; 4) and proportion of patients shifting from no/low analgesic use (AQA ≤ 2) at baseline to strong opioid use (AQA ≥ 3) were reported by month and by SRE type, and are summarized by mean relative change (%) across the time period. Results: In total, 687 patients with first on-study SRE occurrences (PF=450, RB=201, SCC=16, SB=20) were analyzed. A similar proportion of patients with and without a PF had moderate/severe pain, but a higher proportion of patients with a PF shifted from no/low analgesic use to strong opioid use (mean relative increase 80%). Starting 3 months prior to the event, more patients with RB than those without had moderate/severe pain (27% mean relative increase) and shifted from no/low analgesic use to strong opioid use (mean relative increase 269%). Similar pain and analgesic use patterns were noted for patients with SCC (mean relative increase in pain: 63%; in AQA shift: 913%). More patients with SB than those without had moderate/severe pain in the 6 months leading on to SB (mean relative increase 51%). The difference was attenuated after SB, but during this time a much higher proportion of patients with SB shifted from no/mild opioid use to strong opioid use (mean relative increase 220%). Discussion: SREs are associated with increased pain severity and analgesic use in patients with advanced breast cancer and bone metastasis. Patterns of pain severity and analgesic use differed by SRE type. Effective treatments to prevent SREs can decrease pain and the need for treatment with opioid analgesics. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-13-01.

Treatment of bone metastasis with anti-RANKL antibody

Bone metastases are a frequent complication of solid cancers including breast, prostate, and lung cancers. Control of this complication is clinically important, because they cause skeletal-related events including pathological fractures that impair quality of life (QOL) or shorten survival of patient with bone metastasis. Recently, denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-κB ligand was developed as a therapeutic agent for bone metastases. In three phase III trials, denosumab is superior to zoledronic acid, a potent bisphosphonate used as the standard therapy for bone metastases, for patients with prostate or breast cancers and is noninferior for patients with other solid tumors in terms of the median time to first on-study skeletal-related event. It will be an effective new treatment option for patients with bone metastases.

Effect of denosumab versus zoledronic acid in patients with castrate-resistant prostate cancer and bone metastases: Subgroup analyses by prior SRE and baseline pain.

4533 Background: Bone metastases from castrate-resistant prostate cancer (CRPC) are associated with osteoclast-mediated bone destruction and skeletal-related events (SREs). Denosumab is a fully human monoclonal antibody against RANKL, a key mediator of osteoclast formation, function, and survival. Previous results from a phase III trial showed denosumab was superior to zoledronic acid (ZA) in delaying or preventing SREs (pathologic fracture, radiation or surgery to bone, or spinal cord compression) in patients with bone metastases from CRPC. This analysis assesses the effect of denosumab vs ZA treatment among patients with earlier stage CRPC - those with no prior SRE or no/mild pain at baseline. Methods: Patients with CRPC and ≥1 bone metastasis and no prior IV bisphosphonate use were randomized to receive either SC denosumab 120 mg + IV placebo or SC placebo + IV ZA 4 mg (adjusted for creatinine clearance) every 4 weeks. Patients also were instructed to take calcium and vitamin D supplements. Time to 1st on-study SRE (primary endpoint) and time to 1st and subsequent SRE (multiple event analysis) were evaluated in patients with no prior SRE or no/mild pain. The Brief Pain Inventory – Short Form (BPI) was used to assess worst pain scores at baseline. A score of 0 to 4 on the BPI indicates no or mild pain. Results: Of the 1901 patients enrolled (n = 950 denosumab; n = 951 ZA), 1438 were in the subgroup of patients with no prior SRE and 1045 were in the subgroup with no/mild pain (BPI score 0 to 4) at baseline. As compared with ZA, denosumab treatment significantly delayed the time to 1st SRE for the overall population (HR = 0.82 [0.71, 0.95]; P = 0.008), as well as in both subgroups of patients with earlier disease: no prior SRE (HR = 0.80 [0.67, 0.95]; P = 0.011) or no/mild pain at baseline (HR = 0.77 [0.63, 0.95]; P = 0.014). Similar results also were noted with denosumab vs ZA treatment for the time to 1st and subsequent SREs (P ≤ 0.007 for all groups). Conclusions: Denosumab treatment in patients with earlier stage CRPC significantly reduced SREs.

Denosumab

Denosumab, a fully human monoclonal antibody, binds to the receptor activator of nuclear factor-κB ligand (RANKL) and thereby inhibits RANKL-mediated bone resorption. In various individual countries, subcutaneous denosumab is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumours (featured indication), and/or for the treatment of postmenopausal osteoporosis and/or of cancer treatment-induced bone loss in prostate or breast cancer patients. In three, pivotal, double-blind, multinational trials in adult patients with cancer-related bone metastases (total n > 5700), including trials in patients with advanced breast or prostate cancer, subcutaneous denosumab (120 mg every 4 weeks) was shown to be noninferior to intravenous zoledronic acid (4 mg every 4 weeks), as determined by the median time to first on-study skeletal-related event (primary endpoint) at the time of the primary analysis (≈34 or 41 months). Denosumab treatment was superior to zoledronic acid in terms of the primary endpoint in two trials in patients with breast cancer or prostate cancer, based on secondary superiority analyses. In a third trial in patients with solid tumours excluding breast or prostate cancer, superiority of denosumab treatment versus zoledronic acid treatment was not demonstrated. The tolerability profile of denosumab was manageable in patients with bone metastases from solid tumours. Osteonecrosis of the jaw occurred in 1.8% and 1.3% of patients in the denosumab and zoledronic acid groups during the primary treatment phase; the incidence after approximately 4 additional months of denosumab treatment was 2.2%.

Denosumab in bone-metastatic prostate cancer: known effects on skeletal-related events but unknown effects on quality of life

Denosumab in bone-metastatic prostate cancer: known effects on skeletal-related events but unknown effects on quality of life