Zoledronic Acid Patients Research Articles

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]

Zoledronic acid does not reduce MRI erosive progression in PsA but may suppress bone oedema: the Zoledronic Acid in Psoriatic Arthritis (ZAPA) Study

BackgroundThe effect of zoledronic acid (ZA) on articular bone in patients with psoriatic arthritis (PsA) was investigated using MRI.MethodsPatients with erosive PsA were randomised to receive 3-monthly infusions of ZA...

Abstract P1-13-01: Comparing the Effects of Denosumab and Zoledronic Acid on Pain Interference with Daily Functioning in a Randomized Phase 3 Trial of Patients with Breast Cancer and Bone Metastases

Abstract In a recently completed trial of breast cancer patients with bone metastases, denosumab, a fully human monoclonal anti-RANKL antibody, was superior to zoledronic acid (ZA) in delaying/preventing skeletal-related events. Between-treatment differences in patient-reported pain interference with daily functioning were assessed. Eligible breast cancer patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg (double-bind, double-dummy design). Patients completed the Brief Pain Inventory (BPI) to assess pain severity and interference with daily functioning (range 0 [does not interfere]-10 [interferes completely]) at baseline (BL), day 8, and before each monthly visit through end of study. The BPI interference scale generated a total interference score as well as an activity subscale (interference with walking, general activity, and work) and an affective subscale (interference with relations with others, enjoyment of life, and mood). Analyses were conducted on all randomized patients with ≥1 PRO assessment and were performed through week 73, when 30% of patients had dropped out due to death, disease progression, or consent withdrawal. Subgroups included patients with no/mild and moderate/severe worst pain at BL. Analyses included time to improvement (≥2-point decrease) or worsening (≥2-point increase) in pain interference, mean change from baseline, and proportion of patients with improving or worsening pain interference scores. Time to improvement in pain interference with activity (PIWA) tended to occur more quickly with denosumab compared with ZA (N=1124; median: 70 days denosumab v 86 days ZA; P=0.09), and time to worsening PIWA tended to be longer with denosumab compared with ZA (N=1676; median: 394 days denosumab v 310 days ZA; P=0.13). In patients with no/mild pain at BL, denosumab also demonstrated a trend for shorter time to improvement in PIWA (N=388; 93 days denosumab v 120 days ZA; P=0.06) and longer time to worsening PIWA (N=755; 369 days denosumab v 232 days ZA; P=0.12). Overall, a greater proportion of patients on denosumab had improvement in PIWA on study than ZA (Figure). Findings were similar with the total interference score and affective subscale. Figure Proportion of Patients With Improvement in Pain Interference With Activity (≥2-point decrease from BL)* Daily functioning (total interference and interference with activity and affect) tended to be less disrupted by pain in patients on denosumab compared with ZA. Decreased pain interference showed a trend to occur more quickly with denosumab. Overall, a greater proportion of denosumab patients reported decreased pain interference than ZA patients. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-01.

Abstract P1-13-05: The Effect of Treatment with Denosumab or Zoledronic Acid on Health-Related Quality of Life in Patients with Metastatic Breast Cancer

Abstract Background: Patients with breast cancer and bone metastases often experience skeletal-related events (SREs) and pain, which may impact health-related quality of life (HRQoL). Denosumab is a fully human monoclonal antibody against RANKL shown to be superior in delaying/preventing SREs and more effective in delaying moderate or severe pain in patients with advanced breast cancer compared with zoledronic acid (ZA). Previously reported results from this study population showed that both denosumab and ZA patients showed improvement or maintenance in HRQoL relative to baseline (BL), and a greater proportion of denosumab-treated patients had a clinically meaningful improvement in HRQoL. We now describe the effect of denosumab and ZA treatment on HRQoL among patients with varying degrees of pain at BL. Methods: Enrolled patients received subcutaneous (SC) denosumab 120 mg or intravenous (IV) ZA 4 mg every 4 weeks in a double-blind, double-dummy fashion. Pain was evaluated using the Brief Pain Inventory — Short Form (BPI). Patients were divided into 2 subgroups based on the level of pain reported at BL: no/mild pain or moderate/severe pain. Patients completed the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at BL, day 8, and before each monthly visit to assess overall HRQoL. Higher scores (range 0 to 108) represent better HRQoL. Improvement, maintenance, and worsening of HRQoL were assessed through month 18, when 30% of patients had dropped out due to death, disease progression, or withdrawal of consent. A change of ≥5 points (increase or decrease) in the FACT-G total score was considered a meaningful improvement. Results: Among patients who reported no/mild pain at baseline, more denosumab-treated patients had a ≥5-point increase in their FACT-G score from month 4 onwards. Over the 18 month period, an average of 4.1% more (range: −0.6% to 9.3%) denosumab-treated patients experienced meaningful improvement in HRQoL than ZA-treated patients. There were also fewer denosumab-treated patients experiencing ≥5-point decrease in HRQoL over 18 months (average of 2.4% fewer [range:-4.4% to 6.3% fewer]). Similar patterns were also noted for patients with moderate/severe pain at baseline. An average of 3.0% more (range:-1.7% to 7.9%) denosumab-treated patients had ≥5-point increase in FACT-G scores compared with ZA-treated patients over 18 months. A lower proportion of denosumab-treated patients (3.5% fewer [range: −1.1% to 11.5% fewer]) than ZA-treated patients had a decrease ≥5-points in their FACT-G score over 18 months. Conclusion: In patients with breast cancer and bone metastases, a greater proportion treated with denosumab than ZA had a meaningful improvement in HRQoL regardless of their pain level at BL. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-05.

A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer.

LBA4507 Background: Bone metastases from hormone-refractory (castration-resistant) prostate cancer (CRPC) are associated with RANKL-mediated osteoclast activation resulting in bone destruction and skeletal-related events (SRE). Denosumab is a fully human monoclonal antibody against RANKL. This phase III, randomized, double-blind, active-controlled trial compared the efficacy and safety of denosumab vs. zoledronic acid (ZA) in patients with metastatic CRPC. Methods: Patients (n = 1,901) with CRPC and at least 1 bone metastasis, but no prior IV bisphosphonate use, received either SC denosumab 120 mg and IV placebo (n = 950), or SC placebo and IV ZA 4 mg (n = 951) adjusted for creatinine clearance every 4 weeks. All patients were instructed to take supplemental calcium and vitamin D. The primary endpoint was time to first on-study SRE, defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression. Results: Denosumab significantly delayed the time to first on-study SRE compared with ZA, (HR 0.82 ; 95% CI: 0.71, 0.95 ; p = 0.008.) The median time to first on-study SRE was 20.7 mo denosumab vs. 17.1 mo ZA, a difference of 3.6 months. Denosumab also significantly delayed the time to first and subsequent on-study SRE (multiple event analysis) (HR 0.82 ; 95% CI: 0.71, 0.94 ; p = 0.004). Greater suppression of the bone turnover markers uNTx and BSAP occurred in denosumab patients compared with ZA (p < 0.0001 for both). Overall, adverse event (AE) rates (97% each) and serious AEs (63% denosumab, 60% ZA) were similar, irrespective of potential relationship to study drugs. AEs of hypocalcemia were reported in 13% and 6% of denosumab and ZA patients. Osteonecrosis of the jaw occurred in 22 (2.3%) denosumab compared with 12 (1.3%) ZA patients (p = 0.09). Overall survival (HR 1.03 ; 95% CI: 0.91, 1.17 ; p = 0.65) and time to cancer progression (HR 1.06; 95% CI: 0.95, 1.18; p = 0.30) were similar between treatment arms. Conclusions: Denosumab demonstrated superiority over ZA in delaying or preventing SREs in patients with bone metastases from CRPC. Adverse events were consistent in both treatment groups with those previously reported in advanced cancer populations. [Table: see text]

Renal function changes and NHS resource use in breast cancer patients with metastatic bone disease treated with IV zoledronic acid or oral ibandronic acid: a four-centre non-interventional study

Aims: To describe renal function monitoring practice in patients with metastatic bone disease (MBD) treated with IV zoledronic acid (ZA) and oral ibandronic acid (IA), the management pathways and NHS hospital resources used.Methods: Medical records of 189 patients; IA (91), ZA (98) with primary breast cancer and MBD were reviewed, and data collected on renal monitoring and hospital visits during bisphosphonate therapy. Time and motion review of resources to administer the bisphosphonates was also conducted.Results: Only 30% of patients given ZA and no patient given IA had baseline creatinine clearance (CrCl) recorded. Calculated baseline CrCl suggested impaired renal function in 33% ZA and 29% IA patients. Dose reductions were not made correctly in 29 ZA and 2 IA patients whose monitoring suggested it. ZA patients made more clinic and day care attendances than IA-treated patients, at twice the cost. Staff activity and patient time per visit was higher with ZA than IA.Conclusion: Although limited by retrospective design, these results demonstrate that in many patients, CrCl is not calculated before or during treatment with bisphosphonates. Renal function deteriorated in many patients during therapy. In view of these effects, practice should be reviewed to ensure appropriate dosing.

Prevention of Bone Loss by Zoledronic Acid in Premenopausal Women Undergoing Adjuvant Chemotherapy Persist up to One Year following Discontinuing Treatment

Adjuvant chemotherapy is associated with significant reductions in bone mineral density (BMD) in premenopausal women with breast cancer (BC) that is prevented with zoledronic acid (ZA) every 3 months for 1 yr. The aim of the study was to examine the effect on BMD of discontinuing ZA during the subsequent year. We conducted a randomized, double-blind trial. Premenopausal women (mean age, 42 yr) undergoing adjuvant chemotherapy for BC participated in the study. ZA (4 mg iv every 3 months) vs. placebo was administered for 12 months. We measured percentage change in BMD and bone turnover markers at 12 and 24 months (1 yr after last infusion). Of 101 women randomized, 85 completed 12-month and 62 completed 24-month evaluations. In the placebo group, serum C-telopeptide (CTX) increased progressively over the first 12 months, returned toward baseline but remained significantly above baseline by 24 months. Lumbar spine BMD decreased from baseline by 5.5% at 12 and 6.3% at 24 months. Similarly, by 24 months, total hip and femoral neck BMD declined by 2.6 and 2.4%, respectively. In ZA patients, BMD remained stable (P < 0.0001 compared to placebo). Serum CTX declined significantly by 6 months, but returned to baseline by 12 months, remaining there at 24 months. Premenopausal women receiving chemotherapy for BC sustained significant bone loss during the first year, without recovery during the second year. ZA effectively prevented bone loss during the first year of chemotherapy. BMD remained stable 1 yr after completion of ZA. Serum CTX increased significantly by 12 and 24 months. More frequent administration may be required to suppress bone resorption in this patient population.

Zoledronic Acid Prevents Bone Loss in Premenopausal Women Undergoing Adjuvant Chemotherapy for Early-Stage Breast Cancer

Adjuvant chemotherapy for breast cancer (BC) may be associated with increased rates of bone loss and decreased bone mineral density (BMD) and may lead to premature osteoporosis and increased fracture risk. We examined whether zoledronic acid (ZA) prevents bone loss in premenopausal women receiving chemotherapy for early-stage BC. This study is a randomized, double-blind, multicenter, phase III trial comparing ZA (4 mg intravenously every 3 months) versus placebo for 1 year. Premenopausal women underwent serial BMD measurements before initiating chemotherapy and at 6 and 12 months. The primary outcome was percent change in lumbar spine (LS) BMD at 6 months. Secondary outcomes were percent change at any BMD site and markers of bone turnover at 12 months. Linear mixed model analysis for repeated measures was performed. Of 101 women who were randomly assigned and completed baseline evaluation, 96 completed the 6-month evaluation, and 85 completed the 12-month evaluation. Baseline characteristics were comparable between the groups. Mean age was 42 years. Placebo was associated with significant decline in LS BMD at both 6 (2.4%) and 12 (4.1%) months. Similarly, total hip BMD declined by 0.8% at 6 months and 2.6% at 12 months. In contrast, BMD remained stable in ZA patients (P < .0001 compared with placebo). Premenopausal women receiving chemotherapy for BC sustained significant bone loss at the LS and hip, whereas BMD remained stable in women who received ZA. Administration of ZA during the first year of chemotherapy is an effective and well-tolerated strategy for preventing bone loss.

Economic value of zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer: The case of the United Kingdom (UK)

6617 Objectives: Zoledronic acid (ZA) reduces the risk of skeletal-related events (SREs) in lung cancer patients with bone metastases and may improve survival among those patients with high levels of bone metabolism. This analysis assessed, from the UK National Health Service's perspective, the economic impact of ZA therapy in patients with bone metastases secondary to lung cancer. Methods: A literature-based decision analytic model was developed to compare the direct costs and quality adjusted life years (QALY) experienced by lung cancer patients with bone metastases receiving placebo or ZA. Survival, SRE incidence, and number of infusions administered were obtained from a randomized clinical trial comparing 4 mg ZA with placebo. Drug acquisition and administration costs and SRE costs were estimated using published sources and national fee schedules (i.e., NHS reference costs, British National Formulary, Personal Social Services Research Unit reference costs). The impact of SREs on quality of life was estimated using the literature. Consistent with previous economic analyses of bisphosphonates in cancers (e.g., Hillner et al, 2000), patients avoiding SREs were assumed to experience quality of life improvements for 1 month. Results: The average remaining life expectancy was conservatively assumed equal in both groups and was 8.50 months (median, 5.89 months). During those months, patients receiving placebo were projected to experience 2.07 SREs on average compared to 1.32 SREs among ZA patients. QALYs were estimated at 0.3523 per patient (pp) and 0.3350 pp in the ZA and placebo groups, respectively. ZA drug-related costs were estimated at £1,473 pp, based on 5.87 infusions pp and a cost of £251.01 per infusion. The use of ZA was associated with a reduction of £1,562 pp in SRE costs. Overall, ZA saved costs and increased QALYs compared to no therapy, by £89 pp and 0.0173 QALYs pp, respectively. In sensitivity analyses, ZA cost £25,000 or less per QALY under a wide range of assumptions. Conclusions: The use of ZA leads to fewer SREs, better estimated quality of life, and lower costs relative to placebo in UK lung cancer patients with bone metastases. The use of ZA in this population therefore appears highly cost effective. No significant financial relationships to disclose.

Economic value of zoledronic acid compared with placebo in the treatment of skeletal metastases in patients with solid tumors: The case of the United Kingdom (UK)

6603 Background: Zoledronic acid (ZA) reduces the risk of skeletal-related events (SREs) in patients with solid tumors (i.e., renal cell carcinoma, thyroid, head and neck, small cell lung, or others cancers, excluding breast, prostate and non small cell lung [NSCLC] cancers) and bone metastases. This analysis assessed, from the perspective of the UK National Health Service, the economic impact of ZA in this patient population. Methods: A literature-based decision-analytic model was developed to compare the direct costs and quality adjusted life years (QALY) of patients with bone metastases secondary to solid tumors receiving ZA or placebo. Survival, SRE incidence, and number of infusions administered were obtained from a clinical trial comparing patients randomized to 4 mg ZA or placebo for up to 21 months. Drug acquisition and administration costs and SRE costs were estimated using published sources and national fee schedules (e.g., NHS reference costs, British National Formulary). The impact of SREs on quality of life was estimated using the literature. Consistent with previous economic analyses of bisphosphonates in cancers (e.g., Hillner et al, 2000), patients were assumed to experience quality of life improvements lasting 1 month for each SRE avoided. Results: The average remaining life expectancy was conservatively assumed equal in both groups and was 9.54 months (median, 6.61 months). Patients receiving placebo were projected to experience 2.64 SREs on average v. 1.64 SREs among ZA patients. QALYs were estimated at 0.3917 per patient (pp) and 0.3728 pp in the ZA and placebo groups, respectively. ZA drug- related costs were estimated at £1,386 pp, based on an average of 5.52 infusions pp. The use of ZA was associated with a reduction of £1,830 pp in SRE costs. Overall, ZA saved costs and increased QALYs v. no therapy, by £445 pp and 0.0189 QALYs pp, respectively. In sensitivity analyses, ZA cost £25,000 or less per QALY under a wide range of assumptions. Conclusions: The use of ZA leads to fewer SREs, better estimated quality of life, and lower costs relative to placebo in UK patients with bone metastases secondary to solid tumors other than breast, prostate or NSCLC cancer. ZA appears therefore highly cost effective in this population. No significant financial relationships to disclose.

Effect of zoledronic acid on clinically meaningful changes in pain associated with metastatic prostate cancer

4680 Background: Zoledronic acid (ZA) has been shown to significantly decrease skeletal-related events (SREs) in patients with prostate cancer by 11% relative to placebo. Trends were seen in pain improvement with ZA vs placebo, but there were no reliable treatment group differences. The objective of this study was to reexamine the pain outcomes using an alternative analytic framework that focuses on the frequency of clinically meaningful changes in pain scores. Methods: Patients were randomized to ZA 4mg (n=214) or placebo (n=208). The Brief Pain Inventory Composite Score (BPI) was used to assess pain at baseline, 3 weeks, 6 weeks, and every 6 weeks for a total of 60 weeks. We determined whether clinically meaningful pain changes from baseline (+/- 2 BPI points) were related to treatment assignment using a modified non-parametric rank test. Results: The rapid progression of the prostate cancer led to high rates of dropout as only 76 of 214 (35.5%) patients randomized to ZA and 62 of 208 (29.8%) patients randomized to PL completed their 60 week visit (p=0.21). At 10 of 11 assessment times, ZA patients reported more favorable clinically meaningful changes in pain scores (see table). Overall, a typical ZA patient had a 27% chance of having a favorable response (ZA>PL) compared with a typical PL patient who had an 19% chance of a favorable response (PL>ZA)—a difference that was statistically significant (95% CI: 1.1% - 15.5%). Conclusions: Patients receiving ZA were 8% more likely to have clinically beneficial changes in pain scores compared to patients receiving placebo. This is roughly consistent with the 11% difference between groups in the incidence of SREs as reported in the primary clinical analysis. Thus, ZA 4 mg significantly reduces the occurrence of skeletal-related events and the associated changes in pain they produce. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corporation

Effect of zoledronic acid on clinically meaningful changes in pain associated with metastatic prostate cancer

4680 Background: Zoledronic acid (ZA) has been shown to significantly decrease skeletal-related events (SREs) in patients with prostate cancer by 11% relative to placebo. Trends were seen in pain improvement with ZA vs placebo, but there were no reliable treatment group differences. The objective of this study was to reexamine the pain outcomes using an alternative analytic framework that focuses on the frequency of clinically meaningful changes in pain scores. Methods: Patients were randomized to ZA 4mg (n=214) or placebo (n=208). The Brief Pain Inventory Composite Score (BPI) was used to assess pain at baseline, 3 weeks, 6 weeks, and every 6 weeks for a total of 60 weeks. We determined whether clinically meaningful pain changes from baseline (+/- 2 BPI points) were related to treatment assignment using a modified non-parametric rank test. Results: The rapid progression of the prostate cancer led to high rates of dropout as only 76 of 214 (35.5%) patients randomized to ZA and 62 of 208 (29.8%) patients randomized to PL completed their 60 week visit (p=0.21). At 10 of 11 assessment times, ZA patients reported more favorable clinically meaningful changes in pain scores (see table). Overall, a typical ZA patient had a 27% chance of having a favorable response (ZA>PL) compared with a typical PL patient who had an 19% chance of a favorable response (PL>ZA)—a difference that was statistically significant (95% CI: 1.1% - 15.5%). Conclusions: Patients receiving ZA were 8% more likely to have clinically beneficial changes in pain scores compared to patients receiving placebo. This is roughly consistent with the 11% difference between groups in the incidence of SREs as reported in the primary clinical analysis. Thus, ZA 4 mg significantly reduces the occurrence of skeletal-related events and the associated changes in pain they produce. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corporation