Reduction In Skeletal-related Events Research Articles

Prophylactic Radiotherapy Of MInimally Symptomatic Spinal Disease (PROMISSeD): study protocol for a randomized controlled trial

BackgroundEarly palliative/pre-emptive intervention improves clinical outcomes and quality of life for patients with metastatic cancer. A previous signal-seeking randomized controlled trial (RCT) demonstrated that early upfront radiotherapy to asymptomatic or minimally symptomatic high-risk osseous metastases led to reduction in skeletal-related events (SREs), a benefit driven primarily by subgroup of high-risk spine metastasis. The current RCT aims to determine whether early palliative/pre-emptive radiotherapy in patients with high-risk, asymptomatic or minimally symptomatic spine metastases will lead to fewer SREs within 1 year.MethodsThis is a single-center, parallel-arm, in-progress RCT in adults (≥ 18 years) with ECOG performance status 0–2 and asymptomatic or minimally symptomatic (not requiring opioids) high-risk spine metastases from histologically confirmed solid tumor malignancies with > 5 sites of metastatic disease on cross-sectional imaging. High-risk spine metastases are defined by the following: (a) bulkiest disease sites ≥ 2 cm; (b) junctional disease (occiput to C2, C7-T1, T12-L2, L5-S1); (c) posterior element involvement; or (d) vertebral body compression deformity > 50%. Patients are randomized 1:1 to receive either standard-of-care systemic therapy (arm 1) or upfront, early radiotherapy to ≤ 5 high-risk spine lesions plus standard-of-care systemic therapy (arm 2), in the form of 20–30 Gy of radiation in 2–10 fractions. The primary endpoint is SRE, a composite outcome including spinal fracture, spinal cord compression, need for palliative radiotherapy, interventional procedures, or spinal surgery. Secondary endpoints include (1) surrogates of health care cost, including the number and duration of SRE-related hospitalizations; (2) overall survival; (3) pain-free survival; and (4) quality of life. Study instruments will be captured pre-treatment, at baseline, during treatment, and at 1, 3, 6, 12, and 24 months post-treatment. The trial aims to accrue 74 patients over 2 years to achieve > 80% power in detecting difference using two-sample proportion test with alpha < 0.05.DiscussionThe results of this RCT will demonstrate the value, if any, of early radiotherapy for high-risk spine metastases. The trial has received IRB approval, funding, and prospective registration (NCT05534321) and has been open to accrual since August 19, 2022. If positive, the trial will expand the scope and utility of spine radiotherapy.Trial registrationClinicalTrials.Gov NCT05534321. Registered September 9, 2022.Trial statusVersion 2.0 of the protocol (2021-KOT-002), revised last on September 2, 2022, was approved by the WCG institutional review board (Study Number 1337188, IRB tracking number 20223735). The trial was first posted on ClinicalTrials.Gov on September 9, 2022 (NCT05534321). Patient enrollment commenced on August 19, 2022, and is expected to be completed in 2 years, likely by August 2024.

Do disease status and race affect the efficacy of zoledronic acid in patients with prostate cancer? A systematic review and meta-analysis of randomized control trials

BackgroundZoledronic acid (ZA) does not improve the overall survival (OS) of metastatic castration-resistant prostate cancer (mCRPC); however, little is known about the efficacy of ZA in to hormone-sensitive prostate cancer (HSPC), metastatic hormone-sensitive prostate cancer (mHSPC), and non- metastatic castration-resistant prostate cancer (nmCRPC). Therefore, we assessed the efficacy of ZA in patients with prostate cancer (PCa) and different disease statuses.MethodsFifteen eligible randomized-control trials (RCTs) with ZA intervention, including 8280 participants with HSPC, mHSPC, nmCRPC, and mCRPC, were analyzed. The primary and secondary outcome were overall survival(OS), and skeletal-related events (SREs), and bone mineral density (BMD).ResultsThe participants included 8280 men (7856 non-Asian and 424 Asian). Seven trials yielded a pooled hazard ratio (HR) of 0.95 (0.88, 1.03; P = 0.19) for OS. Subgroup analysis revealed no significant improvement in OS in the HSPC, castration-resistant prostate cancer (CRPC), M0 and M1(bone metastasis) groups, with pooled HR (95%CI) of 0.96 (0.88,1.05), 0.78 (0.46,1.33), 0.95 (0.81,1.13), 0.85 (0.69,1.04) respectively. The Asian group exhibited improved in OS with an HR of 0.67 (0.48, 0.95; P = 0.02), whereas the non-Asian group showed no improvement in OS with an HR of 0.97 (0.90, 1.06; P = 0.52). Five trials yielded pooled odds ratio (OR) of 0.65 (0.45, 0.95; P = 0.02) for SREs. In the subgroup, SREs were significantly decreased in the M1 and Asian groups with ORs of 0.65 (0.45, 0.95; P = 0.02) and 0.42 (0.24, 0.71; P = 0.001), respectively. Six trials yielded a pooled mean difference (MD) of 8.08 (5.79, 10.37; P < 0.001) for BMD. In the HSPC we observed a stable improvement in increased BMD percentage with an MD (95%CI) of 6.65 (5.67, 7.62) (P = 0.001).ConclusionsZA intervention does not significantly improve OS in patients with prostate cancer (HSPC, CRPC, M0, M1) but probably improves OS in the Asian populations. M1 and Asian groups had exhibit a significant reduction in SREs regardless of the HSPC or CRPC status after ZA administration. Moreover, ZA treatment increases BMD percentage.

"The use of bisphosphonates to treat skeletal complications in solid tumours".

The skeleton is the most common site of secondary disease in breast cancer and prostate cancer, with up to 80% of patients with advanced disease developing bone metastases (BM). The proportion is also substantial in advanced lung cancer (20%-40%). Because of the high prevalence of cancers of the breast, prostate and lung, these cancers account for more than 80% of cases of metastatic bone disease occurring in solid tumours. Metastatic bone disease is associated with greatly increased bone resorption by osteoclasts, leading to moderate to severe pain and other skeletal complications, with major impact on quality of life (QoL). Skeletal Related Events (SREs) have been defined as: pathological long bone or vertebral fractures; spinal cord compression; need for radiation for pain relief or to prevent fracture/spinal cord compression, need for surgery to bone and hypercalcaemia. More recently, Symptomatic Skeletal Events (SSEs) have been defined to monitor QoL. Although there are currently no curative treatments for metastatic bone disease, patients with breast or prostate cancer and BM are now surviving for several years and sometimes longer, and prevention of SREs is the key aim to optimization of QoL. Since their discovery 50years ago and their introduction more than 30years ago into the field of metastatic bone disease, a range of oral and intravenous bisphosphonate drugs have made a major contribution to prevention of SREs. Large trials have clearly demonstrated the clinical value of different bisphosphonate-based drugs (including the oral drugs ibandronate and clodronate and intravenous agents such as zoledronate and pamidronate), in treatment of hypercalcaemia of malignancy and the reduction of SREs and SSEs in a range of cancers. Despite the success of denosumab in reducing osteolysis, bisphosphonates also remain mainstay drugs for treatment of metastatic bone disease. Recognizing the 50th Anniversary of the discovery of bisphosphonates, this review focuses on their continuing value in BM treatment and their future potential, for example in providing a bone-targeting vehicle for cytotoxic drugs.

Abstract PS14-02: A randomised phase IB/IIA study of CApecitabine plus Radium-223 in breast cancer patients with BONe metastases (CARBON) - Safety and preliminary efficacy findings

Abstract Background: Bone metastases (BMs) occur in approximately 70% of patients (pts) with metastatic breast cancer (MBC). Despite significant advances in the management of BMs with bone-targeted agents and the associated reduction in skeletal-related events, there remains an unmet need for further treatment options to improve median overall survival beyond 2-3 years. Radium-223 [R] dichloride is an alpha-emitting radiopharmaceutical that is avidly taken up, like calcium, into the bone where it emits high-energy, short-range alpha-particles resulting in a targeted anti-tumour effect on BMs. Combining R with current systemic therapy could potentially enhance efficacy in MBC with BMs. Methods: CARBON is a UK, open-label, multi-centre phase IB/IIA study evaluating the combination of capecitabine [C] (1000mg/m2 bd days 4-17, 12x21 day cycles) with R 55kBq/kg day 1 given on a 6-weekly schedule in pts with BMs from MBC (+/- other sites of disease) with ≥2 bone lesions on radionuclide bone scan and/or ≥1 lesion confirmed on plain radiographs, CT or MRI. Other eligibility criteria included ECOG PS 0-2, ≤ 2 lines of chemotherapy for MBC and current use of a bisphosphonate / denosumab for ≥6 weeks. To establish the feasibility and safety of C+R the phase IB opened in August 2016 registering 6 pts; the primary endpoint was dose-limiting toxicities (DLTs), defined as ≥grade 3 gastrointestinal toxicity lasting &amp;gt;48 hours or ≥grade 4 haematological toxicity lasting &amp;gt;7 days. Subsequently, between April 2017 and March 2019 28 pts were randomised (2:1) to C+R vs C in phase IIa to further characterise the safety profile, with frequency of CTC grade 3-4 toxicities and diarrhoea as primary endpoints. Preliminary evaluation of efficacy through assessment of bone turnover marker changes from baseline to end of cycle 5 and time to progression in bone and overall was made. Results: Baseline clinico-pathologic characteristics and prior treatments were well balanced between the arms; 13 C+R and 9 C pts had visceral metastases. There were 0 DLTs in the 6 phase IB pts, therefore the same C+R dose and schedule was studied in phase IIA. 2 pts randomised to C+R received C alone and are included in the C arm. The safety population consists of 34 pts (23 C+R, 11 C). Median number of cycles received was 8.5 (range 3-12) in C+R arm and 12 (range 1-12) in C arm. 38/307 (12%) treatment cycles were delayed (25 [13%] C+R arm, 13 [12%] C arm). 11 (48%) C+R and 6 (55%) C pts had a permanent C dose reduction. 94/95 (99%) prescribed R cycles were administered. 9 (39%) C+R and 9 (82%) C pts completed all 12 cycles. Other reasons for discontinuation were: progressive disease in 12 (52%) C+R and 0 in C pts; toxicity in 1 (4%) C+R and 1 (9%) C pt; clinician decision in 1 (9%) C pt; progressive disease and toxicity in 1 (4%) C+R pt. Only 25/575 (4%) reported AEs were grade 3-4 (n=21 in 11 [48%] C+R pts, n=4 in 4 [36%] C pts) with 0 episodes of grade 3-4 diarrhoea. Table 1 shows maximum grades of diarrhoea and haematological AEs experienced by arm. 18 SAEs occurred (n=11 in 8 C+R pts, n=7 in 2 C pts). 8 (44%) SAEs were grade 3 (C+R: 6, C: 2); none were related to diarrhoea. There were 0 SUSARs. Conclusion: In the first completed trial evaluating R with chemotherapy in MBC pts, the combination of C+R is safe and well-tolerated. Preliminary efficacy analyses including bone markers are ongoing and will be presented at the meeting. The creation of the data was supported in part by Bayer Plc and Yorkshire Cancer Research. Table 1: Maximum CTCAE grade (G) experienced - diarrhoea and haematological AEs.C+R (n=23)C (n=11)Not experiencedG1G2G3G4Not experiencedG1G2G3G4Diarrhoea7 (30%)14 (61%)2 (9%)006 (55%)4 (36%)1 (9%)00Neutropenia18 (78%)02 (9%)3 (13%)010 (91%)01 (9%)00Thrombocytopenia21 (91%)1 (4%)1 (4%)009 (82%)1 (9%)1 (9%)00Anaemia21 (91%)2 (9%)0008 (73%)1 (9%)2 (18%)00 Citation Format: Matthew Winter, Jessica Kendall, Sarah Brown, Emma Rathbone, Caroline Wilson, Sacha Howell, Chris Twelves, Carlo Palmieri, Anjana Anand, Iain MacPherson, Rob Coleman, Janet Brown. A randomised phase IB/IIA study of CApecitabine plus Radium-223 in breast cancer patients with BONe metastases (CARBON) - Safety and preliminary efficacy findings [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-02.

Radium 223 treatment in metastatic prostate cancer: Exploring use of clinical factors for prognostication in routine practice.

e17550 Background: Skeletal metastases are seen in over 90% of metastatic castrate resistant prostate cancer (mCRPC) patients during the course of their disease and is a major cause for significant morbidity and mortality in them. Radium 223 (Ra-223) is a bone seeking calcium mimetic alpha emitter that has demonstrated significant improvement in survival and reduction in skeletal related events (ALSYMPCA trial). Ra-223 treatment was well tolerated and showed benefit before or after chemotherapy. In this study we aimed to assess efficacy of Ra-223 in mCRPC patients treated in our centre and their survival in relation to some common clinical variables that may assist patient selection in routine clinical practice. Methods: We conducted a retrospective audit of mCRPC patients treated with Ra-223 from June 2015 – December 2019. We analysed treatment outcomes and use of Haemoglobin (Hb), Albumin (Alb) and Alkaline Phosphatase (ALP) as potential prognostic factors. Results: There were 46 patients in total with a median age of 76 years (range; 56-90) and 26% were ≥80 years of age. The median follow-up was 10 months (range; 2-38 months). Median baseline PSA was 103.7 (range; 7.2 - 2534) and median baseline ALP was 188 U/L (range; 51 - 2262). Ra-223 was given as 1st or 2nd line treatment in 65% of our patients. Median number of cycles of Ra-223 administered was 4 and 41% of patients completed 6 cycles of treatment. Biochemical response (drop in PSA &gt; 50%) was only seen in 11% of patients but good response in ALP levels (drop in ALP &gt; 50%) was seen in 35%. Median overall survival (OS) was 10 months. Median OS for patients who received Ra-223 as 1st or 2nd line vs subsequent line was 13 and 8.5 months respectively. Median OS for patients with Haemoglobin (Hb) ≥12gm/dl) and lower Hb were 11 and 7 months respectively. Patients with normal albumin at baseline had median OS of 15 months compared to 6 months for those with low albumin. Favourable prognostic group patients (Normal Hb, Normal albumin at baseline and normal ALP after treatment) had a median OS of 31 months compared to 9 months for those in less favourable group. Patients who completed at least 5 cycles had a better survival (13 vs 8.5 months). Fractures were reported in 3 patients (6.5%). Conclusions: Ra-223 treated patients in our centre had a reasonable survival despite having a larger proportion of elderly population compared to the registration trial. Ra-223 treatment seems to be more effective when given at earlier lines in mCRPC setting. Pre-treatment Albumin lower than normal seems to be a predictor for poor overall survival.

The efficacy and safety of zoledronic acid and strontium-89 in treating non-small cell lung cancer: a systematic review and meta-analysis of randomized controlled trials.

Zoledronic acid (ZA) and strontium-89 have been widely used to treat lung cancer with bone metastases. The authors perform this meta-analysis to better evaluate the clinical outcome of ZA and strontium-89 for non-small cell lung cancer (NSCLC) patients. We carried out standard meta-analysis and network meta-analysis based on a comprehensive data retrieval of EMBASE, PubMed, and Cochrane Library databases (up to March 2019). Random and fixed effects models were used where indicated and between-study heterogeneity was assessed. The primary endpoints were overall survival (OS) and skeletal-related events (SREs). The second endpoints were progression-free survival (PFS) and overall response rate (ORR). Seven randomized clinical trials, including 1426 NSCLC patients with seven studies of zoledronic acid and two studies of strontium-89, met the inclusion criteria. Compared with the control group, ZA is associated with a OS benefit (1-year survival rate: RR = 1.76, 95% CI 1.36-2.27; and 24-month survival rate: RR = 2.38, 95% CI 1.35-4.19) and a reduction of SREs (RR = 0.57, 95% CI 0.40-0.84) for the patients with bone metastases. No statistical differences were found in PFS and ORR. Network meta-analysis for the patients with bone metastases showed that ZA + strontium-89 and ZA harbored significantly clinical benefits than strontium-89 and placebo in terms of 1-year survival rate and SREs. Both head-to-head study and network meta-analysis showed that strontium-89 had no statistical impact on OS and SREs compared with placebo. Our analysis demonstrates that ZA +strontium-89 can be considered a priority for NSCLC patients with bone metastases, followed by ZA.

Anti-osteolytic use to prevent skeletal related events in solid tumour bone metastases

Abstract Background Bone metastases from solid tumours remain a serious burden on patient morbidity leading to decreased quality of life, increased narcotic use, and higher healthcare cost. We examined the current use of anti-osteolytics including RANK-L inhibitors and Bisphosphonates with the frequency of Skeletal Related Events (SRE) in coordination with current ESMO treatment guidelines. Methods Patients with bone metastases from solid tumours in the University of Pennsylvania Hospital system (UPHS) between August 2014 and August 2019 were identified. Data regarding treatment of metastases and frequency of SREs were obtained from patient charts in EPIC EMR. This included: type of therapy, documented SRE, and documented reasoning for lack of treatment. SREs were defined as pathological fractures, spinal cord compression, radiotherapy/surgery for fracture risk, and chronic metastatic bone pain. Descriptive statistical analyses and a single two variable relative risk analysis were performed to evaluate data. Results 400 patients were identified in the UPHS to have bone metastases from solid tumours. 240 (65%) received anti-osteolytic treatment while 140 (35%) did not. The total number of SREs numbered 173 (43%). Of those receiving treatment 173 (63%) were treated with denosumab while 87 (33%) were treated with a bisphosphonate. Lack of anti-osteolytic therapy reasoning was documented in 41 cases (29%) while 99 cases (71%) had no documented reasoning. In patients who did receive treatment there was an absolute 16% reduction in SREs from 54% without treatment to 38% with (Relative risk: .540, 95% Confidence Interval: .438 to .666, P-Value: Conclusions The use of anti-osteolytic treatment after diagnosis of bone metastasis was associated with a decrease in the risk of subsequent SREs. However, at 65% use, it would appear that these drugs are being underutilized and could better be employed in accordance with current ESMO guidelines so as to optimize patient care. We suggest further study to better understand reasoning behind lack of use, timing of SREs, and associated metastatic risk in regards to primary tumor type. Legal entity responsible for the study University of Pennsylvania Hospital System - Pennsylvania Hospital. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Prise en charge des lésions osseuses du myélome multiple : quelles particularités ?

Recent advances in the treatment of multiple myeloma have resulted in improved prognosis, but bone lesions remain a major concern in these patients. Multiple myeloma bone disease is characterized by increased bone resorption and decreased bone formation. Myeloma bone lesions are osteolytic and are often associated with pain, pathologic fractures, hypercalcemia, spinal cord compression and increased mortality. A multidisciplinary approach is needed to manage multiple myeloma bone lesions. Current management of multiple myeloma bone disease involves the combination of anti-myeloma therapy, anti-resorptive therapy, and if necessary a local treatment of skeletal lesions. Bisphosphonates are the current standard of care for reduction in skeletal-related events. Radiotherapy or surgery can be used for specific conditions such as uncontrolled pain, pathologic fractures or spinal cord compression. Vertebroplasty or kyphoplasty should be considered in case of symptomatic vertebral fractures. Other treatments targeting dickkopf-1, activin-A, and BAFF are under development.

The Changing Landscape of Smoldering Multiple Myeloma: A European Perspective.

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and bridges monoclonal gammopathy of undetermined significance to multiple myeloma (MM), based on higher levels of circulating monoclonal immunoglobulin and bone marrow plasmocytosis without end-organ damage. Until a Spanish study reported fewer MM-related events and better overall survival among patients with high-risk SMM treated with lenalidomide and dexamethasone, prior studies had failed to show improved survival with earlier intervention, although a reduction in skeletal-related events (without any impact on disease progression) has been described with bisphosphonate use. Risk factors have now been defined, and a subset of ultra-high-risk patients have been reclassified by the International Myeloma Working Group as MM, and thus will require optimal MM treatment, based on biomarkers that identify patients with a >80% risk of progression. The number of these redefined patients is small (∼10%), but important to unravel, because their risk of progression to overt MM is substantial (≥80% within 2 years). Patients with a high-risk cytogenetic profile are not yet considered for early treatment, because groups are heterogeneous and risk factors other than cytogenetics are deemed to weight higher. Because patients with ultra-high-risk SMM are now considered as MM and may be treated as such, concerns exist that earlier therapy may increase the risk of selecting resistant clones and induce side effects and costs. Therefore, an even more accurate identification of patients who would benefit from interventions needs to be performed, and clinical judgment and careful discussion of pros and cons of treatment initiation need to be undertaken. For the majority of SMM patients, the standard of care remains observation until development of symptomatic MM occurs, encouraging participation in ongoing and upcoming SMM/early MM clinical trials, as well as consideration of bisphosphonate use in patients with early bone loss.

Management of bone disease in multiple myeloma

Osteolytic bone disease is the most common complication of multiple myeloma, resulting in skeletal complications that cause significant morbidity and mortality. Currently, bisphosphonates (BPs) are the mainstay for the treatment of myeloma bone disease. Zoledronic acid which has been found to be superior to clodronate, both in terms of reduction of skeletal-related events (SREs) and survival, and pamidronate are used for the management of myeloma-related bone disease. Patients with active disease (not in CR or VGPR) should receive BPs (especially zoledronic acid) even after two years of administration. Radiotherapy and surgical interventions can also be used for specific conditions, such as pathological fractures, spinal cord compression or uncontrolled pain. The better understanding of the biology of myeloma bone disease has led to the production of several novel agents, such as denosumab (targeting RANKL), sotatercept (activin-A antagonist) and romosozumab (targeting sclerostin) that appear very promising and have entered to clinical development.

Abstract P6-07-02: Pharmacoeconomic evaluation of denosumab for the treatment of bone metastases in patients with advanced breast cancer in Canada

Abstract Background: Skeletal-related events (SREs) occur in 80% of patients with advanced breast cancer (BC) and bone metastases. SREs are costly and can be painful and debilitating, impacting patients’ quality of life and morbidity. While intravenous bisphosphonates such as pamidronate (PAM) and zoledronic acid (ZA) have demonstrated clinical benefit in reducing SREs, skeletal metastases remain a problem as treatments that are more efficacious, well tolerated, more convenient and less costly to administer are needed. Denosumab (XGEVA™) is a novel subcutaneous human monoclonal antibody therapy that significantly reduces the risk of developing SREs in patients with bone metastases from BC. Objective: The objective of this project is to estimate the incremental cost-effectiveness of denosumab relative to ZA and PAM in the treatment of advanced BC patients with bone metastases. Methods: A lifetime Markov model with four-week cycle lengths was developed with three health states: on treatment; off treatment; and death. The model included the risk of an SRE for patients on and off treatment and adverse events during treatment. Efficacy was measured as reduction in SREs. Head-to-head efficacy data, transition probabilities, and risk of adverse events were obtained from the clinical trial of denosumab versus ZA. (Stopeck AT et al JCO 2010) Efficacy data compared to PAM was determined from a published network meta-analysis. (Ford JA et al Eur J Cancer 2012) The baseline SRE risk was derived from clinical trial data due to the absence of real-world Canadian data. Analyses were conducted from the Canadian healthcare system perspective and reported in 2011 $CAD. Resource use was determined from a Canadian retrospective chart review of oncology patients with SREs. Costs were based on the published literature, the Ontario Case Costing Initiative, and input from a physician panel. Utility inputs were based on a time trade-off study. (Matza LS et al. Eur J Health Econ 2013) Bisphosphonate administration costs were derived from a published time and motion study. (Dranitsaris G et al. J Oncol Pharm Pract 2001) Outcomes were measured as both SREs avoided and quality-adjusted life years (QALYs) gained. Dominance was assessed or incremental cost-effectiveness ratios calculated per SRE avoided and per QALY gained, for denosumab compared to ZA and PAM. Future costs and QALYs were discounted at 5% per annum. Sensitivity analyses were conducted to test the robustness of the results. Results: Denosumab was dominant and resulted in $5,733 in cost savings compared to ZA and $2,566 in cost savings compared to PAM based on a probabilistic analysis. Cost savings was driven by differences in drug administration costs and reduction in SREs. SREs avoided were 0.27 and 0.57 compared to ZA and PAM respectively. Denosumab resulted in 0.012 QALYs gained and 0.025 QALYs gained per patient compared to ZA and PAM, respectively. Sensitivity analyses showed the results were robust but most sensitive to drug administration costs and the relative risk of SREs. Conclusion: Compared to both ZA and PAM, denosumab is more efficacious and offers better value for money (i.e. dominant) in Canada for managing SREs in patients with advanced BC and bone metastases. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-07-02.

Cellular Players in Breast Cancer Bone Metastases

The current paradigm for bone metastasis is that there is a mutual interaction between osteoclasts and cancer cells, known as the tumor/bone vicious cycle. This model is based largely on findings in immune compromised animals showing amelioration of bone metastases by targeting the osteoclasts. Thus, osteoclast inhibitors are the standard of care in breast cancer bone metastasis. However, clinical studies demonstrate only a 28 % reduction in skeletal-related events in patients with bone metastases treated with bisphosphonates, and currently, there is limited evidence supporting anti-resorptive therapies in reducing the overall incidence of bone metastasis or extending survival. These data indicate that other cells, in addition to the osteoclasts, control tumor growth in bone. This review will discuss the role of the osteoclast, and then focus on additional cellular players, thus expanding the model of bone metastasis pathophysiology to include immune and stromal components.

Cost-effectiveness of denosumab (Dmab) versus zoledronic acid (ZA) for prevention of skeletal-related events (SREs) in patients (pts) with castrate-resistant prostate cancer (CRPC) and bone metastases (BM).

59 Background: It has become more important to understand the incremental cost/benefit of new medicines as healthcare costs rise. Subcutaneous Dmab is superior to intravenous ZA for prevention of SREs in pts with CRPC and BM (Fizazi, 2011). In addition, a lower proportion of pts receiving Dmab progressed to moderate/severe pain than those receiving ZA (Brown, 2011). Dmab can be used in pts regardless of renal status or concomitant use of nephrotoxic drugs. These analyses assess the lifetime, real world cost-effectiveness of Dmab vs ZA in pts with CRPC and BM from a US managed care perspective. Methods: A lifetime Markov model was developed to estimate SREs, quality adjusted life-years (QALYs), and costs. The relative rate reduction in SREs for Dmab vs ZA was based on a large head-to-head phase 3 trial (N=1,901). The real world SRE rate in ZA pts was derived from a large commercial claims database analysis (Hatoum, 2008). SRE QALY decrements were estimated using the time trade-off method (Matza, 2011). SRE costs were estimated from a nationally representative commercial claims database (Barlev, 2010). Wholesale acquisition drug cost (Analysource, 2011), drug administration, and renal monitoring costs (National Fee Analyzer, 2011) were included. Compliance and mortality were assumed to be the same in both groups. Costs and QALYs were discounted at 3% annually. Results: With a median pt survival of 1.7 years, Dmab reduced the number of SREs and increased pts’ QALY vs ZA. The lifetime cost/pt on Dmab was $7,430 higher than ZA. Cost/QALY gained was $65,134, commonly considered good value based on oncologists’ implied threshold in the US (Nadler, 2006). Cost/SRE avoided was $9,212. Conclusions: Dmab is cost-effective in preventing SREs in pts with CRPC and BM compared with ZA in the US. The overall value of Dmab is based on superior efficacy and more efficient administration. [Table: see text]

Effects of Denosumab versus Zoledronic Acid in Patients with Castration-Resistant Prostate Cancer and Bone Metastases

Progression of castration-resistant prostate cancer often leads to bone metastases, increasing the risk of skeletal-related events (SREs). The use of antiresorptive therapies such as denosumab, a human monoclonal antibody and zoledronic acid (ZA), a bisphosphonate, reduces bone destruction by inhibiting osteoclast function and survival. In 2002, ZA was approved for the prevention of skeletal complications in patients with bone disease from myeloma or bone metastases from solid tumors including prostate cancer. Recently, efficacy analysis demonstrated superiority of denosumab to ZA for the prevention or delay of SREs in 1,901 patients with prostate cancer and bone metastases, significantly delaying the time to first SRE and time to first and subsequent SRE compared to ZA. Decreases in bone turnover markers were greater with denosumab, mirroring the reduction in SREs. The reported incidence of adverse events were similar between denosumab and ZA. Advanced prostate cancer patients require long-term disease management where maintenance of overall bone health is an essential component of a comprehensive treatment program.

Emerging novel therapies for advanced prostate cancer

This review examines the development and efficacy of novel treatment options for advanced prostate cancer and discusses novel therapies that are on the horizon. Since the introduction of docetaxel as the standard treatment for patients with metastatic castration-resistant prostate cancer (CRPC), a number of different agents have been tested but failed to demonstrate improvement in overall survival (OS). Recently, three novel compounds have demonstrated OS benefit and one other showed reduction in skeletal-related events (SREs). Sipuleucel-T, a novel vaccine, was approved by the US regulatory authorities in April 2010 for patients with early advanced prostate cancer. A new taxane, cabazitaxel, and abiraterone acetate, an androgen biosynthesis inhibitor, have shown an OS benefit in advanced CRPC after docetaxel, leading to drug approval. A new bone-targeting agent, denosumab, a receptor activator of nuclear factor κB ligand (RANKL) antagonist, showed a modest reduction in SREs in comparison to zoledronic acid in patients with bone metastases. Other promising novel agents are currently being tested in the clinical setting of advanced CRPC. These include, androgen receptor inhibitors (MDV3100), androgen biosynthesis inhibitors, angiogenesis inhibitors (thalidomide, lenalidomine, aflibercept, tasquinimod), a novel form of radiotherapy (radium-223), and immune-modulating compounds (PROSTVAC-VF). Improvements in progression-free survival and OS rates, observed with novel agents, in metastatic prostate cancer have led to a shift in treatment paradigm. The challenge will be to position the current established and expected novel treatments in the new landscape of metastatic prostate cancer and to determine at what point and time in the disease course they can best be administered.

P4-11-14: Number Needed To Treat (NNT) as a Measure of Incremental Drug Benefit: Denosumab vs. Zoledronic Acid for the Prevention of Skeletal Related Events (SREs) in Advanced Breast Cancer.

Abstract Background Intravenous zoledronic acid (ZOL) is the standard of care for the prevention of SREs in advanced breast cancer. However, monthly subcutaneous denosumab (Dmab) was recently approved in the US, as an alternative to ZOL based on the results of a large randomized trial which demonstrated a prolongation in median time to first SRE (HR = 0.82, p = 0.01) and a 5.8% (p = 0.01) absolute reduction in SREs in favour of Dmab over the 34 month study period. The challenge for clinicians and payers is how to reconcile the modest benefits of Dmab with the cost, which is approximately twice that of ZOL. NNT represents the number of patients that need to be treated with a new intervention in order to avoid one additional event, and is a widely accepted approach used to make sense of numerical results from clinical trials. In this analysis, the NNT approach was used to assess the incremental benefit of Dmab over ZOL for the prevention of SREs in advanced breast cancer. Methods: The pivotal randomized trial for Dmab vs. ZOL in breast cancer (Stopeck, JCO 2010 &amp; US PI 2010) was reviewed. As an alternative to ZOL, the NNT with Dmab to avoid any SRE at 12 and 34 months (trial end) was determined. NNT by type of SRE was also estimated. These consisted of pathologic fractures, radiation to bone, spinal cord compressions and surgery to bone. The calculated NNT represents the incremental benefit provided by Dmab above and beyond Zometa therapy. Results: To avoid a single SRE after 12 months of treatment of continuous therapy with Dmab, approximately 36 patients need to be treated. To avoid a single fracture and radiation to bone, approximately 39 and 27 patients need to be treated with Dmab over a 34 month period. Dmab was unable to offer any incremental benefit over ZOL in terms of avoiding spinal cord compressions or surgery to bone after 34 months of treatment. Discussion: The NNT approach is a simple and effective method to express the findings in a clinically meaningful way. In this analysis, the incremental benefit of Dmab would only be realized when a minimum of 36 patients are treated for 12 months. For the more severe skeletal-related events, in terms of clinical and economic burden to patients and society, such as spinal cord compression and surgery to bone, Dmab did not offer any incremental benefit over ZOL in terms of SRE avoidance. This marginal incremental benefit needs to be considered alongside the high cost of Dmab. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-14.

THERAPEUTIC EFFICACY AND PHARMACOECONOMICS EVAULATION OF PAMIDRONATE VERSUS ZOLEDRONIC ACID IN MULTIPLE MYELOMA PATIENTS

Sixty patients of multiple myeloma were randomized into two equal groups to receive Pamidronate and Zoledronic acid intravenously every month for a total of six months. The primary endpoint was to compare the therapeutic efficacy of both drugs by the resolution of hypercalcemia, prevention of skeletal related events and pathological fractures. The secondary endpoints were to assess patient compliance on the basis of quality of life score before and after treatment with Pamidronate and Zoledronic acid and to analyze the cost effectiveness of both drugs., Pamidronate was found to be more effective in the resolution of hypercalcemia as compared to Zoledronic acid, whereas Zoledronic acid reduced the overall proportion of skeletal related events (45.9%) in comparison with Pamidronate (54.1%). Overall Quality of life scores were not significantly influenced by either the response or the occurrence of adverse event but were statistically significant (P=0.000), with in the treatment groups. Patients on Zoledronic acid were more comfortable due to short administration time of l5minutes as compared to 2 hours of Pamidronate. The average cost of six months’ treatment with Zoledronic acid was significantly higher (PKR=90, 000 or USD 1,052) in comparison with Pamidronate (PKR=39, 000 USD 456. Zoledronic acid reduced the risk of developing skeletal complications including hypercalcemia and was significantly more effective in reducing the incidence of hypocalcemia. The incidence of renal impairment among patients treated with Zoledronic acid was significantly higher, but severity of nephrotoxicity was more with Pamidronate. The most common adverse effects were pain, vomiting and fatigue in both treatment groups. Comparatively, Pamidronate was more effective in resolution of hypercalcemia, while Zoledronic acid have better therapeutic effects in reduction of skeletal related events and pathological fractures.

Tumour macrophages as potential targets of bisphosphonates

Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use.Bisphosphonates (BPs), such as zoledronic acid, are anti-resorptive agents approved for treatment of skeletal complication associated with metastatic breast cancer and prostate cancer. These agents act on osteoclasts, key cells in the bone microenvironment, to inhibit bone resorption. Over the past 30 years this has led to a great reduction in skeletal-related events (SRE's) in patients with advanced cancer and improved the morbidity associated with cancer-induced bone disease. However, there is now a growing body of evidence, both from in vitro and in vivo models, showing that zoledronic acid can also target tumour cells to increase apoptotic cell death and decrease proliferation, migration and invasion, and that this effect is significantly enhanced in combination with chemotherapy agents. Whether macrophages in the peripheral tumour microenvironment are exposed to sufficient levels of bisphosphonate to be affected is currently unknown. Macrophages belong to the same cell lineage as osteoclasts, the major target of BPs, and are highly phagocytic cells shown to be sensitive to bisphosphonates in model studies; In vitro, zoledronic acid causes increased apoptotic cell death; in vivo the drug has been shown to inhibit the production of pro-angiogenic factor MMP-9, as well as most recent evidence showing it can trigger the reversal of the TAMs phenotype from pro-tumoral M2 to tumoricidal M1. There is thus accumulating evidence supporting the hypothesis that effects on TAMs may contribute to the anti-tumour effect of bisphosphonates. This review will focus in detail on the role of tumour associated macrophages in breast cancer progression, the actions of bisphosphonates on macrophages in vitro and in tumour models in vivo and summarise the evidence supporting the potential for the targeting of tumour macrophages with bisphosphonates.

End Points and Outcomes in Castration-Resistant Prostate Cancer: From Clinical Trials to Clinical Practice

New therapeutic approaches for castration-resistant prostate cancer (CRPC) introduce new treatment dilemmas: how best to sequence these options to maximally benefit patients, what tests to perform before and after treatment to assess disease status, and how to interpret the test results and use them to guide treatment. New and specific end points for different classes of drugs are needed to provide the information to guide these treatment decisions. In 2008, the Prostate Cancer Working Group 2 consensus criteria for early-phase clinical trials redefined clinical trial end points as first, to control, relieve, or eliminate disease manifestations present when treatment is started and second, to prevent or delay future disease manifestations. Disease manifestations include prostate-specific antigen (PSA), soft-tissue disease (nodes and/or viscera), bone disease (most common site of spread), and symptoms. Recent US Food and Drug Administration (FDA) approvals for CRPC therapies have been based on the prevent/delay end points that reflect unequivocal benefit to a patient: prolongation of life or reduction in skeletal-related events (SREs). For the practicing oncologist, the control/relieve/eliminate outcomes should serve primarily to inform the decision of whether to continue therapy. In this review, we consider individual end points such as PSA, imaging, and patient-reported outcomes in the context of the control/relieve/eliminate and prevent/delay framework. We address the time-to-event end points of metastasis prevention, SRE, time to progression, and overall survival in the context of regulatory approvals. We also discuss circulating tumor cells measured with the CellSearch assay, recently cleared by the FDA for monitoring CRPC.

Denosumab for the treatment of bone metastases in breast cancer: evidence and opinion

Denosumab, a fully human monoclonal antibody, targets the receptor activator of nuclear factor-kappaB (RANK) ligand, a protein essential for osteoclast differentiation, activity and survival. Loss of osteoclasts from the bone surface reduces bone turnover and bone loss in malignant and benign diseases. In breast cancer, bone metastases are frequently observed; cancer treatment-induced bone loss (CTIBL) may result as a consequence of endocrine treatment or chemotherapy. Furthermore, preclinical studies suggest a direct role of the RANK/RANK-ligand pathway in breast tumorigenesis. This paper reviews preclinical and clinical data on denosumab in breast cancer. Studies were identified through the Medline database. Key search terms included: AMG-162, bisphosphonates, denosumab, RANK-ligand and zoledronic acid. Information available in abstract form only was retrieved from major oncology meetings, such as the American Society of Clinical Oncology (ASCO) annual meeting, ASCO breast meeting, European Cancer Organization, European Society of Medical Oncology and the San Antonio Breast Cancer Symposium. Denosumab was consistently well tolerated throughout clinical trials, although the observed incidence of osteonecrosis of the jaw was comparable to that with bisphosphonates. Efficacy as determined by a reduction of skeletal-related events was at least equal to zoledronic acid, and superior in one phase III study conducted in patients with metastatic breast cancer. Clinical trials investigating the role of denosumab for the prevention of CTIBL and breast cancer recurrences are currently ongoing. In conclusion, denosumab appears to be an effective and safe treatment option in patients with bone metastases from breast cancer with the potential of also preventing CTIBL.