Symptomatic Skeletal Events Research Articles

Bone and calcium metabolism associated with malignancy. Bone management of prostate cancer in the novel anti-androgen era.

Androgen deprivation therapy(ADT)is a standard systemic therapy for prostate cancer. ADT induces bone loss(ADTIBL)and muscle loss(sarcopenia)leading to falls and farctures. There are 2 aims in bone management of prostate cancer:one is to prevent fragility fractures in patients without bone metastasis and the other is to prevent symptomatic skeletal events(SSE)which are pathologic fractures, spinal compression, radiation to bones and surgery to bones. Bone fractures and SSE are both correlated with worse overall survival(OS). Concomitant use of novel anti-androgens further increases the risk of falls and fractures. The earlier and appropiriate intervention with vitamin D and bone modifying agents(BMA)is necessary to prevent treatment related bone fractures and SSE. Bone management algorithm aids to decide the timing and doses of BMA. As for sarcopenia physical exercise and life style advices are important. Because abiraterone with glucocorticoid therapy induces stronger bone resorption, it is recommended to start denosumab simultaneously. Ra-223, bone seeking radiopharmaceuticals should not be used with abiraterone and predonisone because of high incidence of fracture and death.

The Clinical Efficacy of Radium-223 for Bone Metastasis in Patients with Castration-Resistant Prostate Cancer: An Italian Clinical Experience

Background/Aim: Prostate cancer frequently causes bone metastases and skeletal events that impair quality of life (QoL) and survival. The alpha emitter radium-223 is a new drug that improves treatment in men with castration-resistant prostate cancer (CRPC) and bone metastases. Our aim was to evaluate the effectiveness of radium-223. Subjects and Methods: In this retrospective study we enrolled 48 subjects. Pain reduction, alkaline phosphatase (ALP), time to first symptomatic skeletal event, and QoL were the variables we evaluated. Results: Radium-223 was well tolerated, with a manageable toxicity profile and a modest objective response rate. A considerable difference in serum ALP levels before and after treatment was observed, with a significant correlation between pain relief and QoL, which showed a value of R² to 0.44 with a slope of 1.50 (p = 0.0021). Conclusions: Radium-223 showed a clinical benefit, with a reduction in pain symptoms in 58% of patients. Radium-223 was shown to be an effective and well-tolerated therapeutic option in patients with metastatic CRPC progressing after docetaxel plus prednisone treatment.

Osteonecrosis of the jaw and survival of patients with cancer: a nationwide cohort study in Denmark.

Osteonecrosis of the jaw (ONJ) is an adverse effect of bone‐targeted therapies, which are used to prevent symptomatic skeletal events following bone malignancy. We examined the association between ONJ and survival among cancer patients treated with bone‐targeted agents. Using nationwide registries and databases in Denmark, we identified 184 cancer patients with incident ONJ between 2010 and 2015, and a comparison cohort of 1067 cancer patients without ONJ and with a history of hospital‐administered treatment with bisphosphonates or denosumab initiating from cancer diagnosis. At the date of confirmed ONJ diagnosis, the comparison cohort was matched to the ONJ patients on age, cancer site, year of cancer diagnosis, and stage at diagnosis. The patients were followed up for survival until emigration or 15 June 2016. We computed overall survival and estimated mortality rate ratios adjusted for sex, and for the presence of distant metastases and other comorbidity at start of follow‐up. A match was found for 149 of the 184 ONJ patients. The 1‐ and 3‐year survival among all 184 cancer patients with ONJ was 70% (95% confidence interval [CI]: 63%–76%) and 42% (95% CI: 34%–51%), respectively. Among the matched patients, ONJ was associated with an adjusted mortality rate ratio of 1.31 (95% CI: 1.01–1.71). ONJ was associated with reduced survival among cancer patients treated with bone‐targeted agents. ONJ may be a marker of advanced disease or of survival‐related lifestyle characteristics.

Increased risk of SSEs in bone-only metastatic breast cancer patients treated with zoledronic acid

BackgroundBone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients. MethodsWe retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis. ResultsThe medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30–87) years. Eighty-seven patients were aged ≥60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647–9.481; p = 0.002). ConclusionsBone-only MBC patients are more likely to experience an SSE even after treatment with ZA.

Phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer

BackgroundRadium-223 dichloride (radium-223) is the first targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with bone metastases. This study investigated the efficacy and safety of radium-223 in Japanese patients with symptomatic CRPC and bone metastases.MethodsIn this open-label, multicenter, phase II study, patients with progressive, symptomatic CRPC and bone metastases were treated with radium-223 (55 kBq/kg, intravenously) in a 4-week cycle for six cycles. The primary endpoint was the percent change in total alkaline phosphatase (ALP) from baseline at 12 weeks. Secondary endpoints included the percent ALP change from baseline to end of treatment (EOT), ALP response rates, percent change in prostate-specific antigen (PSA) from baseline to 12 weeks and EOT, PSA response rates, overall survival (OS), and time to symptomatic skeletal events (SSEs). Adverse events were monitored throughout the study period.ResultsOf the 49 Japanese patients (median age 74 years), 28 completed all infusions. Mean percent change in total ALP and PSA from baseline to 12 weeks was −19.3 and +97.4%, respectively. One-year OS and SSE-free rate at the end of active follow-up were 78 and 89%, respectively. The ALP response rate was 31%, while the PSA response rate was 6%. Grade 3/4 treatment-emergent adverse events observed in ≥10% of patients included decreased lymphocyte count (14%), anemia (14%), anorexia (10%), and bone pain (10%).ConclusionsRadium-223 is effective and well tolerated in Japanese patients with CRPC and bone metastases. Results were comparable with the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial.Clinical trial registrationClinicalTrials.gov NCT01929655.

Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer

BackgroundAbiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer.MethodsIn this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival.ResultsAfter a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group.ConclusionsThe addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly increased overall survival and radiographic progression-free survival in men with newly diagnosed, metastatic, castration-sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285.)

Evaluating the impact of bone-targeted agents in the era of novel androgen targeted therapy for metastatic castration-resistant prostate cancer.

e16500 Background: Patients with metastatic castrate resistant prostate cancer (mCRPC) often develop bone metastases, resulting in a risk of symptomatic skeletal events (SSE). Bone-targeted agent (BTA) has been integrated into the overall treatment strategy, but its role in the era of novel androgen-targeted therapy (ATT) is still unclear. Methods: A retrospective analysis of real-world practice from 2010 to 2015 was conducted. Patients diagnosed with mCRPC and bone metastases who received systemic therapy (docetaxel/abiraterone/enzalutamide) with or without BTA (zoledronic acid/denosumab/alendronate) were included. Results: We obtained data from 299 patients with a median follow-up of 75.5 months. Compared with no BTA, concomitant BTA was associated with decreased incident of SSE (3.8% vs. 19.2%, p&lt; 0.001), especially in the need for bone radiation (1.9% vs. 15.8%, p&lt; 0.001). Compared to patients without SSE, patients with SSE were more likely to have previous fracture history (10.8% vs. 9.7%, p= 0.047), steroid use history (2.4% vs. 1.4%, p= 0.019), smoking history (53.0% vs. 38.9%, p= 0.009), diabetes (19.3% vs. 8.8%, p= 0.012) and reduced baseline mobility (9.6% vs. 4.2%, p= 0.002). Among those who received first-line novel ATT (n = 152), concurrent ATT+BTA significantly decreased the incident of SSE (2.8% vs. 27.3%, p= 0.004) and prolonged the time to SSE (24.3 vs. 3.2 mo, p&lt; 0.001), when compared to ATT alone. But there was no difference in overall survival between two groups (134.2 vs. 138.9 mo, p= 0.99). In patients who responded to systemic treatment with PSA declining, the SSE rate (2.4% vs. 14.3%, p= 0.037) was lower and the time to SSE was longer (49.6 vs. 32.3 mo, p= 0.026) than those who did not respond. Smoking history (adjusted HR = 1.46, p= 0.013) and PSA response (adjusted HR = 0.19, p&lt; 0.001) are independent risk factors for SSE. Conclusions: This real-world database suggests that concomitant BTA with novel ATT was associated with reducing SSEs. PSA decrease might be used as a predictive factor for those under BTA treatment. Further studies are warranted to validate the role of PSA response.

Phase 3 prognostic analysis of the automated bone scan index (aBSI) in men with bone-metastatic castration-resistant prostate cancer (CRPC).

5006 Background: Quantitative measures of metastatic bone disease are needed in men with mCRPC. We recently demonstrated the validity/reproducibility of a computational approach to bone scan imaging that employs artificial intelligence called the automated BSI (aBSI), which quantifies the percent of skeletal mass involved by cancer. We aimed to extend the prognostic validation of aBSI in a multinational prospective phase 3 clinical study of men with bone-metastatic CRPC. Methods: Whole-body bone scans were acquired at screening in a placebo-controlled phase 3 trial of men with mCRPC and bone metastases and treated with tasquinimod/placebo (n = 1,245). The prospective aBSI biomarker analysis plan was locked in Sept 2014 prior to treatment unblinding. All scans generated at 241 trial sites in 37 countries were assessed for image quality and analyzed using the EXINI boneBSI v.2 software and were blindly associated with outcomes. Baseline aBSI was evaluated for its independent prognostic association with overall survival (OS), radiographic progression-free survival (rPFS), and symptomatic skeletal related events (SSEs). Results: The aBSI-population (721 pts) was representative of the entire trial population based on patient characteristics at screening and OS outcomes. Median aBSI was 1.07 (SE 0.05). The aBSI-population was divided into quartiles (n = 180-181) with aBSI-levels of 0 - 0.3 (Q1); &gt; 0.3 - 1.1 (Q2); &gt; 1.1 - 4.0 (Q3); and &gt; 4.0 (Q4) and median OS ranging from 35 months (Q1) to 13 mo (Q4) (p &lt; 0.0001). Baseline aBSI was significantly associated with OS (HR 1.2 per doubling of BSI; p &lt; 0.0001) and remained independently associated with OS after adjustment for treatment, PSA, CRP, LDH and albumin. Baseline aBSI was also strongly associated with rPFS (p = 0.0005), time to symptomatic progression (p &lt; 0.0001), and time to SSE (p = 0.001). Conclusions: This analysis represents the first phase 3 evaluation of aBSI as a clinically validated prognostic biomarker for OS, rPFS, and SSEs in men with bone-metastatic CRPC, providing independent prognostic information over commonly measured clinical characteristics. Clinical trial information: NCT01234311.

Risk stratification for predicting symptomatic skeletal events (SSEs)inbreast cancer patients with bone metastases.

Symptomatic skeletal events (SSEs) affect many patients with bone metastases from breast cancer. However, predictive models of SSEs in patients with bone metastases from breast cancer have not been established for clinical use. The purpose of this study is to examine risk factors for SSEs in those patients and by combining these risk factors patients are classified into several groups. With this risk-stratification model, we can identify patients at higher risk of SSEs and require close follow-up to maintain ADL. Participants included 189 female patients with bone metastases from breast cancer and treated in our institute between 2009 and 2012. To assess risk factors for the first SSEs, clinical data at the time of registration were assessed. To estimate the effects of covariates, we used cause-specific hazard modeling. Multivariate analysis revealed that a high number of metastasized vertebral bodies (≥20) (p<0.001) and elevated carcinoembryonic antigen (CEA) level (>5ng/mL) (p=0.003) were risk factors for SSEs. Patients were classified into four subgroups according to the combination of the number of vertebral metastases and CEA level: patients with CEA level>5ng/mL and ≥20 vertebral metastases; patients with CEA level≤5ng/mL and ≥20 vertebral metastases; patients with CEA level>5ng/mL and <20 vertebral metastases; and patients with CEA level≤5ng/mL and <20 vertebral metastases. Cumulative incidences of SSEs in these four subgroups at 6 months were 35.6%, 15.6%, 9.3%, and 3.7%, respectively. Patients with elevated CEA level (>5ng/mL) and extensive vertebral metastases (≥20) should be closely monitored in routine clinical care, to allow prevention of pathological fracture or paraplegia with the intervention of orthopedists or radiologists.

Safety and efficacy of radium-223 dichloride in Japanese patients with castration-resistant prostate cancer and bone metastases

BackgroundRadiation therapy with radium-223 dichloride improves overall survival, reduces symptomatic skeletal events in Caucasian patients with castration-resistant prostate cancer (CRPC) and bone metastases, and is well tolerated. We report here the results of the first efficacy and safety study of radium-223 dichloride in a Japanese population.MethodsIn this open-label, uncontrolled, non-randomized, phase I trial, radium-223 dichloride was given to Japanese patients with CRPC and ≥2 bone metastases in 4-week cycles. The patients were divided into three cohorts, with cohort 1 and the expansion cohort receiving injections of radium-223 dichloride [55 kBq/kg body weight (BW)] every 4 weeks (Q4W) for up to six injections, and cohort 2 receiving an initial single radium-223 dichloride injection of 110 kBq/kg BW followed by up to five injections of 55 kBq/kg BW Q4W. Safety was determined via adverse event (AE) reporting, and biochemical bone markers were assessed for treatment efficacy.ResultsIn total 19 patients received at least one dose of radium-223 dichloride and 18 patients experienced at least one treatment-emergent AE (TEAE) of which the most common were anemia, thrombocytopenia, and lymphocytopenia. Serious AEs were reported in three patients but none were drug-related. In the patients of cohort 1 + expansion cohort (55 kBq/kg BW Q4W treatment; n = 16), prostate-specific antigen levels remained stable or slightly increased while the bone alkaline phosphatase (ALP) level significantly decreased. The response rates of bone ALP (≥30 and ≥50% reductions) were 81.8 and 36.4% at week 12, and 81.3 and 50.0% at the end of treatment.ConclusionsRadium-223 dichloride was well tolerated in these Japanese patients and, at a dose of 55 kBq/kg BW, efficacy on biomarkers was as expected. The outcomes in Japanese patients were consistent with those reported in other non-Japanese populations.Trial registrationClinicalTrials.gov record NCT01565746.

The treatment patterns of castration-resistant prostate cancer in Japan, including symptomatic skeletal events and associated treatment and healthcare resource use

ABSTRACTBackground: Real-world treatment patterns of bone metastatic castration-resistant prostate cancer (mCRPC) in Japan were examined, focusing on treatment patterns and resource use differences attributed to symptomatic skeletal events (SSEs).Methods: Urologists (N = 176) provided retrospective chart data for patients with mCRPC (N = 445) via online surveys. Descriptive analyses and chi-square tests evaluated treatment patterns and their differences by SSE presence; generalized linear mixed models examined healthcare resource utilization differences as a function of SSEs.Results: Patients were on average 73.6 years old (SD = 8.3), diagnosed with prostate cancer 5.1 years (SD = 6.2), castration-resistant 2.3 years (SD=2.0), and had 7.9 bone metastases sites (SD=12.4). Novel anti-hormones showed increased adoption as mCRPC treatment. Simultaneously, luteinizing hormone-releasing hormone (LHRH) agonist/antagonist use was common (43.6% of patients in 1st line), even as CRPC treatment had started. SSEs were uncommon (2–3% per treatment line; 5% at any time), but were associated with increased opioids, strontium-89, bisphosphonates, and NSAIDs use, plus increased healthcare visits (all p < .05).Conclusions: LHRH agonist/antagonist treatment combinations remain the mCRPC treatment mainstay in Japan. However, novel anti-hormone therapies are becoming well-accepted in practice. SSEs were associated with increased healthcare resource and analgesic use, highlighting the need for efficient symptom management.

Management of metastatic castration-resistant prostate cancer: A focus on radium-223: Opinions and suggestions from an expert multidisciplinary panel.

Radium-223, a calcium mimetic bone-seeking radionuclide that selectively targets bone metastases with alpha particles, is approved for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) and symptomatic bone metastases. In patients with mCRPC, treatment with radium-223 has been associated with survival benefit, regardless of prior docetaxel use, and also has a positive impact on symptomatic skeletal events and quality of life. Radium-223 is best suited for patients with symptomatic mCRPC and bone-predominant disease and no visceral metastases, and may lead to better outcomes when given early in the course of the disease. An expert multidisciplinary panel convened in Milan, Italy to review the current best-evidence literature on radium-223 and to convey their personal expertise with the use of radium-223 and identify possible strategies for best practice. This article summarizes the best available evidence for the use of radium-223, discusses the essential role of the multidisciplinary team in delivering effective treatment for mCRPC, clarifies pre- and post-treatment evaluation and monitoring, and outlines future scenarios for radium-223 in the treatment of men with MCRPC.

Impact of symptomatic skeletal events on health-care resource utilization and quality of life among patients with castration-resistant prostate cancer and bone metastases.

Data regarding the impact of symptomatic skeletal events (SSEs) on health economics and patient-reported outcomes in men with castration-resistant prostate cancer (CRPC) and bone metastases from a clinical setting are lacking. Hence, this study aimed to quantify the effects of SSEs on health-care resource utilization (HRU), health-related quality of life (HRQoL) and pain in men with CRPC metastasized to bone. This cohort study included men with CRPC and bone metastasis treated at a tertiary center during December 1996-July 2015. SSEs, including pathological fracture, radiation to bone, spinal cord compression and bone surgery, as well as HRU were identified retrospectively through medical records and clinical database. A subset of surviving patients completed Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Brief Pain Inventory-Short Form (BPI-SF) questionnaires. The incremental effect of SSEs on HRU was evaluated using multivariable generalized linear regression. Questionnaire scores were compared using effect sizes (ES); ES⩾0.33 indicated meaningful differences between SSE and non-SSE cohorts. Lower scores suggest lower HRQoL and pain. Of the 832 patients, 207 developed ⩾1 SSE (mean 1.5±0.8) during follow-up (median 2.1 years). Radiation to bone was the most common SSE (84.1%). SSE cohort had significantly higher emergency room (incidence rate ratio (IRR)=1.48; P=0.006), outpatient (IRR=1.17; P=0.005) and inpatient (IRR=1.74; P<0.001) visits. Of the 107 eligible survey patients, 103 (96.3%) responded. SSE cohort had lower mean FACT-P functional well-being (17.5 vs 19.8; P=0.158; ES=0.36), higher mean pain severity (2.5 vs 1.6; P=0.048; ES=0.47) and worst pain scores (3.6 vs 2.3; P=0.033; ES=0.50) compared with the non-SSE cohort, indicating meaningful differences between cohorts. This study demonstrated high economic and HRQoL burden of SSEs. The findings underscore the need for better supportive and disease-modifying treatments for these patients.

Abstract OT1-04-05: A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2-negative, hormone receptor–positive breast cancer and bone metastases

Abstract Background: Treatment options for bone-dominant metastatic breast cancer (MBC) are limited. Radium-223, a first-in-class α emitter with a targeted antitumor effect on bone metastases (mets), was well tolerated and reduced bone biomarker levels in a phase 2 study in patients with bone-dominant MBC (Coleman et al. Breast Cancer Res Treat. 2014). In patients with HER2- estrogen receptor+ (ER+) bone-dominant MBC, everolimus + exemestane (EVE+EXE) improved progression-free survival (PFS) versus EXE alone. Radium-223 combined with EVE+EXE may improve outcomes in patients with HER2- ER+ bone-dominant MBC; this trial will evaluate efficacy and safety of radium-223 versus placebo in these patients (NCT02258451). Trial design: Patients are randomized to receive (1:1) radium-223 (50 kBq/kg [55 kBq/kg after National Institute of Standards and Technology update] IV) or placebo × 6 cycles q 4 wk + EXE (25 mg PO q d) + EVE (10 mg PO q d) plus best supportive care. EXE+EVE continues until disease progression or unacceptable toxicity. Stratification is by geographic region (EU/N America vs Asia), prior hormone therapy (1 vs ≥ 2), and presence of visceral disease (yes vs no). Eligibility criteria: Eligible patients are pre- or postmenopausal with HER2- ER+ MBC and have ≥ 2 bone mets or have soft tissue and/or visceral mets. Patients must have measurable disease per RECIST v1.1, ≥ 1 prior line of hormone therapy for MBC, and 1-2 prior skeletal-related events; be on bisphosphonates or denosumab; and have an ECOG score of 0-1. Patients must have had no past or current need for chemotherapy for MBC, no unresolved spinal cord compression, and no prior EVE treatment. Specific aims: The primary end point is symptomatic skeletal event–free survival (SSE-FS). Secondary end points are overall survival; times to opiate use, pain progression, and cytotoxic chemotherapy; radiologic PFS; and safety. Safety and efficacy are assessed every 4 weeks. Long-term safety is assessed until study termination. Statistical methods: Assuming a 1-sided α of 0.1, 90% power, ∼ 160 SSE-FS events will be required for the analysis. Efficacy will be analyzed by a stratified log-rank test. Safety analysis will be descriptive. Present and target accrual: Estimated enrollment is ∼ 311 patients. Currently, 74 patients are randomized. Contact Oana Petrenciuc, Bayer HealthCare Pharmaceuticals, oana.petrenciuc@bayer.com, for more information. Citation Format: Rugo HS, Drumea KC, Campone M, Barnadas A, Petrenciuc O, Zhang A, Li R, Coleman RE. A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2-negative, hormone receptor–positive breast cancer and bone metastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-05.

Bone Health and Bone-targeted Therapies for Prostate Cancer: a Programme in Evidence-based Care — Cancer Care Ontario Clinical Practice Guideline

AimsTo make recommendations with respect to bone health and bone-targeted therapies in men with prostate cancer. Materials and methodsA systematic review was carried out by searching MEDLINE, EMBASE and the Cochrane Library from inception to January 2016. Systematic reviews and randomised-controlled trials were considered for inclusion if they involved therapies directed at improving bone health or outcomes such as skeletal-related events, pain and quality of life in patients with prostate cancer either with or without metastases to bone. Therapies included medications, supplements or lifestyle modifications alone or in combination and were compared with placebo, no treatment or other agents. Disease-targeted agents such as androgen receptor-targeted and chemotherapeutic agents were excluded. Recommendations were reviewed by internal and external review groups. ResultsIn men with prostate cancer receiving androgen deprivation therapy, baseline bone mineral density testing is encouraged. Denosumab should be considered for reducing the risk of fracture in men on androgen deprivation therapy with an increased fracture risk. Bisphosphonates were effective in improving bone mineral density, but the effect on fracture was inconclusive. No medication is recommended to prevent the development of first bone metastasis. Denosumab and zoledronic acid are recommended for preventing or delaying skeletal-related events in men with metastatic castration-resistant prostate cancer. Radium-223 is recommended for reducing symptomatic skeletal events and prolonging survival in men with symptomatic metastatic castration-resistant prostate cancer. ConclusionsThe recommendations represent a current standard of care that is feasible to implement, with outcomes valued by clinicians and patients.

Effect of radium-223 dichloride (Ra-223) on hospitalisation: An analysis from the phase 3 randomised Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial

Symptomatic skeletal events (SSEs) commonly occur in patients with bone metastases, often leading to hospitalisations and decreased quality-of-life. In the ALSYMPCA trial, radium-223 significantly improved overall survival (hazard ratio 0.70, 95% confidence interval [CI] 0.58–0.83, P < 0.001) and prolonged time to first SSE (hazard ratio 0.66, 95% CI 0.52–0.83, P = 0.00037) and subsequent SSE (hazard ratio 0.65, 95% CI 0.51–0.83, P = 0.00039) versus placebo in patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases. Health care resource use (HCRU), including hospitalisation events and days, were prospectively collected in ALSYMPCA. We assessed health care resource use for the first 12 months post-randomisation. Significantly fewer radium-223 (218/589; 37.0%) versus placebo patients (133/292; 45.5%) had at least one hospitalisation event (P = 0.016). However, mean number of hospitalisation events per patient was similar (radium-223 0.69 versus placebo 0.79, P = 0.226), likely due to the significantly longer follow-up time for radium-223 (7.82 months versus 6.92 months for placebo; P < 0.001). There were significantly fewer hospitalisation days per patient for radium-223 (4.44 versus 6.68, respectively, P = 0.004). The reduction in hospitalisation days with radium-223 was observed both before first SSE (2.35 days versus 3.36 days, respectively) and after SSE (7.74 days versus 9.19 days, respectively). Our data suggest that this reduced hospital days along with the survival benefit and reduction in time to SSEs with radium-223 treatment may contribute to improvements in health-related quality-of-life in patients with castration-resistant prostate cancer with symptomatic bone metastases (ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Patient preferences for treatment of castration-resistant prostate cancer in Japan: a discrete-choice experiment.

BackgroundUp to a fifth of patients diagnosed with prostate cancer (PC) will develop castration-resistant prostate cancer (CRPC), which has been associated with a poor prognosis. The aim of this study was to consider the patient perspective as part of the overall treatment decision-making process for CRPC, given that an alignment between patient preference and prescribing has been shown to benefit patient outcomes. This study examines preferences of patients with CRPC in Japan for treatment features associated with treatments like RA-223, abiraterone, and docetaxel and to examine the extent to which treatment preferences may vary between symptomatic and asymptomatic patients.MethodsA two-phase research approach was implemented. In Phase 1, N = 8 patients with CRPC were recruited from a single hospital to complete a qualitative interview to provide feedback on the draft survey. In Phase 2, N = 134 patients with CRPC were recruited from five hospitals to complete a paper survey. The survey included 6 treatment choice questions, each asking patients to choose between two hypothetical treatments for their CRPC. Each treatment alternative was defined by the following attributes: length of overall survival (OS), time to a symptomatic skeletal event (SSE), method of administration, reduction in the risk of bone pain, treatment-associated risk of fatigue and lost work days. A hierarchical Bayesian logistic regression was used to estimate relative preference weights for each attribute level and mean relative importance.ResultsA total of N = 133 patients with CRPC completed the survey and were included in the final analysis. Patients had a mean age of 75.4 years (SD = 7.4) and had been diagnosed with PC a mean of 6.5 years prior (SD = 4.4). Over the attribute levels shown, fatigue (relative importance [RI] = 24.9 %, 95 % CI: 24.7 %, 25.1 %) was the most important attribute, followed by reduction in the risk of bone pain (RI = 23.2 %, 95 % CI: 23.0 %, 23.5 %), and OS (RI = 19.2 %, 95 % CI: 19.0 %, 19.4 %). Although symptomatic patients placed significantly more importance on delaying an SSE (p < .05), no other preference differences were observed.ConclusionsCRPC patients were more concerned about reduced quality of life from side effects of treatment rather than extension of survival, which may have implications for shared decision-making between patients and physicians.

Radium-223 with concomitant bone-targeting agents in metastatic castration-resistant prostate cancer (CRPC) patients treated in an international early access program (EAP)

Background: The bone-targeting agents (BTAs) denosumab and bisphosphonates (BPs) are widely used in the supportive care of patients (pts) with CRPC and bone metastases. We present data on pts treated with radium-223 dichloride (Ra-223) with or without a concomitant BTA in an international EAP.Methods: This was a prospective single-arm phase IIIb study of CRPC pts with symptomatic or asymptomatic bone metastases (no visceral disease) recruited from 14 countries. Pts received Ra-223 55 kBq/kg (iv injection) every 4 weeks for 6 cycles. Co-primary endpoints were safety and overall survival (OS). Exploratory analyses investigated the effects of concomitant denosumab (no BPs) or BPs (no denosumab) on OS and symptomatic skeletal events (SSE). Results: 696 pts received at least one Ra-223 cycle. Of those, 127 (18%) pts were treated with concomitant denosumab (no BPs) and 435 (63%) without any concomitant BTAs. Key baseline characteristics are reported in pts treated with Ra-223 with or without a concomitant BTA (Table). Median OS (mOS) and median time to first SSE (mSSE) were longer in pts treated with Ra-223 and denosumab versus pts without a concomitant BTA (Table). While key baseline characteristics in pts treated with Ra-223 and denosumab were similar to pts treated with Ra-223 and BPs, adding BPs to Ra-223 did not appear to improve mOS. However, mSSE was prolonged in pts receiving Ra-223 and BPs versus pts who received Ra-223 without a concomitant BTA (Table). Conclusions: In this EAP, pts treated with Ra-223 and a concomitant BTA appeared to have longer time to first SSE than those treated without a concomitant BTA. However, improvement in OS was observed with denosumab but not with BPs. Prospective randomized controlled studies are required to confirm the benefit of this specific treatment combination in metastatic CRPC.Table: B7DenosumabBPsNo denosumab/ no BPsN = 127N = 125N = 435Baseline characteristicsECOG PS, n (%)058 (46%)55 (44%)144 (33%)155 (43%)54 (43%)234 (54%)≥214 (11%)16 (13%)57 (13%)Pain, n (%)123122413Mild75 (61%)72 (59%)218 (53%)Moderate-severe19 (15%)24 (20%)113 (27%)None29 (24%)26 (21%)82 (20%)ALP (U/L), n127125433Median121.0137.0168.0PSA (µg/L), n127124433Median91.2118.5174.6Efficacy outcomeOverall survivalMedian, monthsNR12.713.495% CINA10.9–NA11.7–NAHazard ratio (95% CI)0.630 (0.431– 0.922)0.846 (0.584– 1.226)-Time to first SSEMedian, months17.0NR15.895% CI17.0–17.5NA10.9–19.1Hazard ratio (95% CI)0.761 (0.493– 1.173)0.498 (0.294– 0.845)-NR/A = not reached/available. Open table in a new tab NR/A = not reached/available.

1465P - Symptomatic skeletal events (SSEs) versus skeletal-related events (SREs) in patients with advanced cancer and bone metastases treated with denosumab or zoledronic acid

1465P - Symptomatic skeletal events (SSEs) versus skeletal-related events (SREs) in patients with advanced cancer and bone metastases treated with denosumab or zoledronic acid

1463P - Denosumab for the prevention of symptomatic skeletal events (SSEs) in patients with bone-metastatic breast cancer: A comparison with skeletal-related events (SREs)

1463P - Denosumab for the prevention of symptomatic skeletal events (SSEs) in patients with bone-metastatic breast cancer: A comparison with skeletal-related events (SREs)