Summary Background Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of ...skeletal-related events in men with bone metastases from castration-resistant prostate cancer. Methods In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00321620 , and has been completed. Findings 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9–18·5) for patients on denosumab and 11·2 months (IQR 5·6–17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8–24·9) with denosumab compared with 17·1 months (15·0–19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71–0·95; p=0·0002 for non-inferiority; p=0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 13%) than in the zoledronic acid group (55 6%; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 2% vs 12 1%; p=0·09). Interpretation Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer. Funding Amgen.
Summary Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We ...assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. Methods In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen PSA ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov , number NCT00286091. Findings 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 95% CI 25·4–33·3 vs 25·2 22·2–29·5 months; hazard ratio HR 0·85, 95% CI 0·73–0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 95% CI 29·5–38·0 vs 29·5 22·4–33·1 months; HR 0·84, 95% CI 0·71–0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 95% CI 40·1–not estimable months vs placebo, 44·8 40·1–not estimable months; HR 1·01, 95% CI 0·85–1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo. Interpretation This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. Funding Amgen Inc.
Summary Background Abiraterone acetate plus prednisone significantly improves radiographic progression-free survival in asymptomatic or mildly symptomatic, chemotherapy-naive patients with metastatic ...castration-resistant prostate cancer compared with prednisone alone. We describe analyses of data for patient-reported pain and functional status in a preplanned interim analysis of a phase 3 trial. Methods Between April 28, 2009, and June 23, 2010, patients with progressive, metastatic castration-resistant prostate cancer were enrolled into a multinational, double-blind, placebo-controlled trial. Patients were eligible if they were asymptomatic (score of 0 or 1 on item three of the Brief Pain Inventory Short Form BPI-SF questionnaire) or mildly symptomatic (score of 2 or 3) and had not previously received chemotherapy. Patients were randomly assigned (1:1) to receive oral abiraterone (1 g daily) plus prednisone (5 mg twice daily) or placebo plus prednisone in continuous 4-week cycles. Pain was assessed with the BPI-SF questionnaire, and health-related quality of life (HRQoL) with the Functional Assessment of Cancer Therapy—Prostate (FACT-P) questionnaire. We analysed data with prespecified criteria for clinically meaningful pain progression and deterioration in HRQoL. All patients who underwent randomisation were included in analyses. This study is registered with ClinicalTrials.gov , number NCT00887198. Findings 1088 patients underwent randomisation: 546 were assigned to abiraterone plus prednisone and 542 to placebo plus prednisone. At the time of the second prespecified interim analysis, median follow-up was 22·2 months (IQR 20·2–24·8). Median time to progression of mean pain intensity was longer in patients assigned to abiraterone plus prednisone (26·7 months 95% CI 19·3–not estimable) than in those assigned to placebo plus prednisone (18·4 months 14·9–not estimable; hazard ratio HR 0·82, 95% CI 0·67–1·00; p=0·0490), as was median time to progression of pain interference with daily activities (10·3 months 95% CI 9·3–13·0 vs 7·4 months 6·4–8·6; HR 0·79, 95% CI 0·67–0·93; p=0·005). Median time to progression of worst pain was also longer with abiraterone plus prednisone (26·7 months 95% CI 19·4–not estimable) than with placebo plus prednisone (19·4 months 16·6–not estimable), but the difference was not significant (HR 0·85, 95% CI 0·69–1·04; p=0·109). Median time to HRQoL deterioration was longer in patients assigned to abiraterone plus prednisone than in those assigned to placebo plus prednisone as assessed by the FACT-P total score (12·7 months 95% CI 11·1–14·0 vs 8·3 months 7·4–10·6; HR 0·78, 95% CI 0·66–0·92; p=0·003) and by the score on its prostate-cancer-specific subscale (11·1 months 8·6–13·8 vs 5·8 months 5·5–8·3; HR 0·70, 95% CI 0·60–0·83; p<0·0001). Interpretation Abiraterone plus prednisone delays patient-reported pain progression and HRQoL deterioration in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. These results provide further support for the efficacy of abiraterone in this population. Funding Janssen Research & Development.
Abstract Objective To offer recommendations on identification of disease progression, treatment management strategies, and suggestions on timing of initiating and discontinuing specific CRPC ...treatments. Materials and Methods The RADAR II Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence Working Group convened to provide guidance on sequencing, combination, or layering of approved treatments for mCRPC based on available data and clinical experience. Results A consensus was developed to address important questions on mCRPC patient management. Conclusions In the absence of large scale clinical trials, the Working Group recommends that patients may best be managed with a layered approach of approved therapies with unique or complimentary mechanisms of action.
Abstract Study Objective To evaluate the safety of intravenous (IV) fospropofol when used to provide minimal to moderate sedation in patients undergoing minor surgical procedures. Design Phase 3, ...open-label, single-arm study. Setting Multi-center. Patients 123 ASA physical status I, II, III, and IV patients, aged ≥18 years. Interventions Patients were pretreated with fentanyl 50 μg before receiving an initial dose of IV fospropofol 6.5 mg/kg. Patients could receive up to 5 supplemental doses of fospropofol 1.63 mg/kg to reach a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score ≤ 4 to allow the start of the procedure and to maintain adequate sedation levels during the procedure. Measurements Study endpoints included measures of sedation depth, requirement for supplemental sedative doses, use of alternative sedatives, and the frequency and nature of treatment-emergent and sedative-related adverse events. Main Results A mean of 2.4 supplemental doses of fospropofol was administered, and in 60% of patients, two or fewer supplemental doses of fospropofol were sufficient to initiate and complete the procedure. Alternative sedative medication was administered in 6 of 123 patients (4.9%). Mean (SD) MOAA/S score during the procedure was 3.8 (0.5). Sixty-one percent (61%) of patients had a MOAA/S score of 5 (fully alert) within two minutes after the end of the procedure. Few patients (7 of 123; 5.7%) had MOAA/S scores of 0 to 1 (deep sedation) during the procedure, and all 7 were either ASA physical status I (n = 1) or II (n = 6). The most common treatment-related adverse events (TRAEs) were self-limited: paresthesias (62.6%) and pruritus (27.6%). Five patients experienced sedation-related adverse events, including hypotension (n = 4), bradycardia (concurrently with hypotension and managed with atropine; n = 1), or hypoxemia (less than one min and managed with chin lift and verbal stimulation; n = 1). Twenty patients with previous or existing hepatic disease (ranging from minimal to severe) and 5 patients with severe renal impairment had adverse events similar to the overall population. No deaths were reported, and no patient discontinued the study due to adverse events. Conclusion An initial dose of IV fospropofol 6.5 mg/kg with supplemental doses was safe and well-tolerated as moderate sedation for use in minor surgical procedures.
Abstract Background: A microencapsulated, sustained-release formulation of leuprolide acetate 3.75 mg has been developed. Objective: This study investigated the effectiveness, pharmacokinetics, and ...safety profile of a 1-month leuprolide acetate 3.75-mg depot formulation for suppressing testosterone concentrations in patients with prostate cancer. Methods: This was a Phase III, open-label, international multicenter clinical trial. Patients with prostate cancer who, in the judgment of the investigators, could benefit from androgen deprivation therapy received 6 monthly intramuscular injections of leuprolide acetate 3.75-mg depot. Plasma testosterone concentrations were determined at specific times throughout the study. The primary end point was the proportion of successful patients over the total number of evaluable patients (ie, patients with evaluable testosterone concentrations at all monthly assessments and no missing values due to treatment-related adverse events). Treatment success was defined as testosterone suppression below the clinical castration level (ie, ≤0.5 ng/mL) at day 28 and maintenance of clinical castration until study completion (day 168). The frequency of patients with testosterone concentrations ≤0.2 ng/mL was also studied. Results: The study included 160 patients with a mean (SD) age of 71.6 (9.2) years, weight of 83.7 (15.5) kg, and predominantly white race (87.5% 140/160). All 160 patients received at least one dose of study drug; 157 of them were fully evaluable, and 152 completed the study. The proportion of successful patients over the total number of evaluable patients was 96.8% (152/157; 95% CI,92.7%–99.0%). Five of the 157 evaluable patients (3.2%) did not achieve the primary end point of testosterone concentration ≤0.5 ng/mL by day 28. Of the evaluable patients, 78.7% (122/155) achieved testosterone suppression by day 21. By day 28, 96.8% (151/156) of the evaluable patients had achieved castrate levels, and 73.1% (114/156) achieved testosterone concentrations <0.2 ng/mL. At study end, 100% (152/152) of the patients completing the study maintained castrate levels, and 92.8% (141/152) had testosterone concentrations ≤0.2 ng/mL. The pharmacokinetic profile of leuprolide during the first 3 months of treatment, evaluated in a subset of the study population (n = 12), showed sustained release of leuprolide from the formulation. Values for AUC0−t calculated from day 0 to day 28, days 28 to 56, and days 56 to 84 were 25,976.5 (7892.0), 30,685.5 (9348.4), and 31,030.9 (10,745.0) pg/mL per day, respectively. The most common treatment-related adverse event was hot flashes (45.0% 72/160). Fatigue, hyperhidrosis, night sweats, and headache each occurred in ≤6.3% (10/160) of the patients. The most frequently reported local adverse reaction was pain at the injection site, experienced by 8.1% (13/160) of the patients. Conclusions: Leuprolide acetate 3.75-mg depot was effective in achieving and maintaining testosterone suppression and was well tolerated throughout the study in this cohort of patients with prostate cancer. ClinicalTrials.gov identifier: NCT00128531.
The specialty of urology has historically adapted to the changing health care environment. Urologists have been quick to adopt new technology, new therapeutics, and devices to render state-of-the-art ...patient care with improved clinical outcomes. The busy urology practice is now in the position to deliver many novel and unique therapies across multiple disease states. As a result, clinicians can provide state-of-the-art care in a clinic setting and potentially reduce the overall costs of health care delivery. This article reviews some of these potential new opportunities available to the practicing urologist.
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