Vinflunine–gemcitabine versus vinflunine–carboplatin as first-line chemotherapy in cisplatin-unfit patients with advanced urothelial carcinoma : results of an international randomized phase II trial (JASINT1)

Background: There is no standard first-line chemotherapy for advanced urothelial carcinoma (aUC) in cisplatin-ineligible (cisplatin-unfit) patients. The study assessed the efficacy and tolerability profile of two vinflunine-based cytotoxic regimens in this setting. Patients and methods: Patients with aUC a creatinine clearance (CrCl) of <60 but ≥30 ml/min, performance status 0 or 1 and no prior chemotherapy for advanced disease were randomized (1 : 1). They received vinflunine 250 or 280 mg/m2 (based on baseline CrCl) on day 1, plus either gemcitabine [750 mg/m2 escalated to 1000 mg/m2 in cycle 2 if no toxicity grade (G) ≥2 on days 1 and 8 (VG) or plus carboplatin area under the curve 4.5 day 1 (VC) every 21 days]. To detect a 22% improvement in each arm compared with H0 (41%) in the primary end point, disease control rate (DCR = complete response + partial response + stable disease), 31 assessable patients per arm were required (α = 5%, β = 20%). Results: Sixty-nine patients were enrolled (34 VG, 35 VC). Less G3/4 haematological adverse events (AEs) were reported with VG: neutropaenia was seen in 38% (versus 68% with VC) and febrile neutropaenia in 3% (versus 14% with VC) of patients. No major differences were observed for non-haematological AEs. DCR was 77% in both groups; overall response rate (ORR) was 44.1% versus 28.6%, with a median progression-free survival of 5.9 versus 6.1 months and median OS of 14.0 versus 12.8 months with VG and VC, respectively. Conclusion: Both vinflunine-based doublets offer a similar DCR, ORR and OS. The better haematological tolerance favours the VG combination, which warrants further study

Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL):a randomised, double-blind, placebo-controlled phase 3 trial

International audienceBACKGROUND:Patients with metastatic castration-resistant prostate cancer have few treatment options. We investigated the safety and efficacy of lenalidomide, an immunomodulatory agent with anti-angiogenic properties, in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer.METHODS:In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned chemotherapy-naive patients with progressive metastatic castration-resistant prostate cancer in a 1:1 ratio to receive docetaxel (75 mg/m(2)) on day 1 and prednisone (5 mg twice daily) on days 1-21 and either lenalidomide (25 mg) or placebo once daily on days 1-14 of each 21 day treatment cycle. Permuted block randomisation was done with an interactive voice response system and stratified by Eastern Cooperative Oncology Group performance status, geographic region, and type of disease progression. Clinicians, patients, and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy analysis was by intention to treat. Patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00988208.FINDINGS:1059 patients were enrolled and randomly assigned between Nov 11, 2009, and Nov 23, 2011 (533 to the lenalidomide group and 526 to the control group), and 1046 patients received study treatment (525 in the lenalidomide group and 521 in the placebo group). At data cutoff (Jan 13, 2012) after a median follow-up of 8 months (IQR 5-12), 221 patients had died: 129 in the lenalidomide group and 92 in the placebo group. Median overall survival was 17·7 months (95% CI 14·8-18·8) in the lenalidomide group and not reached in the placebo group (hazard ratio [HR] 1·53, 95% CI 1·17-2·00, p=0·0017). The trial was subsequently closed early due to futility. The number of deaths that occurred during treatment or less than 28 days since the last dose were similar in both groups (18 [3%] of 525 patients in the lenalidomide group vs 13 [2%] of 521 patients). 109 (21%) patients in the lenalidomide group and 78 (15%) in the placebo group died more than 28 days from last dose, mainly due to disease progression. At least one grade 3 or higher adverse event was reported in 381 (73%) of 525 patients receiving lenalidomide and 303 (58%) of 521 patients receiving placebo. Grade 3-4 neutropenia (114 [22%] for lenalidomide vs 85 [16%] for placebo), febrile neutropenia (62 [12%] vs 23 [4%]), diarrhoea (37 [7%] vs 12 [2%]), pneumonia (24 [5%] vs five [1%]), dyspnoea (22 [4%] vs nine [2%]), asthenia (27 [5%] vs 17 [3%]), and pulmonary embolism (32 [6%] vs seven [1%]) occurred more frequently in the lenalidomide group than in the placebo group.INTERPRETATION:Overall survival with the combination of lenalidomide, docetaxel, and prednisone was significantly worse than with docetaxel and prednisone for chemotherapy-naive men with metastatic, castration-resistant prostate cancer. Further research with this treatment combination is not warranted.FUNDING:Celgene Corporation

Association of Survival Benefit With Docetaxel in Prostate Cancer and Total Number of Cycles Administered: A Post Hoc Analysis of the Mainsail Study.

Importance The optimal total number of docetaxel cycles in patients with metastatic castration resistant prostate cancer (mCPRC) has not been investigated yet. It is unknown whether it is beneficial for patients to continue treatment upon 6 cycles.Objective To investigate whether the number of docetaxel cycles administered to patients deriving clinical benefit was an independent prognostic factor for overall survival (OS) in a post hoc analysis of the Mainsail trial.Design, setting, and participants The Mainsail trial was a multinational randomized phase 3 study of 1059 patients with mCRPC receiving docetaxel, prednisone, and lenalidomide (DPL) or docetaxel, prednisone, and a placebo (DP). Study patients were treated until progressive disease or unacceptable adverse effects occurred. Median OS was found to be inferior in the DPL arm compared with the DP arm. As a result of increased toxic effects with the DPL combination, patients on DPL received fewer docetaxel cycles (median, 6) vs 8 cycles in the control group. As the dose intensity was comparable in both treatment arms, we investigated whether the number of docetaxel cycles administered to patients deriving clinical benefit on Mainsail was an independent prognostic factor for OS. We conducted primary univariate and multivariate analyses for the intention-to-treat population. Additional sensitivity analyses were done, excluding patients who stopped treatment for reasons of disease progression and those who received 4 or fewer cycles of docetaxel for other reasons, minimizing the effect of confounding factors.Main outcomes and measures Total number of docetaxel cycles delivered as an independent factor for OS.Results Overall, all 1059 patients from the Mainsail trial were included (mean [SD] age, 68.7 [7.89] years). Treatment with 8 or more cycles of docetaxel was associated with superior OS (hazard ratio [HR], 1.909; 95% CI, 1.660-2.194; P < .001), irrespective of lenalidomide treatment (HR, 1.060; 95% CI, 0.924-1.215; P = .41). Likewise, in the sensitivity analysis, patients who received a greater number of docetaxel cycles had superior OS; patients who received more than 10 cycles had a median OS of 33.0 months compared with 26.9 months in patients treated with 8 to 10 cycles; and patients who received 5 to 7 cycles had a median OS of 22.8 months (P < .001).Conclusions and relevance These findings suggest that continuation of docetaxel chemotherapy contributes to the survival benefit. Prospective validation is warranted

Alpha emitter radium-223 and survival in metastatic prostate cancer

BACKGROUND: Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. METHODS: In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. RESULTS: At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. CONCLUSIONS: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.)