In the phase III MAINSAIL trial reported in The Lancet Oncology, Daniel P. Petrylak, MD, of Yale Cancer Center, New Haven, Connecticut, and colleagues found that the addition of lenalidomide (Revlimid) to docetaxel-prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer was associated with significantly worse overall survival.¹ The trial was stopped early due to futility.

Study Details

In this double-blind trial, 1,059 patients with progressive disease from 223 centers in Europe, United States, Russia, Australia, South Africa, Israel, Mexico, and Canada were randomized between November 2009 and November 2011 to receive docetaxel 75 mg/m² on day 1 and prednisone 5 mg twice daily on days 1 to 21 and either lenalidomide 25 mg (n = 533) or placebo (n = 526) once daily on days 1 to 14 of each 21-day treatment cycle. The primary endpoint was overall survival in the intention-to-treat population.

The lenalidomide and placebo groups were generally balanced for age (median 70 years in both), region (North America for 26% in both, Europe and Australia for 62% and 63%), type of disease progression (prostate-specific antigen [PSA] only in 30% and 28%, radiographic in 70% and 72%), metastatic sites (bone only in 32% and 30%, soft tissue in 20% and 18%, both in 49% and 52%), median PSA level (105 and 85 ng/mL), and median circulating tumor cell count (5 cells/7.5 mL vs 11 cells/7.5 mL).

At the fourth scheduled protocol-defined safety and efficacy review, the independent data monitoring committee concluded that the study was unlikely to show superiority of lenalidomide and that there was an increased incidence of serious adverse events in the lenalidomide group. In November 2011, the trial was discontinued for futility.

Worse Overall Survival

The duration of treatment was shorter in the lenalidomide group than in the placebo group (median 18.0 vs 24.0 weeks), as were the durations of docetaxel treatment (median 20.1 vs 24.0 weeks) and prednisone treatment (19.2 vs 23.9 weeks). Median relative dose intensities for lenalidomide or placebo, docetaxel, and prednisone were similar in the two groups. Dose reductions for lenalidomide or placebo were required in 15% of the lenalidomide group vs 8% of the placebo group, and dose reductions for docetaxel were required in 21% vs 16%.

At data cutoff in January 2012, after a median follow-up of 8 months, median overall survival was 17.7 months (95% confidence interval [CI] = 14.8–18.8 months) in the lenalidomide group vs not reached in the placebo group (hazard ratio [HR] = 1.53, P = .0017). Overall survival at 1 year was 71.4% vs 78.2%.

Median progression-free survival was 10.4 vs 10.6 months (HR = 1.32, P = .0187), and progression-free survival at 1 year was 33.8% vs 45.3%. Objective response was observed in 23% vs 25% (odds ratio = 0.884, P = .3975). PSA reduction of at least 50% from baseline occurred in 59% vs 58%.

Adverse Events

Adverse events of grade ≥ 3 occurred in 73% of the lenalidomide group vs 58% of the placebo group. Grade 3 or 4 neutropenia (22% vs 16%), febrile neutropenia (12% vs 4%), diarrhea (7% vs 2%), pulmonary embolism (6% vs 1%), asthenia (5% vs 3%), pneumonia (5% vs 1%), and dyspnea (4% vs 2%) were more common in the lenalidomide group. Adverse events led to treatment discontinuation in 29% of the lenalidomide group vs 16% of the placebo group and to discontinuation of docetaxel and prednisone in 32% vs 24%.

Mortality

Death during treatment or at up to 28 days since the last dose occurred in 3% vs 2% of patients, and death at more than 28 days since the last dose, mainly due to disease progression, occurred in 21% vs 15% (P = .016). Treatment-related death occurred in 1% of patients in each group. In both groups, dose reductions of lenalidomide or placebo were more frequent in North America (27% vs 18%) than in Europe and Australia (11% vs 5%) and the rest of the world (6% vs 2%).

Deaths in the lenalidomide group were more common in North America (33%; 45/137) than in Europe and Australia (21%; 67/325) and the rest of the world (24%; 15/63). By comparison, in the placebo group, the frequency of death in patients from North America (22%; 30/134) was closer to that observed in Europe and Australia (15%; 50/326) and the rest of the world (18%; 11/61).

The investigators concluded: “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.” ■

Disclosure: The study was funded by Celgene Corporation. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. Petrylak DP, Vogelzang NJ, Budnik N, et al: 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. Lancet Oncol 16:417-425, 2015.

Robert J. Jones, MD, of the University of Glasgow College of Medicine and the Institute of Cancer Sciences, offers his perspective on the MAINSAIL trial discussed above.