Lenalidomide Fails to Improve Metastatic Prostate Cancer Survival

Prostate cancer patients with metastatic, castration-resistant disease do not benefit from the addition of lenalidomide to a docetaxel plus prednisone regimen

medwireNews: The MAINSAIL trial has failed to find survival benefits with the immunomodulatory and anti-angiogenesis agent lenalidomide in men with chemotherapy-naive, metastatic castration-resistant prostate cancer.

Indeed, the 533 men who were randomly assigned to receive lenalidomide 25 mg/day (days 1–14 of a 21-day cycle) alongside docetaxel (75 mg/m2 on day 1) and prednisone (5 mg twice daily, days 1–21) had significantly poorer overall survival (OS) than the 521 men given docetaxel and prednisone with placebo.

Data cutoff after a median of 8 months gave a median OS of 17.7 months for lenalidomide-treated patients but was not reached in controls, giving a hazard ratio (HR) of 1.53.

This resulted in the phase III trial being halted for futility, report Daniel Petrylak, from Yale Cancer Center in New Haven, Connecticut, USA, and co-authors in The Lancet Oncology.

The lenalidomide group had significantly lower 1-year rates than the placebo groups for both OS (71.37 vs 78.18%) and progression-free survival (33.75 vs 45.34%).

“Further studies of this combination are not warranted,” the researchers therefore conclude.

Of concern, 73% of patients given lenalidomide experienced at least one grade 3 or more severe adverse event compared with 58% of placebo-treated patients. Lenalidomide was associated with higher rates of side effects than placebo, including neutropenia, febrile neutropenia, pneumonia, dyspnoea, pulmonary embolism and diarrhoea.

Lenalidomide-treated patients were also more likely to discontinue both the trial drug (29 vs 16%) and docetaxel plus prednisone (32 vs 24%).

Francesco Boccardo, from University of Genoa in Italy, questions the decision to conduct the MAINSAIL trial following only “scanty” preclinical and clinical results for lenalidomide in prostate cancer.

Noting that castration-resistant disease is “notoriously heterogeneous”, he suggests in an accompanying comment that a formal phase II trial may have avoided the overestimation of the lenalidomide combination’s superiority to placebo and the underestimation of associated toxicity.

“This point is crucial: underestimation of toxicity in MAINSAIL exposed a large number of patients to undue toxic effects, and resulted in decreased treatment duration and relative dose intensity, and increased treatment discontinuations, probably contributing to the negative efficacy findings”, Francesco Boccardo emphasises.

He concludes: “[T]he true lesson to learn from this study is that biomedical research cannot ignore the best interests of the patients, nor should the developmental pathways for drugs be rushed inappropriately.”


Petrylak DP, Vogelzang NJ, Budnik N, et al. Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial.Lancet Oncol 2015; Advance online publication 2 March. Doi: dx.doi.org/10.1016/S1470-2045(15)70025-2

Boccardo F. The MAINSAIL trial: an expected failure. Lancet Oncol 2015; Advance online publication 2 March. doi: dx.doi.org/10.1016/S1470-2045(15)70058-6

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