“The data speak for themselves,” stated Robert Jones, MD, of the Beatson West of Scotland Cancer Center, Glasgow, UK, during discussion of the MAINSAIL trial at the 2012 ESMO Congress.

The study raises some important questions, he continued: What are the implications for designing future trials? Could failure have been avoided? How should we interpret the seemingly detrimental effect of lenalidomide? Are there other lessons for the future?

“As far as implications go, there is no future for this combination in metastatic castration-resistant prostate cancer. There is probably no future for lenalidomide in prostate cancer in any context. Further, there are direct consequences for patients who took part in the experimental arm. We lost 1,059 patients who participated in this trial for future trials,” Dr. Jones told listeners.

Avoidable Consequences

Using the benefit of hindsight, Dr. Jones believes the negative consequences could have been avoided. He said, “Preclinical data showed enhanced cytotoxicity of docetaxel plus lenalidomide, with overlapping toxicity profiles. There is no proof of concept for the lenalidomide-plus-docetaxel combination in prostate cancer, with no randomized phase II data for support. The prior hypothesis for the combination was by no means proven prior to the trial. Further, the planned interim analysis was conducted too late, after the last patient entered the trial, which wouldn’t have prevented patients from receiving the drugs if no benefit were found.” He added that the explanation for the detrimental effect of lenalidomide is not clear.

There are some lessons for future trials, Dr. Jones continued. “All phase III trials combining docetaxel with novel agents have been negative to date. This is also the fourth negative trial that fails to harness the power of antiangiogenic therapy in prostate cancer,” he noted.

“I believe future combination studies should demand proof of concept. We have an obligation to patients to minimize avoidable risks. Randomized phase II trials should probably be required prior to initiating phase III studies. We could consider better use of early stopping rules. We are still challenged by lack of a robust endpoint for early stopping,” Dr. Jones told listeners. ■

Disclosure: Dr. Jones reported no potential conflicts of interest.