Metastasis-free survival is a strong surrogate for overall survival for men with localized prostate cancer, a meta-analysis shows. The intermediate outcome measure could help accelerate the evaluation of novel adjuvant therapies in this patient population.

A new intermediate trial endpoint could help speed the development of novel therapies for men with regionally localized prostate cancer.

According to a meta-analysis of radiotherapy and surgical trials, the time until the first evidence of distant metastases was a strong predictor of overall survival (OS) among those with localized or locally advanced prostate cancer who had an increased risk for disease recurrence, dissemination, and death (J Clin Oncol 2017 Aug 10 [Epub ahead of print]). The findings suggest that using metastasis-free survival (MFS) as a surrogate outcome measure could shave years off the time needed to show that an experimental drug works in this patient population.

“The association of MFS and OS is strong enough to provide convincing evidence of clinical benefit,” says Andrew Armstrong, MD, of Duke University in Durham, NC, who was not involved in the study. “Having a potential surrogate for early-stage prostate cancer clinical trials offers investigators a slightly shorter timeline for answers and for bringing advances to patients.”

Currently, most trials for early-stageprostate cancer last 10 to 15 years owing to the long survival times associated with the disease and the lack of accepted surrogates'such as progression-free survival—to guide prognosis and evaluate treatments. Few drug companies have therefore been willing to bear the risk and financial burden of these kinds of studies, even though treatments for localized prostate cancer can often be curative. “We are only doing a limited number of studies in this setting—and most of them have been done by cooperative trials groups—because the timelines have been too long,” says Christopher Sweeney, MD, of Dana-Farber Cancer Institute in Boston, MA.

To validate surrogate endpoints, Sweeney teamed up with more than 50 other prostate cancer researchers to form the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) Working Group. The group pooled data from 28,905 patients enrolled in 28 trials over the past 30 years. They considered MFS and another candidate endpoint, disease-free survival (DFS), which incorporates local or regional recurrence in addition to metastases. Both MFS and DFS were evaluated 5 years after study initiation and compared to 8-year OS.

The ICECaP researchers found that 5-year MFS was the stronger surrogate. MFS was tightly correlated with risk of death after 8 years and, although the finding was less statistically robust owing to missing follow-up data from some trials, MFS seemed to be associated with 10-year survival as well.

“You can now design trials around that,” says Sweeney—and many drug companies already have. Johnson & Johnson, for example, is using MFS as the primary endpoint in the phase III ATLAS registration trial of its experimental antiandrogen drug apalutamide for patients with high-risk localized disease. OS is a secondary outcome measure.

That kind of trial design might have helped researchers prove much sooner that another antiandrogen therapy, bicalutamide, is effective when combined with radiotherapy for men whose disease progressed despite prostatectomy. Earlier this year, researchers reported that bicalutamide treatment increased the percentage of patients alive at 12 years compared with placebo in a large phase III trial (N Engl J Med 2017;376:417–28). Notably, a planned interim analysis after 7 years had already shown a statistically significant difference in MFS.

According to Howard Sandler, MD, of the Cedars-Sinai Medical Center in Los Angeles, CA, the ICECaP Working Group, of which he's a part, is now looking at prostate-specific antigen levels and other candidate endpoints that might offer trial readouts even sooner than MFS. “The work's not done,” Sandler says. –Elie Dolgin

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