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Metastasis-free survival viable endpoint for prostate cancer trials
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Metastasis-free survival could be a surrogate endpoint for OS in clinical trials designed to evaluate adjuvant therapy options for patients with localized prostate cancer who are at a higher risk for death, according to a systematic review published in Journal of Clinical Oncology.
“Advances in understanding prostate cancer biology and drug development have resulted in new therapies that have prolonged the lives of some men with metastatic castration-resistant prostate cancer,” Christopher J. Sweeney, MBBS, medical oncologist at the Dana-Farber Cancer Institute, and colleagues wrote. “Use of these therapies in the adjuvant setting — when micrometastases, if present, are more sensitive to therapies — may actually eradicate the disease and further decrease the number of men who die of prostate cancer; however, adjuvant clinical trials in prostate cancer take more than a decade to reach the irrefutable endpoint of OS.”
No intermediate clinical endpoints are currently accepted as robust surrogates in prostate cancer trials. However, these endpoints could serve as surrogates for OS when no curative salvage therapy for relapsed disease is available or when there is a substantial risk for death.
Sweeney and colleagues conducted a systematic review of 102 completed or ongoing randomized controlled trials for localized prostate cancer to evaluate the surrogacy of DFS and metastasis-free survival (MFS) for OS. The trials enrolled patients from 1987 to 2011 with a median follow-up of 10 years.
Because many patients with intermediate- or high-risk localized prostate cancer are cured and die of other causes, researchers also investigated time to disease recurrence and time to metastasis as surrogates for disease-specific survival, for which nonprostate cancer deaths were not counted as an event.
The analysis included individual data from 28 trials with 22,825 patients. However, not all trials collected all endpoints of interest. DFS analysis included 21,140 patients from 24 trials; MFS analysis included 12,712 patients from 19 trials.
Overall, observed 5-year rates were 76% for DFS, 79% for MFS and 84% for OS.
Radiation trials accounted for 61% of patients with DFS events and 90% of patients with MFS events. Sixty-three percent of patients with DFS events and 66% with MFS events had high-risk disease.
At the individual patient level, the correlation — measured by Kendall’s tau from a copula model — was 0.85 (95% CI, 0.85-0.86) between OS and DFS and 0.91(95% CI, 0.91-0.91) between OS and MFS.
After censoring nonprostate cancer deaths, the correlation between OS and disease-specific survival was 0.68 (95% CI, 0.67-0.69) for time to disease recurrence and 0.91 (95% CI, 0.91-0.92) for time to metastasis.
“The tight correlation between endpoints is reflected by the tight correlation between the trial and arm-specific Kaplan-Meier estimates of OS or disease-specific survival at 8 years vs. the Kaplan-Meier estimates of the surrogates at 5 years,” Sweeney and colleagues wrote.
The researchers performed weighted linear regression between trial and arm-specific OS rates at 8 years compared with 5-year DFS and MFS rates. The proportion of variance was 0.86 (95% CI, 0.78-0.9) between 8-year OS and 5-year DFS and 0.83 (95% CI, 0.71-0.88) between 8-year OS and 5-year MFS.
At the trial level, the researchers investigated the correlation between treatment effects on independent clinical endpoints and OS, measured by log HRs. The proportion of variance was 0.73 (95% CI, 0.53-0.82) for DFS and 0.92 (95% CI, 0.81-0.95) for MFS.
Thus, a clinical trial that achieved a 30% reduction in risk for patients developing metastatic disease would predict a 25% decreased risk for death.
Given this strong correlation, “clinical trials can be designed using metastatic-free survival as a primary endpoint instead of OS,” which would allow trials to be completed “in a more expeditious manner,” Sweeney said in a press release.
The idea is to “get a readout of the clinical trial sooner and get drugs to patients sooner,” he added.
The researchers noted surrogacy appeared independent of primary local interventions and type of adjuvant therapy.
Also, linear regression graphs may generate the surrogate threshold effect to define relative improvements in MFS that are associated with clinically meaningful improvements in OS.
“The discovery of this surrogate endpoint has enormous implications for patients with prostate cancer,” Howard Soule, PhD, chief science officer and executive vice president of the Prostate Cancer Foundation, said in the release. “Reducing the time needed to conduct clinical trials will accelerate the development of new treatments that can be administered at the earliest stage possible, when cancer might still be curable.” – by Kristie L. Kahl
Disclosures: A Prostate Cancer Foundation Challenge Award and grants from Astellas Pharma, Janssen Pharmaceuticals, Medivation, Sanofi, Sotio and Takeda Oncology funded this study. Sweeney reports consultant/advisory roles with Astellas Pharma, AstraZeneca, Bayer, Genentech, Janssen Biotech, Pfizer and Sanofi; research funding from Astellas Pharma, Bayer, Janssen Biotech, Sanofi and Sotio; patents, royalties and other intellectual property from Exelixis and Leuchemix; and stock and other ownership from Leuchemix. Soule reports a leadership role with WindMIL Therapeutics, a consultant/advisory role with Compugen, and travel expenses from Compugen and Sanofi. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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