Metastatic Pancreatic Cancer
Efficacy Endpoints in Metastatic Pancreatic Cancer Research
Targeted therapy has revolutionized the systemic treatment of cancer, fueling debate over the choice of end points in clinical trials in oncology-especially as it relates to the use of progression-free survival as a surrogate for overall survival. Progression-free survival is measured earlier than overall survival and requires a smaller sample size than overall survival to achieve the desired power; however, progression-free survival may not fully reflect or capture the most important outcomes to patients (ie, prolonged survival and improved quality of life). Here, the expert panelists weigh in on both the value and the limitations of progression-free survival, from the advanced pancreatic cancer perspective.
Which is the best measure of efficacy from randomized controlled trials for evaluating the effectiveness of treatments in metastatic pancreatic cancer: overall survival or progression-free survival?
Professor of Medicine, Division of Medical Oncology
I think overall survival should be the indicator of efficacy. Pancreatic cancer is still a disease where we have an increasing number of treatments but a modest number of options. It is possible to perform a trial and see an overall survival benefit, unlike in some cancers where there are multiple lines of therapy, and the ability to detect an overall survival benefit in an earlier line is affected by all of the subsequent therapies. Nonetheless, as we start getting more lines of therapy, it is going to be increasingly difficult (at least for first-line studies) to show overall survival benefits, unless we are talking about drugs that have dramatic efficacy. Therefore, we are going to have to start thinking about progression-free survival. There does seem to be a correlation between progression-free survival and overall survival in pancreatic cancer, but I think we should be looking for overall survival. One slight caveat in all of this is if we start talking about molecular testing and finding subgroups that have unique markers where there could be major improvements and outcome, then we may start thinking about progression-free survival or response rate in some of those studies. But in those studies, which will be with drugs that have dramatic efficacy, it should be easy to see that overall survival would be affected by those drugs. Indeed, the US Food and Drug Administration will probably require those studies to be done, even if they give approval to a drug at an earlier stage in development based on very impressive activity. So far in pancreatic cancer, even when we talk about PARP inhibitors and BRCA-mutated tumors, we have not seen enormous improvements in outcome. I think this would dictate not being able to use response rate yet, but hopefully that time will come. Right now, overall survival is the best measure, in my opinion.
“There does seem to be a correlation between progression-free survival and overall survival in pancreatic cancer, but I think we should be looking for overall survival.”
Professor of Medicine
The best endpoint to use to assess treatment of advanced cancer is a source of controversy in clinical trial study design in pancreatic cancer and in many other solid tumors. In pancreatic cancer, the choice has always been overall survival, largely because overall survival time is so short in patients with pancreatic cancer. Overall survival as an endpoint could complete studies successfully and potentially attempt to bring drugs to cancer patients relatively quickly given the short life expectancy in patients with metastatic pancreatic cancer. As that has changed with more patients living longer with first-line therapy, the same treatment that affects other cancers, such as breast cancer, colorectal cancer, and prostate cancer, has come up in pancreatic cancer as well. In our efforts to bring drugs more rapidly to patients with pancreatic cancer, should we use surrogate endpoints, such as progression-free survival, rather than the hard endpoint of overall survival? The argument for using progression-free survival as the primary endpoint is that it could allow early introduction of new effective treatments, and certain studies have shown that in randomized clinical trials between efficacy and overall effectiveness, the relationship does vary between the use of a surrogate versus the hard endpoints of overall survival. Another issue is that the many patients who are randomly assigned to receive certain drugs in a clinical trial may actually get that drug in the posttrial setting, which would also confound results of the original trial. So, there are a lot of ongoing issues surrounding this question, and I think that is an argument that is going to continue for a while. For now, any new drug in pancreatic cancer is welcome using any endpoint. We really are starved for appropriate sequencing strategies as well as more rapid approval of new therapeutics, so I will welcome any study design used in this setting.
"In pancreatic cancer, the choice has always been overall survival, largely because overall survival time is so short in patients with pancreatic cancer.”
Hamada T, Nakai Y, Isayama H, et al. Progression-free survival as a surrogate for overall survival in first-line chemotherapy for advanced pancreatic cancer. Eur J Cancer. 2016;65:11-20.
Lakdawalla DN, Shafrin J, Hou N, et al. Predicting real-world effectiveness of cancer therapies using overall survival and progression-free survival from clinical trials: empirical evidence for the ASCO value framework. Value Health. 2017;20(7):866-875.