An article by staff at the U.S. Food and Drug Administration (FDA) in this week’s New England Journal of Medicine (NEJM) addresses the use of metastasis-free survival (MFS) as the primary endpoint in the trial that led to approval of apalutamide (Erleada) earlier this year.
Apalutamide was approved, based on data from the SPARTAN trial, for the treatment of men with non-metastatic, castration-resistant prostate cancer (nmCRPC) — because there was a large and clinically significant difference between the time to median MFS for the men taking standard androgen deprivation therapy (ADT) + apalutamide (40.5 months) and those taking ADT + a placebo (16.2 months).
The article by Beaver et al. addresses
- The background to the decision to use MFS as a primary endpoint to support the approval of drugs for the treatment of specific sets of patients with progressive forms of prostate cancer
- The upsides and the downsides of using MFS as a primary endpoint to support the approval of drugs for the treatment of prostate cancer (and perhaps other forms of cancer too)
Critical points made in this article, which will certainly impact the future approval of other drugs developed for the management of advanced forms of prostate cancer, include the following:
- New developments in our ability to identify earlier and smaller foci of metastasis are almost certainly going to affect the definition of MFS over time, and this will also — probably — affect the details of trials designed to seek an improvement in metastasis-free survival. Clearly MFS as defined by a metastatic tumor site visible on a bone scan is almost certainly a later event than MFS as defined by a metastatic tumor site visible on (say) an Axumin scan or a gallium-68 PET/CT scan. But in a clinical trial the actual form of imaging to be used to assess what is and what is not MFS has to be determined prospectively.
- How should we manage patient anxiety in clinical trials when men with significant, rising PSA levels are demonstrating serial negative scans and are therefore still — from a clinical perspective — metastasis free?
- What is a “metastasis” (at least in prostate cancer)? Does this only include metastasis to the bones or other distant metastasis to soft tissues like the liver, or can it include evident “metastasis” to the lymph nodes?
- The approval of apalutamide for treatment of nmCRPC has already made the future approval of other drugs for the treatment of nmCRPC harder because the standard of care has now changed and treatment of such patients in clinical trials for this indication will require any new drug to be studied in a head to head trial compared to ADT + apalutamide — or perhaps ADT + enzalutamide (see below).
But on the upside,
- The FDA has now clearly acknowledged that “a prolonged delay in development of metastatic disease is an objective and clinically relevant measure” (at least in the progression of prostate cancer).
- It is certainly possible that other, future drugs may well be approved for the treatment of nmCRPC (or perhaps for the treatment of hormone-sensitive prostate cancer) on the basis of MFS.
Indeed, in this same issue of the NEJM, Hussain et al. report the complete results of the PROSPER trial, in which enzalutamide (Xtandi) demonstrated comparable effects to apalutamide in the treatment of men with nmCRPC. Although enzalutamide has not yet been formally approved for the treatment of nmCRPC, it was granted a priority review for this indication by the FDA earlier this year, and your sitemaster expects approval of enzalutamide for this indication pretty much any time now. Whether any other drug will ever be approved for the treatment of nmCRPC without having to be compared to the new “standard of care” for this set of men with prostate cancer remains to be seen.
Note that the results of the SPARTAN trial and the results of the PROSPER trial were both initially presented at the Genitourinary Oncology Symposium in February this year and reported on this web site at that time. The results of the SPARTAN trial were also previously reported in the NEJM.
Filed under: Drugs in development, Living with Prostate Cancer, Management, Treatment | Tagged: approval, castration-resistant, indication, metastasis-free, non-metastatic, survival |
THE "NEW" PROSTATE CANCER INFOLINK 
Distant metastasis-free survival is probably a better surrogate endpoint if the study can’t run for 15 to 20 years. This surrogate endpoint is particularly important for intermediate- and high-risk survival, who will likely survive a long time. While there are often not enough deaths to see a difference in a shorter time frame, there were enough metastatic events to see a difference. An analysis last year — by the blue-ribbon ICECaP Working Group panel — of 12,712 patients in 19 clinical trials of radiation in localized prostate cancer showed that 5-year metastasis-free survival was almost perfectly correlated with overall survival.
By reducing the time needed to accumulate data, this might increase the relevance of such trials while reducing their costs.
Dear Allen (and others):
Overall survival (OS) is a secondary endpoint in the PROSPER trial and in the SPARTAN trial. If — over time — we see overall survival benefits that correspond closely with the metastasis-free survival benefits, then I think we will all have a much clearer appreciation of the accuracy of MFS as a surrogate endpoint for OS.