MFS as an endpoint in clinical trials

Earlier this year, two drugs (apalutamide/Erleada and enzalutamide/Xtandi) were each approved for the treatment of non-metastatic, castration-resistant prostate cancer (nmCRPC) based on the use of metastasis-free survival (MFS) as the study endpoint in clinical trials.

We should be clear immediately that no one is questioning whether or not these two drugs should have been approved for this indication based on the SPARTAN and the PROSPECT trials, respectively. However, …

In a new article in the Journal of Clinical Oncology, Parikh and Prasad have laid out a strong and carefully argued set of cautions about the potential, long-term use of MFS as an endpoint in clinical trials (in prostate cancer and in other forms of cancer too). The full text of this article appears to be available on line to any interested reader.

The authors note a number of critical factors that are specifically relevant in the case of prostate cancer, as follows:

  • What we mean by “metastasis-free survival” is changing as new imaging techniques make it possible to identify smaller metastases earlier in the course of progressive disease (such that a man who would have been classified as metastasis-free in 2011 or even 2015 might not be seen as metastasis-free today).
  • There is a good rational for thinking that other types of endpoint may be more accurate surrogates for overall survival than MFS. Examples include the use of assays like PSA doubling time and time to initiation of taxane-based chemotherapy.
  • Increasing knowledge about the subtypes of advanced prostate cancer are changing the traditional nature of clinical trials in late-stage cancer in general — and in late-stage prostate cancers in particular — as we start to utilize genomic data to target highly definable forms of cancer with very specific forms of therapy.
  • Although MFS in and of itself is a meaningful endpoint for many patients, it does not take into account the differences between symptomatic and asymptomatic metastasis (which may be of considerable importance in relation to overall survival and patient quality of life).
  • Early visceral metastases (e.g., to the liver and other soft tissues) tend to be less common but more dangerous (in prostate cancer) than early metastases to bone.
  • The very nature of the studies used to validate the idea that MFS is a surrogate for overall survival comes with unresolved questions.

On the other hand, we do have a small bone to pick with the authors, who write that:

Biochemically recurrent prostate cancer after definitive local therapy is presumed to be metastatic, regardless of whether a metastasis is detected on imaging.

We may be splitting hairs in regard to what Parikh and Prasad meant when they used the term “definitive local therapy”, but we would consider that statement to be inaccurate. Biochemical recurrence frequently occurs as a consequence of a failure to remove or kill small amounts of cancerous tissue that were localized to the prostate or to the immediately surrounding tissues of the prostate bed at the time of first-line treatment. A man who has post-surgical biochemical recurrence as a consequence of positive surgical margins, for example, does not necessarily have metastatic disease. This is why physicians can and commonly do use radiation therapy as a form of salvage therapy for many men exhibiting biochemical progression after first-line surgery. But …

It is true that by the time the average prostate cancer patient gets referred to a medical oncologist as a consequence of biochemical progression, the oncologist (correctly) can reasonably assume that that patient probably has metastatic disease, whether mestastasis is evident on some type of scan or not.

Obviously, there are sophisticated and highly technical issues that need to be resolved here. No criticism is intended of anyone involved in the SPARTAN and PROSPECT trials or the decision to use MFS as the primary endpoint in these trials, but The “New” Prostate Cancer InfoLink agrees with Parikh and Prasad that there is still a great deal we need to understand about how to use surrogate endpoints in cancer drug development and in prostate cancer drug development in particular.

The potential exists for overly early use of costly new drugs with serious side effects when there may be limited, real-world, clinical benefit to their application. Resolving the ways to ensure that such therapies really do benefit patients is going to be an important aspect of pharmaceutical and biopharmaceutical development over the next 20 years. This will and should be top of mind for regulatory authorities, for drug and biotech companies themselves, and for the researchers that participate in the clinical trials used to validate the clinical efficacy and safety of such new drugs.

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