FDA finalizes guidance on metastasis-free survival as an endpoint for prostate cancer trials

The US Food and Drug Administration (FDA) on Friday finalized guidance on the use of metastasis-free survival (MFS) as an endpoint in clinical trials for nonmetastatic castration-resistant prostate cancer (nmCRPC).

The final guidance comes three years after the agency released the draft version for comment and expands on some of the recommendations made within the document; it also contains some editorial changes for clarity. The guidance contains recommendations for sponsors on general trial design, imaging, and considerations related to the interpretation of trial results and analyses of MFS.

FDA explains that the prolonged assessment period and low death rates makes the use of overall survival (OS) "impractical as a primary endpoint to support approval of products in this disease setting." Such issues were acknowledged during a 2011 Oncologic Drugs Advisory Committee meeting where members suggested that other endpoints that can be measured earlier in the course of disease, including MFS, "would be useful in assessing the treatment effect of products in patients with nmCRPC."

"The Oncologic Drugs Advisory Committee noted that the transition from nmCRPC to radiographically detectable metastatic disease (e.g., bone or visceral disease) is a clinically relevant event that can be associated with morbidity and the need for additional medical interventions. Conversely, local progression events may be treated with local therapies, may never progress to distant disease, and may not lead to systemic morbidity. Thus, a large treatment effect on MFS with an acceptable safety profile could demonstrate clinical benefit and support product approval," FDA explains in the guidance. (RELATED: FDA drafts guidance on using metastasis-free survival endpoints in prostate cancer, Regulatory Focus 13 November 2018)

Just prior to FDA's issuance of the draft guidance in February 2018, FDA approved Janssen's Erleada (apalutamide) as the first drug to treat nmCRPC on the basis of MFS. The agency also approved Astellas' Xtandi (enzalutamide ) to treat patients with both nmCRPC and metastatic CRPC in July 2018 and Bayer's Nubeqa (darolutamide) for nmCRPC in July 2019 using MFS as the primary endpoint.

FDA, Federal Register notice

FDA finalizes guidance on metastasis-free survival as an endpoint for prostate cancer trials

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