FDA Releases New Guidance on MFS as a Primary End Point for Prostate Cancer Trials

Metastasis-free survival (MFS) can be an effective end point in clinical trials to support approval of castration-resistant prostate cancer (CRPC) therapies under certain conditions when overall survival (OS) is not feasible as an end point, according to new recommendations by the FDA.

For many studies involving nonmetastatic CRPC (nmCRPC), OS may be an impractical end point to support approval, as patients with nmCRPC can have a prolonged disease course after rising prostate-specific antigen (PSA) levels are detected. In these cases, PSA levels rise despite castrate levels of testosterone and a lack of radiographic evidence of metastatic disease. Even with earlier detection of localized prostate cancer and advances in surgical and radiologic therapies, many patients’ PSA levels will continue to rise after local therapy, salvage therapies, and androgen deprivation therapy. This leads to a prolonged assessment period before the documentation of distant metastases or death, and a patient could undergo multiple therapy regimens during that time.

Due to this complexity, MFS may be a more appropriate end point for certain clinical trials over OS. It is measured earlier on in the disease, allowing the drug to demonstrate clinical benefit and an acceptable safety profile earlier on.

“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,” the FDA states in its recommendation.

According to the FDA, several considerations should be taken into account when designing a trial with MFS as a primary end point. Considerations include trial design, imaging considerations, interpretation of trial results, and considerations related to the analysis of MFS. 

In terms of general trial design, care should be taken to establish the definition of MFS prior to study initiation. Local progression events, such as progression in pelvic lymph nodes below the aortic bifurcation, should be excluded from the definition. Additionally, investigators should consider randomization stratification by prior local definitive therapy or lack of prior definitive therapy, as well as by PSA doubling time. Efforts should also be made to reduce attrition in both treatment arms caused by patients who withdraw due to concerns about persistently rising PSA values. Sensitivity analysis should be planned in order to assess the effect of patient discontinuation for reasons other than progression. Patients who could benefit from local therapy should be excluded. They could be included after enrollment if PSA levels continue to rise and meet entry criteria. Lastly, entry criteria should include the maximum allowable serum testosterone and minimum absolute PSA value for eligibility. 

When it comes to imaging consideration, several factors should be considered. Investigators should prespecify acceptable imaging modalities and assessment frequencies. The same methods should be used in the same patients for trial duration and frequency should be standardized across all arms. Asymmetrical frequencies could bias the assessment of MFS. Additionally, the radiographic definition of nonmetastatic disease and the radiographic definition of local disease/local progression, and metastatic disease should also be prespecified. Lastly, the expected magnitude of MFS improvement should also be greater than imaging frequency in order for MFS to be interpretable.

For considerations related to trial results interpretation, interim efficacy analysis should be discouraged as it could lead to the over-or-underestimation of MFS improvement. The same caution should be applied to follow-up before efficacy assessment. The magnitude of improvement needed for FDA approval will depend on study design. A formal interim analysis of OS should also be conducted in order to ensure OS is not being adversely affected by the investigational agent. Patient-reported outcomes surrounding symptomatic adverse events, disease-related symptoms, and physical function should be collected if patient-reported outcomes are planned.

In terms of considerations related to MFS analysis, investigators should describe how analysis will be conducted in study protocol. Additionally, procedures should be in place in order to minimize missing data, as it could complicate analysis. In addition to a primary analysis, the FDA also recommends that 1 or more sensitivity analyses are also conducted in order to evaluate the effect of missing data from results. Lastly, progression-free survival should also be taken into consideration for efficacy support. 

_REFERENCE:

_{Nonmetastatic castration- resistant prostate cancer: considerations for metastasis-free survival endpoint in clinical trials guidance for industry. FDA website. August 2021. Accessed August 11, 2021. https://bit.ly/3ADzYIJ}