Nonmetastatic Castration-
Resistant Prostate Cancer: 
Considerations for 
Metastasis-Free Survival 
Endpoint in Clinical Trials 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
August 2021 
Clinical/Medical 
 
        
 
Nonmetastatic Castration-
Resistant Prostate Cancer: 
Considerations for 
Metastasis-Free Survival 
Endpoint in Clinical Trials 
Guidance for Industry 
 
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guidances 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
August 2021 
Clinical/Medical  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION ...................................................................................................... 1 
II.  BACKGROUND ........................................................................................................ 1 
III.  METASTASIS-FREE SURVIVAL CONSIDERATIONS ......................................... 2 
A.  General Trial Design Considerations .............................................................................. 2 
B.  Imaging Considerations................................................................................................. 3 
C.  Considerations Related to Interpretation of Trial Results ................................................ 3 
D.  Considerations Related to Analyses of MFS .................................................................... 4 
 
  Contains Nonbinding Recommendations 
Nonmetastatic Castration-Resistant Prostate Cancer: 
Considerations for Metastasis-Free Survival 
Endpoint in Clinical Trials 
Guidance for Industry1 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page. 
 
 
 
I.  INTRODUCTION 
 
This guidance provides recommendations to sponsors about using metastasis-free survival (MFS) 
as an endpoint in clinical trials for nonmetastatic castration-resistant prostate cancer (nmCRPC) 
development programs for drug or biological products2 regulated by FDA. 
 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract.  This document is 
intended only to provide clarity to the public regarding existing requirements under the law.  
FDA guidance documents, including this guidance, should be viewed only as recommendations, 
unless specific regulatory or statutory requirements are cited.  The use of the word should in 
Agency guidances means that something is suggested or recommended, but not required. 
 
 
II.  BACKGROUND 
 
Nonmetastatic castration-resistant prostate cancer is defined by rising prostate-specific antigen 
(PSA) despite castrate levels of testosterone and no radiographic evidence of metastatic disease.  
Despite earlier detection of localized prostate cancer and advances in surgical and radiation 
techniques, many patients will continue to have rising PSA after local therapy (e.g., surgery, 
radiation), subsequent salvage therapies (if received for locally recurrent disease), and 
subsequent androgen deprivation therapy.  Patients with nmCRPC can have a prolonged disease 
course following the detection of a rising PSA until documentation of distant metastases or 
death.  Such a prolonged assessment period (in which patients may receive multiple therapies) 
 
1 This guidance has been prepared by the Office of Hematology and Oncology Products in the Center for Drug 
Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug 
Administration. 
 
2 For the purposes of this guidance, all references to products include both human drugs and biological products 
unless otherwise specified. 
1  Contains Nonbinding Recommendations 
with low death rates may make the use of overall survival (OS) impractical as a primary endpoint 
to support approval of products in this disease setting. 
 
These issues were discussed at an Oncologic Drugs Advisory Committee meeting in 2011, 
during which the committee acknowledged that endpoints that can be measured earlier in the 
course of disease, such as MFS, defined as the time from randomization to distant radiographic 
disease or death, would be useful in assessing the treatment effect of products in patients with 
nmCRPC.3  Additionally, 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. 
 
 
III.  METASTASIS-FREE SURVIVAL CONSIDERATIONS 
 
A.  General Trial Design Considerations 
 
Sponsors should consider the following in trials using MFS as an endpoint for nmCRPC product 
development programs: 
 
  Sponsors should establish the definition of MFS before initiating the trial, and the 
definition should exclude local progression events (e.g., progression in pelvic lymph 
nodes below the aortic bifurcation). 
 
  Sponsors should consider stratification of randomization by prior local definitive therapy 
(e.g., surgery, radiation), or lack of prior definitive therapy, and by PSA doubling time 
(with timing and number of PSA measurements specified before trial initiation). 
 
  The protocol should prespecify procedures to reduce attrition in both treatment arms 
caused by patients who withdraw from the trial because of concern about persistently 
rising PSA values (e.g., PSA blinding or targeted patient and investigator education).  
Sponsors should plan for sensitivity analyses to assess the effect of patient discontinuation 
for reasons other than disease progression. 
 
  A superiority trial design should be used. 
 
  Trials should exclude patients who could benefit from local therapy (e.g., surgery or 
radiation) to the prostate or pelvis.  Such patients could be enrolled after completing local 
therapy if their PSA continues rising and meets trial entry criteria for castration-resistant 
prostate cancer and minimum PSA value. 
 
3 See the Oncologic Drugs Advisory Committee meeting material, available at https://www.fda.gov/advisory-
committees/human-drug-advisory-committees/oncologic-drugs-advisory-committee. 
2  Contains Nonbinding Recommendations 
 
  The trial entry criteria should include and justify the definition of castration-resistant 
disease, including the maximum allowable serum testosterone and the minimum absolute 
PSA value for eligibility. 
 
B.  Imaging Considerations 
 
Sponsors should consider the following for imaging modalities and assessments in clinical trials 
with MFS as an endpoint for nmCRPC product development: 
 
  Sponsors should prespecify acceptable imaging modalities and assessment frequencies.  
The same modalities should be used in the same patients for the duration of the trial. 
Imaging assessment frequency should also be the same on all treatment arms, as 
asymmetrical frequencies may bias the assessment of MFS. 
 
  For trial entry criteria, sponsors should prespecify and justify the radiographic definition 
of nonmetastatic disease.  For example, patients entering these trials may have enlarged 
pelvic lymph nodes, so sponsors should provide criteria concerning the acceptable size 
and location of these nodes at trial entry. 
 
  Sponsors should prespecify the radiographic definition of local disease/local progression 
(e.g., pelvic lymph nodes) and metastatic disease (e.g., distant lymph nodes, bone 
metastases, visceral disease).  Sponsors should confirm solitary bone metastases with 
additional imaging.  When confirmatory imaging is performed, the date of recurrence 
should be the date when the metastasis was first identified.  Evidence of unequivocal 
progression (e.g. development of multiple bone lesions or unequivocal visceral lesions) 
may not require confirmation. 
 
  For MFS to be interpretable, the expected magnitude of improvement in MFS should be 
substantially greater than the imaging frequency. 
 
FDA recommends a blinded independent central review of imaging studies to assess any 
potential assessment bias.  Sponsors may also consider using an audit where a random sample of 
scans are sent for independent review.  Sponsors should seek advice from the Agency about the 
design of an audit for MFS. 
 
C.  Considerations Related to Interpretation of Trial Results 
 
Sponsors should consider the following for interpreting results of clinical trials with MFS as an 
endpoint for nmCRPC product development: 
 
  Interim efficacy analyses of MFS are discouraged because these may lead to over- or 
underestimation of the magnitude of MFS improvement.  Adequate follow-up of the 
study population before efficacy assessment should be carefully considered so as not to 
risk significant probability of over- or underestimation of the magnitude of benefit.  
3  Contains Nonbinding Recommendations 
Sponsors should meet with the Agency to discuss a study designed with interim analyses 
before initiation. 
 
  The acceptable magnitude of improvement in MFS required to support drug approval will 
depend primarily on the trial design (e.g., add-on design, active control versus placebo 
control), toxicity profile, enrolled population, and overall benefit-risk assessment. 
 
  Although FDA does not require demonstration of an OS benefit, sponsors should conduct 
a formal interim analysis of OS at the time of final MFS analysis.  To support a favorable 
benefit-risk assessment, this analysis should demonstrate a favorable numeric trend and 
provide assurance that OS is not adversely affected by the treatment.  Sponsors should 
also plan for a long-term follow-up and analysis of OS.  If the study has only limited 
power to show an OS benefit, the sponsor should seek advice on the length of follow-up 
needed. 
 
  Sponsors may collect patient-reported outcome (PRO) and other clinical outcome 
assessment data to inform the benefit-risk assessment.  If PROs are planned, sponsors 
should focus collection and analysis on the following domains: symptomatic adverse 
events, disease-related symptoms, and physical function.  Sponsors are encouraged to 
meet with FDA to discuss their PRO development strategies.  For further guidance on 
patient-focused drug development, see the guidance for industry Patient-Focused Drug 
Development: Collecting Comprehensive and Representative Input (June 2020).4 
 
D.  Considerations Related to Analyses of MFS 
 
Sponsors should consider the following for analyses of MFS in clinical trials for nmCRPC 
product development: 
 
  Sponsors should describe in the protocol and statistical analysis plan the precise 
methodology for assessing, measuring, and analyzing MFS. 
 
  Missing data can complicate analyzing MFS.  Sponsors should put in place procedures to 
minimize missing data, and they should prespecify in the protocol and statistical analysis 
plan methodology for analyzing incomplete and/or missing follow-up assessments, 
including rules for censoring observations. 
 
  The statistical analysis plan should specify the primary analysis and one or more 
sensitivity analyses to evaluate the effect of missing observations on the results. 
 
  Sponsors can consider additional analyses of progression-free survival (including both 
local and metastatic progression) to support the primary MFS analysis. 
 
4 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
4