FDA Final Guide to MFS in nmCRPC
A prolonged evaluation period and low mortality rate mean that the usefulness of overall survival (OS) may be impractical as a primary endpoint to support drug approvals for patients with breast cancer. prostate. These questions were explored at the 2011 Oncology Medicines Advisory Committee meeting, where members recommended exploring other parameters that can be measured earlier in the course of the disease, such as MFS, which may prove useful in assessing the impact of treatment on this patient population. .
The guide highlighted several general considerations for clinical trial designs that use MFS as an endpoint. For example, the FDA recommends defining MFS before starting the trial, which should rule out local progression events such as pelvic lymph node progression under the aortic bifurcation, as well as considering stratification of randomization by previous definitive local treatment or no previous definitive treatment. . The prostate-specific antigen (PSA) doubling time should also be taken into account, as directed.
Other recommendations include the use of a superiority trial design and the exclusion of patients who may benefit from topical treatment. This patient population could be recruited after topical treatment provided their PSA continues to increase and the other recruitment criteria for CRPC and minimum PSA value are met.
In terms of imaging review, the guidelines state that sponsors should pre-specify the acceptable imaging modalities and the frequency with which assessments should be performed. In addition, it is important to pre-specify and justify the radiographic definition of non-metastatic disease. Radiographic definition of local disease and its progression, as well as metastatic disease, should also be pre-specified. In order to interpret the results with MFS, the magnitude of improvement in MFS must be significantly greater than the frequency of imaging.
“The FDA recommends an independent, blinded central review of imaging studies to assess any potential assessment bias. Sponsors may also consider using an audit where a random sample of analyzes is sent for independent review. Sponsors should seek advice from the Agency on designing an audit for MFS, ”the guide says.
When it comes to interpreting the results of trials using MFS as an endpoint, interim efficacy analyzes of MFS are discouraged in order to avoid overestimating and underestimating the benefits of MFS . Additionally, the extent of improvement in MFS required to support drug approval will be based on trial design, safety, patient population, and overall risk / benefit assessment. In addition, although demonstration of the benefit of OS is not required, a formal interim OS analysis should be performed at the time of final FSM analysis.
Finally, the guidance highlighted several final considerations for MFS analyzes. Since missing data can complicate MFS analyzes, it is imperative to have procedures in place that minimize missing data.
“The statistical analysis plan should specify the primary analysis and one or more sensitivity analyzes to assess the effect of missing observations on the results,” the guide says. “Sponsors may consider additional analyzes of progression-free survival (including local and metastatic progression) to support the primary analysis of MFS. “
Prior to the publication of the draft guidelines, the FDA had approved the use of apalutamide (Erleada) in February 2018 for patients with nmCRPC, marking it as the first drug approved based on a clinical trial with a criterion MFS primary assessment.2 The phase 3 SPARTAN trial (NCT01946204) enrolled 1207 patients with nmCRPC who were treated with apalutamide or placebo. Results indicated that apalutamide gave a median MFS of 40.5 months versus 16.2 months in those who received placebo (RR: 0.28; 95% CI: 0.23-0.35; P <.001>3
Likewise, enzalutamide (Xtandi) received approval in July 2018 for the treatment of nmCRPC with MFS, which was defined as the time between randomization and locoregional and / or distant radiographic progression or the death up to 112 days after discontinuation of treatment without radiographic progression. , as the primary endpoint of the support trial.4 Results from the phase 3 PROSPER trial (NCT020032924) indicated that enzalutamide gave a median MFS of 36.6 months versus 14.7 months in the control arm (RR: 0.29; 95% CI, 95% CI, 0.24 to 0.35; P <.001>5
Finally, the FDA approval of darolutamide (Nubeqa) on July 30, 2019 was based on the results of the phase 3 ARAMIS trial (NCT02200614), in which 1509 patients with nmCRPC achieved significant improvement in MFS, the main criterion to study.6 For this trial, MFS was defined as the time from randomization to the first signs of distant metastasis or death from any cause within 33 weeks of the patient’s last evaluable examination. Those who received the investigational agent had a median MFS of 40.4 months versus 18.4 months among those in the placebo arm (RR: 0.41; 95% CI: 0.34-0.050; P <.0001 notably the operating system data was not mature.>7
- FDA. Non-Metastatic Castration-Resistant Prostate Cancer: Endpoint Considerations for Metastasis-Free Survival in Clinical Trials, version 8.21. Accessed August 9, 2021. https://bit.ly/3s0o4FG
- The FDA approves a new treatment for a certain type of prostate cancer using a new clinical endpoint. Press release. FDA. February 14, 2018. Accessed August 6, 2021. https://bit.ly/3fL8Cs5
- Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N English J Med. 2018; 378 (15): 1408-1418. doi: 10.1056 / NEJMoa1715546
- The FDA approves enzalutamide for castration-resistant prostate cancer. Press release. July 13, 2018. Accessed August 9, 2021. https://bit.ly/3ixxcyn
- Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with non-metastatic, castration-resistant prostate cancer. N English J Med. 2018; 378: 2465-2474. doi: 10.1056 / NEJMoa1800536
- The FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. Press release. FDA. July 30, 2019. Accessed August 9, 2021. https://bit.ly/2XaVnKR
- Fizazi K, Shore N, Tammela TL et al. Darolutamide in non-metastatic, castration-resistant prostate cancer. N Engl J Med. 2019; 380: 1235-1246. doi: 10.1056 / NEJMoa1815671