OS Remains Best Endpoint For Ovarian Cancer Trials

Author: By Lynda Williams, Senior medwireNews Reporter

medwireNews: Analysis of individual patient data pooled from 17 clinical trials of first-line therapy for advanced ovarian cancer has failed to demonstrate a strong correlation between progression-free survival (PFS) and overall survival (OS) outcomes. 

Although there was a strong correlation between the survival endpoint hazard ratios (HRs) for individual participants, these findings did not translate into a correlation at study level, and “therefore do not support PFS as a substitute for OS in randomized clinical trials”, say lead author Xavier Paoletti, from Institut Curie in Saint-Cloud, France, and team in JAMA Network Open. 

The meta-analysis included data from 11,029 patients who participated in seven trials of standard therapies, five of maintenance therapies and five of treatment intensifications, all of which were published between 2001 and 2016. 

The correlation between PFS and OS was high for individual patient outcomes, with a Kendall τ value of 0.724. But the correlation on a trial level was low, with an R2 model of just 0.24, where an R2 value of 0.80 or above is required for PFS to be considered a surrogate for OS, the researchers explain. 

PFS was also a poor predictor of treatment effect on OS at a trial level when considering maintenance and nonmaintenance studies separately, and when analysing data only from investigational studies of carboplatin and taxanes. 

Xavier Paoletti and team also conducted an external validation for 16 of the 20 trials they were unable to access individual patient data for. None of these trials demonstrated a statistically significant relationship between PFS and OS, and although 14 of the OS HRs fell within the 95% prediction intervals of the PFS HRs, the researchers note that these “intervals are relatively large, reflecting the uncertainty”. 

While acknowledging the challenges associated with using OS as the primary endpoint, such as the long period of patient survival after disease progression, the researchers agree with the EMA and FDA guidelines that recommend PFS be used as a primary endpoint to “represent a favorable risk-benefit association with a large magnitude of the effect or it should contribute to delaying administration of more toxic therapies as second-line treatments”.

“[T]herefore, if PFS is chosen, OS must be measured as a secondary end point and PFS must be supported by additional end points, such as predefined patient-reported outcomes, especially for maintenance therapy”, they write.

Reference 

Paoletti X, Lewsley L-A, Daniele G, et al. Assessment of progression-free survival as a surrogate end point of overall survival in first-line treatment of ovarian cancer. A systematic review and meta-analysis. JAMA Network Open; 3: e1918939. Published online 10 January 2020. doi:10.1001/jamanetworkopen.2019.18939