OS Preferred End Point for Trials of First-Line/Maintenance Therapy in Ovarian Cancer

A systematic review and meta-analysis of several independent studies suggests that overall survival (OS) is the preferred end point in trials examining first-line or maintenance therapy for ovarian cancer (JAMA Netw Open. 2020;3[1]:e1918939).

Furthermore, results showed that if progressive-free survival (PFS) is used as a primary end point, it must be supported by additional end points.

According to Xavier Paoletti, PhD, Groupe d’investigateurs national des Etudes des Cancers Ovariens (GINECO), Paris, France, and colleagues, the Gynecologic Cancer InterGroup (GCIG) has recommended that PFS can be used as a primary end point replacing OS in clinical trials of patients with advanced ovarian cancer.

However, data confirming the validity of PFS as a surrogate marker of OS in the modern era of different treatment types is lacking.

Thus, Dr Paoletti et al conducted a comprehensive search for randomized clinical trial data evaluating the systematic treatment of patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer in the MEDLINE database. They also asked GCIG groups about any potentially complete but unpublished trial data.

Clinical trials that included a minimum of 60 patients and had PFS and OS rates available were included in the analysis.

“Investigational treatments considered included initial, maintenance, and intensification therapy consisting of agents delivered at a higher dose and/or frequency compared with that in the control arm,” Dr Paoletti and colleagues said.

Between January 7, 2019, and March 20, 2019, the investigators performed a meta-analysis of clinical trials published between January 1, 2001, and September 25, 2016, and used the Kendall τ model to estimate correlations between PFS and OS at the individual level. The Plackett copula bivariate (R2) model was used to estimate between-treatment effects on PFS and OS at the trial level, and criteria for PFS surrogacy required R2 ≥0.80 at the trial level.

The main outcome measures of the analysis were OS and PFS based on measurement of cancer antigen 125 levels confirmed via radiology exam or by combined GCIG criteria.

Ultimately, this meta-analysis comprised data for 11,029 patients (median age, 58 years) and spanned 17 randomized studies of standard (n = 7), intensification (n = 5), and maintenance (n = 5) chemotherapies or targeted treatments. Although findings showed a high correlation between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717-0.732), the trial level yielded a low correlation (R2 = 0.24; 95% CI, 0-0.59).

Similar findings were observed in subgroup analyses, and 14 of the 16 hazard ratios for OS in the published studies fell within the 95% prediction interval from PFS as per external validation.

“This large meta-analysis of individual patient data did not establish PFS as a surrogate end point for OS in first-line treatment of advanced ovarian cancer, but the analysis was limited by the narrow range of treatment effects observed or by poststudy treatment,” Dr Paoletti and colleagues said.

“These results suggest that if PFS is chosen as a primary end point, OS must be measured as a secondary end point,” they concluded.—Hina Porcelli