Optimizing disease progression assessment using blinded central independent review and comparing it with investigator assessment in the PRIMA/ENGOT-ov26/GOG-3012 trial: challenges and solutions.

Objective: Progression-free survival is an established clinically meaningful endpoint in ovarian cancer trials, but it may be susceptible to bias; therefore, blinded independent centralized radiological review is often included in trial designs. We compared blinded independent centralized review and investigator-assessed progressive disease performance in the PRIMA/ENGOT-ov26/GOG-3012 trial examining niraparib monotherapy.
Methods: PRIMA/ENGOT-ov26/GOG-3012 was a randomized, double-blind phase 3 trial; patients with newly diagnosed stage III/IV ovarian cancer received niraparib or placebo. The primary endpoint was progression-free survival (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), determined by two independent radiologists, an arbiter if required, and by blinded central clinician review. Discordance rates between blinded independent centralized review and investigator assessment of progressive disease and non-progressive disease were routinely assessed. To optimize disease assessment, a training intervention was developed for blinded independent centralized radiological reviewers, and RECIST refresher training was provided for investigators. Discordance rates were determined post-intervention.
Results: There was a 39% discordance rate between blinded independent centralized review and investigator-assessed progressive disease/non-progressive disease in an initial patient subset (n=80); peritoneal carcinomatosis was the most common source of discordance. All reviewers underwent training, and as a result, changes were implemented, including removal of two original reviewers and identification of 10 best practices for reading imaging data. Post-hoc analysis indicated final discordance rates between blinded independent centralized review and investigator improved to 12% in the overall population. Median progression-free survival and hazard ratios were similar between blinded independent centralized review and investigators in the overall population and across subgroups.
Conclusion: PRIMA/ENGOT-ov26/GOG-3012 highlights the need to optimize blinded independent centralized review and investigator concordance using early, specialized, ovarian-cancer-specific radiology training to maximize validity of outcome data.
Competing Interests: Competing interests: TJH has served on advisory boards (Aravive, AstraZeneca, Caris, Clovis Oncology, Eisai, Epsilogen, GSK, Immunogen, Johnson & Johnson, Merck, Roche Genentech, Seagen) and as a consultant for Abbvie. SAW reports consulting fees (GSK and BioClinica). MRM reports personal fees and other (Karyopharm Therapeutics, Sera Prognostics, Roche); institutional grants and no financial interest (Apexigen, AstraZeneca, Deciphera, GSK, Ultimovacs); personal fees and invited speaker (AstraZeneca, GSK); personal fees and advisory boards (AstraZeneca, Biocad, Boehringer Ingelheim, GSK, Karyopharm, Merck, Mersana, ImmunoGen, Clovis Oncology, Roche, Zailab); personal fees, stocks and a member of board of directors (Karyopharm). BP reports research funding (AstraZeneca, Celgene, Celsion, Clovis, Genentech, SeaGen, GSK, Merck, Mersana, SeaGen, Takada, Toray) and consulting fees (AstraZeneca, Celsion, Eisai, GSK, GOG Foundation, Immunogen, Inxmed, Lily, Merck, Mersana, SeaGen, Toray). IV reports consulting fees (Agenus, Akesobio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Exelixis, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncoXerna, Regeneron, Sanofi, Seagen, Sotio, Verastem Oncology, Zentalis), travel grants (Karyopharm, Genmab, Novocure), and contracted research grants (Amgen, Roche, Oncoinvent AS). WSG reports advisory board and speaker fees (GSK). IAM, WY, and DG are employees of GSK. JAH is an employee of GSK and reports stocks in GSK. AGM reports personal fees for educational/advisory-related activities (Alkermes, Amgen, AstraZeneca, Clovis, Genmab, GSK, Immunogen, Mersana, MSD, Novocure, Oncoinvent, PharmaMar, Roche, SOTIO, Takeda). BJM reports consulting fees (Acrivon, Adaptimmune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Eisai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyoparm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, GSK, US Oncology Research, VBL, Verstem, Zentalis); speakers honoraria (AstraZeneca, Clovis, Eisai, Merck, Myriad, Roche/Genentech, GSK); investigator honoraria (Gradalis).
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