GANNET53 Part II: A European Phase I/II Trial of the HSP90 inhibitor Ganetespib in high-grade Platinum-Resistant Ovarian Cancer - A Study of the GANNET53 consortium

Abstract

Purpose: Mutant TP53 stabilized by heat shock protein 90 (HSP90) is a novel target in oncology. The open-label randomized phase II GANNET53 trial is the first to evaluate the HSP90 inhibitor Ganetespib (G) with Paclitaxel (P) in platinum-resistant epithelial ovarian cancer (EUDRACT 2013-003868-31; EU FP7 #602602). Patients and Methods: Patients were randomized 2:1 to receive G+P or P alone until progression. Primary endpoints were progression-free survival (PFS) and PFS rate at six months. Exploratory endpoints were biomarkers based on p53 and HSP90. Results: A total of 133 patients were enrolled. Median PFS was 3.5 (G+P) and 5.3 months (P) (HR 1.3, 95% CI: 0.897-1.895, P = 0.16), PFS rates at six months were 22% (G+P) and 33% (P). No significant differences were found in overall survival, objective response rate and post progression PFS between arms. Most frequent adverse events (AEs) were diarrhea (79% vs. 26%), anemia (46% vs. 51%), nausea (41% vs. 40%), and peripheral neuropathy (36% vs. 47%). Serious AEs were more common in G+P (39.5% vs. 23.3%). Gastrointestinal perforation was a new safety finding. Despite of a high TP53 mutation frequency, HSP90-p53 complexes were detected in only 39.6% of the cases and were also detected stably during treatment. In-vitro, no synergistic effects of G+P were observed, and mutp53 depletion did not sensitize ovarian cancer cells to treatment. Conclusions: Although no major safety findings were observed, G+P did not lead to survival benefit. Our companion diagnostic programme confirmed that G+P do not favorably cooperate in killing ovarian cancer cells.