Ulrich Canzler

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 p53 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 6 months. Exploratory endpoints were biomarkers based on p53 and HSP90. Results: A total of 133 patients were enrolled. The median PFS was 3.5 (G + P) and 5.3 months (P) (HR = 1.3; 95% confidence interval, 0.897–1.895; P = 0.16), and PFS rates at 6 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. The most frequent adverse events were diarrhea (79% vs. 26%), anemia (46% vs. 51%), nausea (41% vs. 40%), and peripheral neuropathy (36% vs. 47%). Serious adverse events were more common in G + P (39.5% vs. 23.3%). Gastrointestinal perforation was a new safety finding. Despite 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 mutant p53 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 program confirmed that G + P do not favorably cooperate in killing ovarian cancer cells.

Prognostic role of thrombocytosis in recurrent ovarian cancer: a pooled analysis of the AGO Study Group

Although thrombocytosis in patients with primary ovarian cancer has been widely investigated, there are only very few data about the role of thrombocytosis in recurrent ovarian cancer. The aim of our study was to investigate the impact of pretreatment thrombocytosis prior to chemotherapy on clinical outcome in patients with recurrent platinum eligible ovarian cancer. In our retrospective analysis we included 300 patients who were treated by AGO Study Group Centers within three prospective, randomized phase-III-trials. All patients included had been treatment-free for at least 6 months after platinum-based chemotherapy. We excluded patients who underwent secondary cytoreductive surgery before randomization to the trial. Thrombocytosis was defined as a platelet count of ≥ 400⋅10 Pretreatment thrombocytosis was present in 37 out of 300 (12.3%) patients. Patients with thrombocytosis responded statistically significantly less to chemotherapy (overall response rate 35.3% and 41.6%, P = 0.046). The median progression-free survival (PFS) for patients with thrombocytosis was 6.36 months compared to 9.00 months for patients without thrombocytosis (hazard ratio [HR] = 1.19, 95% confidence interval [CI] = 0.84-1.69, P = 0.336). Median overall survival (OS) of patients with thrombocytosis was 16.33 months compared to 23.92 months of patients with a normal platelet count (HR = 1.46, 95% CI = 1.00-2.14, P = 0.047). The present analysis suggests that pretreatment thrombocytosis is associated with unfavorable outcome with regard to response to chemotherapy and overall survival in recurrent ovarian cancer.