Related Experiment Video
Updated: Sep 20, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
GANNET53 Part II: A European Phase I/II Trial of the HSP90 Inhibitor Ganetespib in High-Grade Platinum-Resistant
Nicole Concin1,2, Ioana Braicu3,4, Pierre Combe5
1Department of Obstetrics and Gynecology, Medical University of Innsbruck, AGO Austria, Innsbruck, Austria.
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.
Insights
The HSP90 inhibitor ganetespib combined with paclitaxel did not improve progression-free survival in platinum-resistant ovarian cancer. This combination therapy showed no survival benefit and revealed new safety concerns like gastrointestinal perforation.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Mutant p53 protein, stabilized by heat shock protein 90 (HSP90), is a potential therapeutic target in cancer treatment.
- HSP90 inhibitors represent a novel approach to targeting these mutant p53 proteins.
Purpose of the Study:
- To evaluate the efficacy and safety of ganetespib (an HSP90 inhibitor) in combination with paclitaxel for patients with platinum-resistant epithelial ovarian cancer.
- To assess progression-free survival (PFS) and identify potential biomarkers related to p53 and HSP90.
Main Methods:
- An open-label, randomized phase II clinical trial (GANNET53) involving 133 patients with platinum-resistant ovarian cancer.
- Patients were randomized 2:1 to receive ganetespib plus paclitaxel (G + P) or paclitaxel alone (P).
- Primary endpoints included PFS and the PFS rate at 6 months; exploratory endpoints focused on p53 and HSP90 biomarkers.
Main Results:
- Median PFS was 3.5 months for G + P versus 5.3 months for P (HR = 1.3, P = 0.16).
- PFS rates at 6 months were 22% for G + P and 33% for P.
- No significant differences in overall survival or objective response rate were observed. Increased serious adverse events, including gastrointestinal perforation, were noted in the G + P arm.
Conclusions:
- The combination of ganetespib and paclitaxel did not demonstrate a survival benefit in platinum-resistant ovarian cancer.
- Companion diagnostics indicated that ganetespib and paclitaxel do not synergistically enhance cancer cell killing.
- While no major safety concerns were initially identified, the combination showed a higher incidence of serious adverse events and a novel safety finding of gastrointestinal perforation.
Related Concept Videos
02:56Treatment Resistant Cancers
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...