KEY TAKEAWAYS
- The phase II trial aimed to determine the efficacy and safety of adding ATRi berzosertib to gemcitabine in platinum-resistant ovarian cancer pts.
- The secondary endpoint was OS.
- The study found this combination did not improve OS in the overall population. This may benefit pts with short PFI or low RS tumors.
Researchers aimed to determine the efficacy and safety of adding ATR inhibitor(ATRi) berzosertib to gemcitabine in patients(pts) with platinum-resistant ovarian cancer.
Pts received multiple prior lines of cytotoxic therapy in the platinum-sensitive setting. No more than one line in the platinum-resistant setting was randomized in a 1:1 ratio to receive either gemcitabine/berzosertib or gemcitabine alone. The randomization was stratified based on the platinum-free interval (PFI), with PFI≤3 months versus > 3 months as criteria. Crossover from gemcitabine to gemcitabine/berzosertib was permitted upon disease progression according to RECIST 1.1 criteria. Overall survival (OS) was a secondary endpoint, with preplanned exploratory correlative studies involving the assessment of DNA repair pathways and replication stress (RS) alterations using targeted gene sequencing and/or immunohistochemistry (IHC).
The study involved 70 pts, and they were randomly assigned to receive either gemcitabine/berzosertib (34 pts) or gemcitabine alone (36 pts), with 15 pts switching from gemcitabine to gemcitabine/berzosertib later. The final analysis showed including all pts, the median overall survival (OS) was 59.4 weeks in the gemcitabine/berzosertib group and 43.0 weeks in the gemcitabine alone group.
The difference was insignificant (HR 0.79, 90% CI 0.52-1.2, one-sided P= 0.18). When excluding pts who switched treatments, a significant OS benefit was observed with gemcitabine/berzosertib (HR 0.60, 90% CI 0.37−0.97). The benefit was more pronounced in pts with a progression-free interval (PFI) of ≤3 months (HR 0.26, 90% CI 0.1−0.7) and in those with RS-low tumors (HR 0.39, 90%CI 0.17−0.91, defined as tumors harboring no genomic RS alterations related to loss of RB pathway regulation and/or oncogene-induced RS). No significant benefit was seen in pts with RS-high tumors (HR 0.74, 90% CI 0.35−1.56). Additional genetic and immunohistochemical analyses, as well as adjustments for patient crossovers, will be presented later.
The study found this combination did not improve OS in the overall population. Still, it may benefit pts with short PFI or low RS tumors.
Source: https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.5512#
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT02595892
Panagiotis A. Konstantinopoulos, Elizabeth Katherine Lee, SuChun Cheng, Alexandre Andre B. A. Da Costa, Andrea Elisabeth Wahner Hendrickson, Doga Gulhan, Bose Kochupurakkal, David Kolin, Elise C. Kohn, Joyce F. Liu, Elizabeth Stover, Jennifer Curtis, Hannah Sawyer, Madeline Polak, Dipanjan Chowdhury, Anniina Färkkilä, Alan D. D’Andrea, Geoffrey Shapiro, and Ursula A. Matulonis. DOI: 10.1200/JCO.2023.41.16_suppl.5512 Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) 5512-5512.
