Phase 3 TRIDENT Trial Misses Survival End Point in Glioblastoma

Initiating tumor treating fields (TTFields; Optune) therapy concurrently with chemoradiation did not significantly improve overall survival compared with starting the therapy during the maintenance phase of treatment in patients with newly diagnosed glioblastoma, according to topline results from the phase 3 TRIDENT trial (NCT04471844).¹

In the intention-to-treat population, median overall survival was 17.7 months among patients who began TTFields therapy at the start of chemoradiation (early start arm) compared with 17.5 months among those who began TTFields therapy during the maintenance phase after chemoradiation was completed (maintenance start arm) (HR, 0.953; P =.519).

Study Design

TRIDENT enrolled 981 patients with newly diagnosed glioblastoma who were randomized shortly after surgery, including patients who experienced clinical or radiographic deterioration during chemoradiation.² The median patient age was 60 years. Baseline characteristics were balanced between arms: 38% of patients had a Karnofsky performance status score of 70 or 80, 39% had a methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter, and 5% had IDH-mutant tumors.¹ Extent of resection was also similar between arms, with 51% of patients undergoing gross total resection, 37% partial resection, and 12% biopsy only. Approximately 25% of patients across both arms did not go on to the maintenance phase of treatment.

TRIDENT is a global, open-label, two-arm trial; secondary end points include progression-free survival, overall radiologic response by 2010 Response Assessment in Neuro-Oncology (RANO) criteria, and progression-free survival at 6 and 12 months. In both arms, TTFields therapy and maintenance temozolomide continued after completion of chemoradiation.

The full results have been accepted for presentation at the American Society for Radiation Oncology (ASTRO) 2026 Annual Meeting.

Efficacy Outcomes

Although the trial did not meet its primary end point, overall survival was durable in both groups. One-, 2-, and 3-year survival rates were 70.9%, 33.9%, and 22.5%, respectively, in the early start arm, and 72.0%, 31.6%, and 18.4%, respectively, in the maintenance start arm. TTFields therapy initiated during chemoradiation was feasible, and no new safety signals emerged; device-related safety was consistent with prior studies of TTFields therapy in glioblastoma.

TTFields therapy uses noninvasive, locoregional electric fields delivered through a scalp-worn device to disrupt cancer cell division; the modality is already approved for use during the maintenance phase of treatment for newly diagnosed glioblastoma based on the phase 3 EF-14 trial (NCT00916409) which showed an overall survival benefit when TTFields therapy was added to maintenance temozolomide after chemoradiation.³ TRIDENT was designed to test whether moving the start of TTFields therapy earlier—into the concurrent chemoradiation phase—would extend that benefit further.

“TRIDENT represents the largest glioblastoma trial focused on optimizing the integration of [TTFields] therapy into standard chemoradiotherapy,” said Wenyin Shi, MD, PhD, professor of radiation oncology and co-director of the Jefferson Brain Tumor Center at the Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University, in a news release.¹ “Although the study did not meet its primary end point, it reaffirmed the clinical value of [TTFields] therapy and demonstrated promising signals that earlier initiation of TTFields treatment may improve outcomes for selected patients.”

“ In glioblastoma, we're still trying to find effective systemic therapies beyond the Stupp protocol… We have yet to find a new systemic therapy that has really evolved the treatment paradigm significantly,” said Raj Singh, MD, radiation oncologist at the Eugene M. and Christine E. Lynn Cancer Insittue, part of Baptist Health, in an interview with Targeted Oncology.

For clinicians managing newly diagnosed glioblastoma, the topline results suggest that the timing of TTFields initiation relative to chemoradiation does not, on its own, change overall survival in an unselected population, and that the maintenance-phase start used in current practice remains an appropriate standard. Whether specific patient subgroups—based on factors such as MGMT methylation status, extent of resection, or performance status—derive differential benefit from earlier initiation awaits the planned subgroup analyses and full presentation of data at ASTRO 2026.

REFERENCES

1. Novocure Announces Topline Data from the Phase 3 TRIDENT Trial Evaluating Earlier Use of Tumor Treating Fields Therapy in Newly Diagnosed Glioblastoma. News release. Novocure. June 18, 2026. Accessed June 26, 2026. https://tinyurl.com/223btcp9

2. Pivotal, Randomized, Open-label Study of Optune® (Tumor Treating Fields) Concomitant With RT & TMZ for the Treatment of Newly Diagnosed GBM (EF-32). ClinicalTrials.gov. Updated March 30, 2026. Accessed June 26, 2026. https://clinicaltrials.gov/study/NCT04471844

3. Stupp R, Taillibert S, Kanner A, et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA. 2017 Dec 19;318(23):2306-2316. doi: 10.1001/jama.2017.18718. Erratum in: JAMA. 2018 May 1;319(17):1824. doi: 10.1001/jama.2018.3431. PMID: 29260225; PMCID: PMC5820703.