Earlier use of tumor treating fields (TTFields) does not improve survival among patients with newly diagnosed glioblastoma compared with starting the therapy during maintenance treatment, according to results of the phase 3 TRIDENT trial.

The trial, involving nearly 1000 patients with glioblastoma, found that median overall survival was nearly identical whether patients received TTFields earlier — during chemoradiotherapy — or during the maintenance phase of treatment alongside temozolomide.

Experts stressed that the findings, presented at the American Society for Radiation Oncology (ASTRO) 2026 Annual Meeting in Boston, do not detract from the benefit of TTFields in this patient group. The results only suggest that earlier use offers no survival advantage over standard timing, at least for most patients.

“TRIDENT is ultimately a trial to evaluate the timing optimization of TTFields. It is not to redefine the role of tumor treating fields,” lead investigator Wenyin Shi, MD, of Thomas Jefferson University in Philadelphia, told meeting attendees.

While earlier use did not improve overall survival across the trial population, exploratory analyses raised the possibility that it might benefit patients with MGMT-methylated tumors.

Shi stressed, however, that the finding is hypothesis-generating and requires further validation.

The Timing Question

TTFields uses low-intensity alternating electric fields to disrupt cancer cell division. The fields are generated by a wearable device and delivered via transducer arrays placed near the tumor site (on the scalp in the case of glioblastoma). The therapy is FDA-approved for patients with newly diagnosed glioblastoma, in combination with maintenance temozolomide after completion of chemoradiotherapy.

That approval was based on the phase 3 EF-14 trial showing that the addition of TTFields to maintenance therapy improved overall survival from a median of 16 months to 20.9 months.

TTFields has since won approvals in additional cancer types, including non-small cell lung cancer and pancreatic cancer, and is under study for the treatment of various others.

TRIDENT looked at whether earlier use of TTFields could further improve outcomes for patients with newly diagnosed glioblastoma. It enrolled 981 adult patients (median age, 60 years) and randomly assigned them to start 200-kHz TTFields concurrently with a 6-week course of radiation and temozolomide (early-start group; n = 492) or with maintenance temozolomide after completion of chemoradiation (maintenance-start group; n = 489).

Randomization was stratified by MGMT promoter methylation status and extent of resection; about 39% of patients had MGMT-methylated tumors.

The trial’s primary endpoint was not met. Median overall survival in the intention-to-treat population was 17.7 months vs 17.5 months with early TTFields vs with maintenance-start TTFields (P = .519). Survival rates at 1, 2, and 3 years were not significantly different between the groups. Neither was progression-free survival, with a median of 7.6 months vs 7.3 months (P = .162).

Praveen Pendyala, MD, radiation oncologist at the Cleveland Clinic in Cleveland, Ohio, who wasn’t involved in the study, echoed Shi’s caution in interpreting the findings.

“The dangerous misinterpretation of the study is that TTFields in general don’t work,” he told Medscape Medical News. “The study really was not assessing the merit or benefit of TTFields, but more specifically addressing the optimal timing.”

Pendyala also noted that patients’ actual TTFields exposure differed by only about 1.5 months between the two treatment groups, which may not have been enough to translate into a meaningful survival difference.

Another important caveat, he said, was that roughly one quarter of patients never made it to the maintenance phase. TRIDENT randomized patients at diagnosis, whereas EF-14 enrolled patients only after they had successfully completed chemoradiation — meaning they were “inherently a healthier population,” Pendyala said.

Post Hoc Signals

In a post hoc pooled analysis, average TTFields device use of at least 50% during the first 3 months of treatment was associated with longer survival (median overall survival, 18.7 months vs 15.2 months; P < .01). The association remained significant in multivariable analysis.

A separate exploratory analysis suggested a possible signal in patients with MGMT-methylated tumors: Among patients who completed induction treatment per protocol and had at least 50% mean TTFields use during the induction period, those with MGMT-methylated tumors had longer median overall survival with early-start TTFields than with maintenance-start TTFields (29.9 vs 23.8 months; hazard ratio, 0.71; P = .027).

Pendyala called the signal “intriguing” and offered a possible biologic explanation: TTFields are best known for disrupting mitosis, but preclinical data suggest they may also affect proteins involved in DNA replication. MGMT promoter methylation, meanwhile, reduces expression of the MGMT DNA repair protein, so the combination could theoretically increase replication stress — “basically two hits on DNA replication,” Pendyala explained.

He stressed, however, that this is speculative, not proven.

As for safety, rates of adverse events were broadly similar between the two treatment groups. But device-related events were more common with early TTFields use, at 76.2% vs 58.9% with maintenance start — mostly consisting of low-grade skin reactions. Grade 3 or higher device-related events occurred in 6.2% and 3.1% of patients, respectively.

Shi said the higher rates of device-related side effects were likely related to the longer duration of TTFields exposure and its concurrent administration with chemoradiation.

Pendyala told Medscape Medical News that in his experience at Cleveland Clinic, uptake of TTFields among eligible patients is only around 10%. Many are not willing to wear the device — though among patients who do choose the therapy, adherence is usually good, Pendyala noted.

“The hurdle, the barrier, is getting patients to opt in for TTFields,” he said.

The trial was sponsored by Novocure, which manufactures the TTFields device. Shi disclosed consulting fees from Novocure, Brainlab, and Varian. Pendyala disclosed serving as a speaker for Novocure at ASTRO.