BERLIN — The investigational drug gedatolisib substantially extends progression-free survival (PFS) among patients with advanced hormone receptor (HR)-positive, HER2-negative breast cancer that has progressed after treatment with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, according to findings from the phase 3 VIKTORIA-1 trial.

The results, reported at the European Society for Medical Oncology (ESMO) Annual Meeting 2025, showed benefits specifically for patients with breast cancers that lack a PIK3CA mutation — a group particularly in need of new treatment options.

Over 10 months, triplet therapy with gedatolisib, fulvestrant (Faslodex), and palbociclib (Ibrance) reduced the risk for disease progression or death by 76% vs fulvestrant alone. Doublet therapy with gedatolisib and fulvestrant was nearly effective, cutting the risk by 67%.

The findings point to a potential new standard of care for this patient population, said lead investigator Sara A. Hurvitz, MD, of Fred Hutchinson Cancer Center in Seattle.

Resistance to first-line endocrine therapy and CDK4/6 inhibition is common in patients with HR-positive, HER2-negative advanced breast cancer; and for those who lack a PIK3CA mutation, treatment options are limited.

Gedatolisib is a multitarget inhibitor of the PI3K/AKT/mTOR (PAM) pathway, a molecular driver of breast cancer growth that contributes to resistance to endocrine therapy and CDK4/6 inhibition. In earlier work, gedatolisib showed clinical activity in HR-positive, HER2-negative advanced breast cancer, regardless of patients’ PIK3CA mutation status.

For VIKTORIA-1 trial, Hurvitz and her colleagues enrolled 392 patients with PIK3CA wild-type disease who had progressed on or after treatment with a CDK4/6 inhibitor. Patients were randomized to receive either gedatolisib (180 mg IV, once weekly, 3 weeks on, 1 week off) plus fulvestrant and palbociclib, gedatolisib plus fulvestrant, or fulvestrant alone, with optional crossover to the triplet or doublet arm at disease progression.

Patients could have had up to two lines of prior endocrine therapy, but no prior chemotherapy.

Overall, Hurvitz reported, both doublet and triplet therapy significantly improved median PFS: from 2 months with single-agent fulvestrant to 7.4 months with the doublet regimen (hazard ratio [HR], 0.33; P < .0001) and 9.3 months with the triplet (HR, 0.24; P < .0001).

PFS was extended across all subgroups analyzed, including patients with visceral or liver metastases, in both the doublet and triplet arms. Notably, the type of prior CDK4/6 inhibitor did not influence response — even for patients who had progressed on prior palbociclib and were therefore being re-treated in the triplet arm.

“This is the first time that data in a randomized setting suggest a benefit to palbociclib rechallenge,” Hurvitz said.

Discussant Alessandra Gennari, MD, PhD, of Maggiore University Hospital, Novara, Italy, said the results show that “combination matters” when considering treatment after progression on CDK4/6 inhibitors.

“Currently, treatment options for patients who were pretreated with CDK4/6 inhibitors are disappointing,” she said, explaining that subsequent endocrine therapy hits a ceiling of 2-6 months for median PFS.

“But with combination treatment, the picture is changing,” Gennari said.

She pointed to several recent studies, including the FINER and CAPitello-291 trials, which found that combining fulvestrant with targeted therapy (ipatasertib and capivasertib, respectively) extended PFS compared to fulvestrant alone.

“If we put all these new trials together…we see that finally we can move forward and break the 6-month progression-free survival ceiling after CDK4/6 inhibitors,” Gennari said.

Regarding safety, the most common treatment-related adverse events with gedatolisib were stomatitis, rash, hyperglycemia, and diarrhea — mostly grade 1 or 2. Hurvitz noted, however, that the rates of hyperglycemia (9.2% with triplet therapy and 11.5% with doublet) and diarrhea (16.9% and 12.3%, respectively) were unexpectedly low for a drug that targets the PAM pathway.

Overall survival was a key secondary endpoint, with results expected in 2027. At interim analysis, there were 99 deaths, with rates of 22.9% in the triplet arm and 24.6% in the doublet arms vs 28.2% in the control arm.

Hurvitz called it “a promising trend,” but stressed that the data are not yet mature.

As for the question of whether doublet or triplet therapy is the better option, the picture is unclear. In an analysis comparing the two regimens, Hurvitz and her colleagues did find signals that triplet therapy benefitted certain subgroup, including pre- or perimenopausal patients (median PFS, 11.1 vs 5.6 months with doublet), patients with visceral metastases (10.7 vs 7.3 months), and those who received palbociclib as prior CDK4/6 inhibitor (16.6 vs 7.7 months).

In August, Celcuity, Inc. announced that the FDA agreed to accept its New Drug Application for gedatolisib in HR-positive, HER2-negative advanced breast cancer.

The study was funded by Celcuity, Inc. Hurvitz is a coordinating principal investigator for Celcuity, Inc. Gennari reported having no association with the company.

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for more than 30 years about all areas of medicine.