Treatment with gedatolisib plus fulvestrant, with or without palbociclib, significantly improves progression-free survival (PFS) in patients with HR+/HER2– PIK3CA wild-type (WT) advanced breast cancer (ABC) compared with fulvestrant alone, according to the VIKTORIA-1 trial presented at ESMO Breast Cancer 2026.
“VIKTORIA-1 represents the first phase III study to demonstrate that comprehensively blocking the PI3K/AKT/mTOR (PAM) pathway can significantly improve outcomes for patients with PIK3CA mutations compared to therapies only targeting a single component of this pathway,” said study author Dr Sara Hurvitz from Fred Hutchinson Cancer Center in Seattle, Washington, US, in a press release.
Study 1 of the phase III VIKTORIA-1 trial included 392 patients with HR+/HER2– PIK3CA-WT ABC who had progressed on or after treatment with a CDK4/6 inhibitor and a nonsteroidal aromatase inhibitor. The participants were randomized into three groups: gedatolisib triplet therapy (gedatolisib* plus fulvestrant** with palbociclib***; n=131), gedatolisib doublet therapy (gedatolisib plus fulvestrant; n=130), or fulvestrant monotherapy (n=131). [ESMO Breast Cancer 2026, abstract 510P]
At a median follow-up of 10.1 months, patients who received gedatolisib triplet therapy had a significantly longer median PFS per blinded independent central review (BICR) than those treated with fulvestrant only (9.3 vs 2 months). The difference corresponded to a 76-percent reduction in the risk of disease progression or death in favour of the triplet regimen (adjusted hazard ratio [adjHR], 0.24; p<0.0001).
Similarly, gedatolisib doublet therapy significantly prolonged median PFS compared with fulvestrant monotherapy (7.4 vs 2 months; adjHR, 0.33; p<0.0001).
The PFS benefit observed with the gedatolisib triplet and doublet regimens was consistent across all key subgroups, according to the researchers.
An interim analysis of overall survival (OS) data demonstrated a trend favouring both gedatolisib-based regimens (median 23.7 months [triple] and not reached [doublet]) over fulvestrant alone (median 18.5 months).
The BICR-assessed objective response rate (ORR) was higher with the gedatolisib-based combinations compared with fulvestrant monotherapy (31.5 percent [triplet] and 28.3 percent [doublet] vs 1 percent).
The median duration of response (DoR) for the gedatolisib triplet and doublet regimens was 17.5 and 12 months, respectively, whereas it was not reached in the in the fulvestrant group.
In terms of safety, the rates of serious treatment-related adverse events (TRAEs) were 10.8, 9.2, and 0.8 percent in the gedatolisib triplet, gedatolisib doublet, and fulvestrant monotherapy groups, respectively.
The most common grade 3 TRAE associated with gedatolisib-based therapy was stomatitis (19.2 percent [triplet] and 12.3 percent [doublet]), but most cases improved within 1–2 weeks. [ESMO Breast Cancer 2026, abstract 505P]
Notably, the rates of hyperglycaemia and diarrhoea observed with the gedatolisib-based regimens were low, which was unexpected for a drug targeting the PAM pathway, noted the researchers.
“VIKTORIA-1 is the first study to demonstrate a statistically significant and clinically meaningful improvement in PFS with PAM inhibition. These results validate the PAM pathway as a molecular driver in PIK3CA-WT disease,” the researchers said.
“The addition of gedatolisib to fulvestrant, with or without palbociclib, represents a potential new standard of care in this patient population,” they added.