Benefits Persist With Inavolisib in Breast Cancer

New findings from the phase 3 INAVO120 trial underscore the durable benefits of inavolisib added to standard therapy for PIK3CA-mutated hormone receptor–positive (HR+) human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer. 

The drug, in combination with palbociclib and fulvestrant, was approved in October 2024 by the US Food and Drug Administration based on previously published progression-free survival benefits.

Now, mature overall survival (OS) results and longer follow-up strengthen evidence for the triplet combination, said lead author and oncologist, Nicholas C. Turner, MD, PhD, during a press conference for the American Society of Clinical Oncology (ASCO) 2025 annual meeting. 

“Importantly, this is the first time that OS has been improved by a PI3 kinase pathway targeted drug…we delayed the time to chemotherapy by almost 2 years, and the adverse event profile was consistent with previous reports, with low inavolisib discontinuation rates due to adverse events,” said Turner. 

The INAVO120 trial included 325 patients with HR+ HER2− advanced breast cancer and a PIK3CA-mutation who had either failed hormone therapy or progressed within 1 year.

Patients were randomized to either standard therapy consisting of palbociclib and fulvestrant (placebo, n = 164) or the triplet combination that included standard therapy plus inavolisib (n = 161).

With a median follow-up now up 34.2 months, the study showed a 33% reduction in the risk of death in the inavolisib arm, translating to an OS of 34 months compared with 27 months in the placebo group (stratified hazard ratio [sHR] 0.67; P = .0190), he reported, in the press conference.

“We also looked at an endpoint that is really important for patients, which is the time until they have to consider chemotherapy-based care, and this was substantially improved…with almost a 2-year delay on average, to the time of needing to have chemotherapy,” he said. 

Specifically, while patients in the placebo group needed chemotherapy at a median of 12.6 months, this was delayed until 35.6 months in the inavolisib group (sHR, 0.43).

Additionally, the previously published primary endpoint of median progression-free survival, which strongly favored inavolisib after a follow-up of roughly 21 months, (15.0 vs 7.3 months, sHR 0.43; P < .001) was maintained with longer follow-up (17.2 vs 7.3 months; sHR, 0.42).

With the extended time on therapy, adverse events remained “generally manageable,” said Turner, although he cautioned “this is not a drug without side effects.”

In total, 90.7% of patients in the inavolisib arm, and 84.7% in the placebo arm had grade 3/4 adverse events. Hyperglycemia (any grade) was experienced by 63.4% of the inavolisib group and 13.5% of the placebo group, and adverse events leading to discontinuation occurred in 6.8% and 0.6% or trial participants in each of the groups, respectively.

Previously, attempts to combine PI3K inhibitors with CDK4/6 inhibitors were not possible because side-effects were much worse, explained Turner. But the specificity of inavolisib has decreased that risk.

“So, that maximizes your ability to hit PI3 kinase in the tumor while relatively sparing normal cells in the body and reducing side effects,” Turner said, during the press conference.

Commenting on the study, ASCO chief medical officer and spokesperson Judy Gralow, MD, said she was particularly impressed with the therapy’s benefit on time to next chemotherapy.

“Delaying the need, in the metastatic setting, to go on chemotherapy by almost 2 years is certainly an outcome that matters to patients,” she said. “It is clear that, at least in a majority of breast cancers at the time of recurrence, we should be testing for PIK3CA mutations, as well as other alterations that direct therapy.”

However, she cautioned that the triplet therapy is only indicated in a subset of PIK3CA-mutated HR+ HER2− advanced breast cancer: namely those who have progressed either during, or within a year of hormone therapy. “So, this is not all comers, [such as] patients who had tumors that 5 years later, 7 years later, showed evidence of recurrence.”

Calling the study results “a big step forward” for this patient group, Jane Lowe Meisel, MD, co-director, Breast Medical Oncology, at the Winship Cancer Institute of Emory University School of Medicine, Atlanta, said the study “illustrates the importance of genomic testing at the time of diagnosis of hormone receptor–positive metastatic breast cancer, so that patients with PIK3CA mutations who qualify for this approach can be readily identified.” 

Turner disclosed consulting or advisory roles with AstraZeneca, Exact Sciences, Gilead Sciences, GlaxoSmithKline, Guardant Health, Inivata, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Relay Therapeutics, Repare Therapeutics, and Roche. He also received research funding with AstraZeneca; Guardant Health; Inivata; Invitae; Merck Sharpe & Dohme; Natera; Personalis; Pfizer; and Roche. 

Meisel disclosed consulting or advisory roles with AstraZeneca, GE Healthcare, Genentech, Novartis, Olema Oncology, Pfizer, Seagen, Sermonix Pharmaceuticals, and Stemline. She also disclosed research funding from AstraZeneca, Olema Oncology, Pfizer, Seagen, and Sermonix Pharmaceuticals. 

Gralow disclosed having no conflicts of interest. 

The study was funded by F. Hoffmann–La Roche and a grant (P30CA008748) to the Memorial Sloan Kettering Cancer Center. 

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