ABOUT 6 IN 10 PEOPLE with hormone receptor-positive, HER2-negative metastatic breast cancer have tumors without a detectable PIK3CA mutation. This lack of mutations makes them ineligible for some treatments that target the PI3K/AKT/mTOR (PAM) pathway.

However, a newly approved therapy that targets multiple parts of the PAM pathway, may expand treatment options for these patients once their cancer has progressed on endocrine therapy.

On July 14, 2026, the Food and Drug Administration (FDA) approved the PAM inhibitor Revtorpyk (gedatolisib) when given with the endocrine therapy fulvestrant, with or without the CDK4/6 inhibitor Ibrance (palbociclib), for adults with locally advanced or metastatic hormone receptor-positive, HER2-negative breast cancer that has progressed on endocrine therapy and lacks mutations in the PIK3CA gene.

The FDA based its approval on the results from a phase III study published March 9, 2026, in the Journal of Clinical Oncology involving 392 people with locally advanced inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer that did not have a detectable PIK3CA mutation and that had progressed on or after treatment with an aromatase inhibitor plus a CDK4/6 inhibitor. Participants received one of three treatments: a triplet regimen of Revtorpyk, fulvestrant and Ibrance; a doublet regimen of Revtorpyk and fulvestrant; or fulvestrant alone.

At a median follow-up of 10.1 months, people on the triplet had lived a median of 9.3 months without progression or death, compared with two months for people receiving fulvestrant alone. People on the doublet had lived 7.4 months without progression or death, which was also an improvement over fulvestrant alone. Although the median progression-free survival was numerically longer in the triplet group than in the doublet group, the trial was designed to compare each of the Revtorpyk treatments with fulvestrant alone, not each other, notes Yara Abdou, a breast medical oncologist at UNC Lineberger Comprehensive Cancer Center, in Chapel Hill, North Carolina, who was not involved in the trial. “We therefore cannot conclude from these numbers that adding [Ibrance] improves outcomes,” she says. Overall survival results are not yet mature.

People with hormone receptor-positive, HER2-negative advanced breast cancer, typically receive endocrine therapy plus a CDK4/6 inhibitor as an initial treatment. But most cancers eventually progress.

“At that point, treatment becomes much more individualized,” Abdou says. Doctors consider the patient’s past treatments and how the cancer responded, its rate of progression, its location, and whether it has any mutations that would make it susceptible to a particular targeted therapy.

One treatment strategy targets the PI3K/AKT/mTOR signaling pathway, which is involved in cell growth and survival. “PI3K receives growth signals and helps activate AKT, which then influences mTOR and other proteins that promote cell growth and survival,” Abdou explains.

Different PAM inhibitors target different proteins in the PAM pathway. Piqray (alpelisib) and Itovebi (inavolisib) target PI3K. Truqap (capivasertib) targets AKT, and Afinitor (everolimus), targets mTOR.

Revtorpyk, in contrast, targets both PI3K and mTOR. “What’s unique about this is that it is much more completely inhibiting this pathway, which is very active in the majority of breast cancer that’s hormone receptor positive, but is doing so without leading to insurmountable toxicity,” says Sara Hurvitz, a medical oncologist at Fred Hutch Cancer Center, in Seattle. Hurvitz is the lead investigator of the phase III clinical trial that led to the drug’s approval.

The FDA approved some PAM inhibitors exclusively in cancers with targetable mutations. The FDA approved Piqray and Itovebi for breast cancers with PIK3CA mutations. Truqap is approved for breast cancers with alterations in PIK3CA, AKT or PTEN. Afinitor, on the other hand, was approved without regard to a particular mutation. The new approval gives people whose breast cancer lacks a detectable PIK3CA mutation another targeted treatment option after progression on endocrine therapy.

“The toxicity that stands out most with [Revtorpyk] is stomatitis,” Abdou says. Stomatitis refers to mouth sores. Trial participants in the Revtorpyk groups used a steroid-containing mouthwash to prevent mouth sores, and Revtorpyk’s label instructs everyone receiving the drug to do the same. Other side effects to monitor include rash and hyperglycemia, or high blood sugar, Abdou says. For people who also received Ibrance, neutropenia, or low levels of white blood cells called neutrophils, was an additional side effect. “I would characterize the safety profile as manageable, but not trivial,” Abdou says.

Since the FDA approved Revtorpyk with fulvestrant with or without Ibrance, patients and clinicians must decide whether to add the CDK4/6 inhibitor. Abdou says that she would make the decision with each patient individually, considering how the patient had tolerated previous CDK4/6 inhibitors, the characteristics of their disease, their comorbidities, and their preferences.

Ashley P. Taylor is a writer and science journalist based in New York City.