The PI3K/AKT/mTOR (PAM) pathway is a major treatment resistance pathway in HR+/HER2- metastatic breast cancer (MBC) and an important therapeutic target after CDK4/6 inhibitor progression. At the recent 2026 ASCO Annual Meeting, data from several studies on gedatolisib, inavolisib, alpelisib, and emerging mutant-specific PI3K inhibitors were presented.

Following these presentations, featured expert Adam M. Brufsky, MD, PhD, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Brufsky on these findings are presented here.

The PI3K pathway is a very important biologic pathway. It has a lot to do with metabolic signaling in the body, particularly because PI3K is part of INSR signaling. This biology is important clinically because the same pathway that can drive cancer resistance can also create toxicity when it is inhibited. PI3K goes through AKT and then mTOR, so we often think of this as the PAM pathway.

Why is this important in HR+/HER2- MBC? It turns out that this is one of the primary treatment resistance pathways that cells develop over time. Most of us will treat patients with a CDK4/6 inhibitor and endocrine therapy in the first-line metastatic setting. After anywhere from 2 to 5 years, some patients do really well for a long time, but many ultimately develop resistance and progression. One of the primary drivers of that progression is the activation of the PAM pathway.

Alpelisib was the first major PI3K inhibitor to be developed in this space, and it nearly doubled progression-free survival (PFS) when it was added to fulvestrant in patients with HR+/HER2- MBC with PIK3CA mutations who had progressed on endocrine therapy. The problem was substantial hyperglycemia. In fact, 36.6% of patients in the alpelisib and fulvestrant group had grade 3 or 4 hyperglycemia because the drug was inhibiting INSR signaling and causing insulin resistance.

Capivasertib, an AKT inhibitor, was the next major advance for patients with HR+/HER2- MBC. The idea was that by targeting downstream AKT rather than PI3K itself, there might be less hyperglycemia. This has largely been the case, although capivasertib has more rash and a little bit more diarrhea associated with its use than alpelisib does. In current practice, many of us use capivasertib for patients with PIK3CA pathway alterations after CDK4/6 inhibitor progression.

Against this background, at ASCO 2026, the biggest news related to the PI3K pathway was the success of gedatolisib. Gedatolisib is an intravenous combination mTOR and PI3K inhibitor, given weekly, 3 weeks out of 4. The important issue is how it may fit in the treatment of patients with HR+/HER2- MBC after progression on CDK4/6 inhibition, including in those with or without PIK3CA-mutated disease.

In the VIKTORIA-1 trial, data presented previously in patients with PIK3CA wild-type advanced breast cancer showed that those on the triplet of gedatolisib, palbociclib, and fulvestrant had a median PFS (mPFS) of 9.3 months vs 2 months for those on fulvestrant alone, and patients on the doublet of gedatolisib and fulvestrant had an mPFS of 7.4 months. Even with recognizing that some people may question the control arm, these outcomes were better than just about anything we had in the wild-type setting.

Data from VIKTORIA-1 presented at ASCO 2026 by Sara A. Hurvitz, MD, FACP, extended the question of whether gedatolisib could improve outcomes across PI3K pathway subgroups, including in patients with PIK3CA mutations for whom alpelisib plus fulvestrant was already a standard targeted option (abstract LBA1008). Patients on the gedatolisib triplet had an mPFS of 11.1 months vs 5.6 months for those on alpelisib and fulvestrant. That is pretty much a doubling of PFS. Nothing that we have in our field has done this. I do not know whether it is a “home run,” but I think that it is a good “double”—maybe even a “triple.” It is a substantial improvement of outcomes.

The main drawback is that gedatolisib is an intravenous drug, while most of the agents we use now are oral medications. However, on the other hand, a doubling of PFS is something that I think is truly a game changer. Assuming that FDA regulatory approval proceeds in the wild-type setting, these PIK3CA-mutant data could become the basis for a supplemental application and may meaningfully change second-line treatment.

Inavolisib is another oral PI3K inhibitor, and it is an option for patients with HR+/HER2- disease who progress very rapidly in the first-line metastatic setting. In the INAVO120 trial, patients with PIK3CA-mutated, HR+/HER2-, endocrine-resistant advanced breast cancer received fulvestrant, inavolisib, and palbociclib together, and the triplet demonstrated PFS and overall survival advantages. At ASCO 2026, INAVO120 subgroup analyses of Asian patients presented by Yoon Sim Yap, PhD, MBBS, FRACP, showed efficacy that was consistent with the overall study population and no new safety signals (abstract 28). This reinforces the benefit of this regimen in patients with PIK3CA-mutated endocrine-resistant disease when they are first diagnosed with metastatic disease and the importance of testing patients for a PIK3CA mutation to see whether they are eligible for inavolisib therapy.

A practical point is that PIK3CA mutations are often truncal. They are there from the beginning, going back to the primary tumor. If you do not find the mutation on a liquid biopsy, you can often go back to the primary tumor to look for the mutation.

A poster presented at this year’s ASCO meeting that raised an especially interesting question was on the CAPTURE study, which compared alpelisib plus fulvestrant with capecitabine in patients with PIK3CA-mutated ER+/HER2- advanced breast cancer and was presented by Eileen Geoghegan, MBBS (abstract 1064). Capecitabine “won” by a lot. It was not a huge trial, but it raises the question of whether we should sometimes use capecitabine first and use the PI3K inhibitor later.

Looking ahead, I would like to see more data on mutant-specific PI3K inhibitors. These agents are designed to bind only to mutant PI3K, and, in theory, they should have fewer side effects because they do not bind to wild-type PI3K, which is involved in INSR signaling. At ASCO 2026, ReDiscover-2 was presented by Hope S. Rugo, MD, FASCO, as a trials-in-progress study of one of these mutant-specific PI3Kα inhibitors for HR+/HER2- MBC (abstract TPS1148). We do not have those data yet, but I think that this is where a lot of us want to see the field go.