Dr Ma on the Use of AKT Inhibitors vs PI3K Inhibitors in Breast Cancer

Cynthia Ma, MD, PhD, medical oncologist, Siteman Cancer Center, Washington University Medical Campus, discusses the use of AKT inhibitors vs PI3K inhibitors in breast cancer.

At the 2023 Bridging the Gaps in Breast Cancer meeting, Ma delved into an in-depth exploration of the pivotal role played by the PI3K pathway in breast cancer tumorigenesis, shedding light on this pathway’s involvement in mediating resistance to both endocrine therapy and CDK4/6 inhibitors. Focusing specifically on estrogen receptor-positive breast cancer, the discussion encompassed various genetic alterations, including mutations in PIK3CA and AKT, as well as loss-of-function mutations of p10. Furthermore, the phenomenon of hyperactivation resulting from pathway rewiring subsequent to the administration of CDK4/6 inhibitors and endocrine therapy was examined.

In response to these insights, a multitude of agents are currently in development that target the PI3K pathway. Alpelisib (Vijoice), a selective PI3K inhibitor, secured FDA approval in 2019 for patients with hormone receptor (HR)–positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer based on data from the phase 3 SOLAR-1 trial (NCT02437318) and the subsequent phase 2 BYLieve study(NCT03056755). In these trials, alpelisib generated progression-free survival advantages, even in patients who had previously received CDK4/6 inhibitors, Ma explains.

The November 2023 FDA approval of capivasertib (Truqap) plus fulvestrant (Faslodex)for patients with advanced HR-positive HER2-negative breast cancer with PIK3CA, AKT1, or PTEN alterations was backed by findings from the phase 3 CAPItello-291 study (NCT04305496). This regulatory decision marks a noteworthy development in this treatment paradigm, Ma expands. Additionally, the consideration of mTOR inhibitors in breast cancer adds another layer of complexity to the therapeutic arena, she says.

The complexity of potential mechanisms of resistance to alpelisib or capivasertib was examined throughout the discission at the meeting, with an understanding that certain alterations may signify resistance and indicate a potential sensitivity to an AKT inhibitor, she states. This nuanced perspective invites contemplation on the replacement potential of AKT inhibitors, particularly considering their safety profile, which is more tolerable than that of other agents, Ma notes.