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Inavolisib: a second-generation PI3Kα inhibitor in HR+/HER2-negative breast cancer

Elaria Abdy1, Jean-Pierre Betancourt1, Supratik Kar1

  • 1Chemometrics and Molecular Modeling Laboratory, Department of Chemistry and Physics, Kean University, Union, NJ, USA.

Expert Opinion on Drug Metabolism & Toxicology
|July 24, 2026
PubMed
Abstract

Insights

Inavolisib shows promise for hormone receptor-positive breast cancer with PIK3CA mutations. This PI3Kα inhibitor improved progression-free and overall survival in a Phase III trial, offering a new targeted therapy option.

Area of Science:

  • Oncology
  • Pharmacology
  • Genetics

Background:

  • Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common subtype.
  • PIK3CA mutations activate PI3K/AKT/mTOR signaling, contributing to therapeutic resistance and relapse in up to 40% of patients.
  • There is a critical need for more selective and tolerable targeted therapies for this patient population.

Purpose of the Study:

  • To review the pharmacology, development, and therapeutic role of inavolisib, a novel PI3Kα-selective inhibitor.
  • To evaluate the efficacy and safety of inavolisib in combination therapy for HR+/HER2- breast cancer.
  • To discuss the potential of inavolisib in precision oncology.

Main Methods:

  • Review of preclinical studies on inavolisib's pharmacology, including its dual inhibitory and degradation activity against mutant p110α.
  • Analysis of data from the Phase III INAVO120 trial, assessing the addition of inavolisib to palbociclib and fulvestrant.
  • Examination of safety data, identifying common adverse events.

Main Results:

  • Inavolisib demonstrated improved isoform selectivity and reduced off-target toxicity compared to earlier agents in preclinical studies.
  • The addition of inavolisib to palbociclib and fulvestrant nearly doubled progression-free survival and extended overall survival by seven months in the INAVO120 trial.
  • The safety profile of inavolisib was manageable, with hyperglycemia and stomatitis being the most frequent adverse events.

Conclusions:

  • Inavolisib represents a significant advancement for PIK3CA-mutated HR+/HER2- breast cancer due to its PI3Kα selectivity and mutant p110α degradation.
  • Its demonstrated clinical activity and improved tolerability position inavolisib as a key therapeutic candidate.
  • Ongoing trials are exploring inavolisib in resistant disease, HER2-positive settings, and novel combinations, highlighting its evolving role in precision oncology.
Keywords:
HR+/HER2-negativeInavolisibPI3Kα inhibitorPIK3CA mutationbreast cancerendocrine resistancetargeted therapy

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