# PI3K/AKT-pathway inhibitor + endocrine therapy (± CDK4/6)

Source: https://onco.cc/pairings/pi3k-pathway-plus-endocrine/  
OnCo record `pi3k-pathway-plus-endocrine` (Pairing). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Blocking the PI3K growth pathway alongside hormone therapy works only when the tumour carries a mutation in that pathway, and works best early.

## Summary

This combination adds a PI3K or AKT pathway inhibitor, such as inavolisib, capivasertib or alpelisib, to endocrine therapy such as fulvestrant, sometimes with a CDK4/6 inhibitor, in HR-positive, HER2-negative breast cancer. PI3K pathway activation is a dominant escape from oestrogen receptor dependence, so blocking both removes the tumour's two survival inputs and works best early in the disease course. SOLAR-1 with alpelisib, CAPItello-291 with capivasertib and INAVO120 with inavolisib plus palbociclib and fulvestrant were all positive phase 3 trials, with benefit restricted to, or largest in, tumours carrying PIK3CA, AKT1 or PTEN alterations, and INAVO120 also showed an overall survival gain. Hyperglycaemia, rash and diarrhoea differ by agent and shape the choice between them.

## Fields

- Kind: Pairing
- Last checked: 2026-09-07
- Pairs: Inavolisib + Endocrine therapy (SERMs, AIs, SERDs)
- Type: combination
- Rationale: PI3K pathway activation is a dominant escape from ER dependence; combined blockade removes both survival inputs.
- Evidence: Three positive phase 3 trials with biomarker selection.

## Sources

- INAVO120: inavolisib-based therapy in PIK3CA-mutated advanced breast cancer (NEJM 2024): https://doi.org/10.1056/NEJMoa2404625
- CAPItello-291: capivasertib in hormone receptor-positive advanced breast cancer (NEJM 2023): https://doi.org/10.1056/NEJMoa2214131

## Connected records

- cancers: [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/)
- targets: [AKT](https://onco.cc/targets/akt/), [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/)
- drugs: [Alpelisib](https://onco.cc/drugs/alpelisib/), [Capivasertib](https://onco.cc/drugs/capivasertib/), [Fulvestrant](https://onco.cc/drugs/fulvestrant/), [Inavolisib](https://onco.cc/drugs/inavolisib/)
- pathways: [Oestrogen receptor signalling](https://onco.cc/pathways/er-signaling/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/)
- technologies: [Endocrine therapy (SERMs, AIs, SERDs)](https://onco.cc/technologies/endocrine-therapy/)

---
JSON: https://onco.cc/api/v1/entities/pi3k-pathway-plus-endocrine.json