# CDK4/6 inhibitor + endocrine therapy

Source: https://onco.cc/pairings/cdk46-plus-endocrine/  
OnCo record `cdk46-plus-endocrine` (Pairing). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Cut the fuel (oestrogen) and jam the engine (CDK4/6) at the same time.

## Summary

This combination pairs CDK4/6 inhibitors with Endocrine therapy (SERMs, AIs, SERDs) in HR-positive / HER2-negative breast cancer, cutting the fuel and jamming the engine at once. The mechanism is that the oestrogen receptor drives cyclin D1 transcription, so blocking CDK4/6 shuts the downstream engine and residual ER signalling or an ESR1 mutation cannot bypass it, linking the Oestrogen receptor signalling and p53 / RB / cell-cycle checkpoint pathways. Multiple phase 3 trials (MONALEESA, MONARCH 2) showed improved progression-free and overall survival in advanced disease, and NATALEE and monarchE showed adjuvant benefit. The linked drugs are Palbociclib, Ribociclib and Abemaciclib, and the pairing is regarded as one of the most successful combinations in oncology.

## Fields

- Kind: Pairing
- Last checked: 2026-09-04
- Pairs: CDK4/6 inhibitors + Endocrine therapy (SERMs, AIs, SERDs)
- Type: combination
- Rationale: ER drives cyclin D1 transcription; CDK4/6 inhibition blocks the downstream engine so that residual ER signalling or ESR1 mutation cannot bypass it.
- Evidence: Multiple phase 3 with OS benefit.

## Sources

- NATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancer (New England Journal of Medicine 2024): https://doi.org/10.1056/NEJMoa2305488

## Connected records

- cancers: [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/)
- drugs: [Abemaciclib](https://onco.cc/drugs/abemaciclib/), [Palbociclib](https://onco.cc/drugs/palbociclib/), [Ribociclib](https://onco.cc/drugs/ribociclib/)
- pathways: [Oestrogen receptor signalling](https://onco.cc/pathways/er-signaling/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/)
- technologies: [CDK4/6 inhibitors](https://onco.cc/technologies/cdk46-inhibitor/), [Endocrine therapy (SERMs, AIs, SERDs)](https://onco.cc/technologies/endocrine-therapy/)

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