# HR-positive metastatic breast cancer after CDK4/6 inhibitors

Source: https://onco.cc/cancers/hr-positive-metastatic-post-cdk46/  
OnCo record `hr-positive-metastatic-post-cdk46` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

When hormone-positive breast cancer grows through a CDK4/6 inhibitor, a blood test picks the next drug. Tumours with an acquired ESR1 mutation respond to the oral degraders elacestrant, camizestrant and imlunestrant; tumours with PIK3CA, AKT1 or PTEN changes to capivasertib, inavolisib or alpelisib; and once endocrine options run out, antibody-drug conjugates come before chemotherapy.

## Summary

Resistance to first-line endocrine therapy with a CDK4/6 inhibitor follows a few well-mapped routes. Aromatase inhibitors select for mutations in the ligand-binding domain of ESR1 (Y537S, D538G and others) that make the oestrogen receptor active without oestrogen; these are rare in untreated tumours, appear in a third or more of patients at progression and are best detected in circulating tumour DNA. PIK3CA mutations are present from the outset in about 40 percent, and AKT1 mutations and PTEN loss in a further tenth; loss of RB1, cyclin E amplification and FGFR alterations drive CDK4/6 resistance itself. Guidelines now ask for an ESR1 test on plasma at each progression and a PIK3CA, AKT1 and PTEN test on tissue or plasma before the second line.

For ESR1-mutant disease the oral degraders replaced fulvestrant. EMERALD randomised 478 patients to elacestrant or standard endocrine therapy and halved the risk of progression in the ESR1-mutant group (hazard ratio 0.55), giving the first oral SERD approval in January 2023. SERENA-6 changed the timing: 315 patients on an aromatase inhibitor and CDK4/6 inhibitor whose plasma showed a new ESR1 mutation before any scan showed growth were switched to camizestrant while continuing the CDK4/6 inhibitor, and progression-free survival rose from 9.2 to 16.0 months (hazard ratio 0.44). EMBER-3 (874 patients) showed imlunestrant beat standard endocrine therapy in ESR1-mutant disease (hazard ratio 0.62) and that imlunestrant with abemaciclib beat imlunestrant alone whatever the ESR1 status (hazard ratio 0.57); postMONARCH showed a modest gain from continuing CDK4/6 inhibition with abemaciclib and fulvestrant after progression (6.0 against 5.3 months); the PROTAC degrader vepdegestrant followed in 2026, and giredestrant with everolimus improved progression-free survival in evERA.

For the PI3K and AKT pathway, SOLAR-1 showed alpelisib with fulvestrant extends progression-free survival from 5.7 to 11.0 months in PIK3CA-mutant tumours at the cost of severe hyperglycaemia in about 37 percent; CAPItello-291 (708 patients) showed capivasertib with fulvestrant helps after a CDK4/6 inhibitor with a hazard ratio of 0.60 overall and 0.50 in tumours with a PIK3CA, AKT1 or PTEN alteration, and was approved in November 2023; INAVO120 moved the mutant-selective inhibitor inavolisib into the first line for PIK3CA-mutant disease relapsing during or soon after adjuvant endocrine therapy, with palbociclib and fulvestrant, extending progression-free survival from 7.3 to 15.0 months and overall survival from 27.0 to 34.0 months. After endocrine therapy is exhausted, trastuzumab deruxtecan comes before chemotherapy for HER2-low and ultralow tumours (DESTINY-Breast06), sacituzumab govitecan extends survival after chemotherapy (TROPiCS-02, 14.4 against 11.2 months) and datopotamab deruxtecan is an alternative (TROPION-Breast01). The order in which to use degraders, pathway inhibitors and antibody-drug conjugates is the open question.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: Endocrine-resistant metastatic breast cancer; ESR1-mutant breast cancer; PIK3CA-mutant breast cancer; AKT pathway-altered breast cancer; Second-line HR-positive metastatic breast cancer
- Tags: subtype-page
- Group: breast
- Burden: Nearly every patient treated with a CDK4/6 inhibitor and endocrine therapy for metastatic hormone receptor-positive disease eventually progresses, typically after two to three years; about four in ten tumours carry a PIK3CA mutation and a third or more acquire an ESR1 mutation under aromatase inhibitor pressure.
- Subtypes: ESR1-mutant disease acquired under aromatase inhibitors (oral SERDs); PIK3CA-mutant luminal disease (capivasertib, inavolisib, alpelisib); AKT1-mutant or PTEN-altered disease (capivasertib); Endocrine-sensitive relapse without a targetable mutation (fulvestrant with a second CDK4/6 inhibitor, or everolimus); HER2-low or HER2-ultralow luminal disease (trastuzumab deruxtecan); Endocrine-refractory disease (antibody-drug conjugates, then chemotherapy)
- Biomarkers: ESR1 mutation on circulating tumour DNA, retested at each progression; PIK3CA, AKT1 and PTEN alterations on tissue or plasma; HER2 immunohistochemistry score (0, ultralow, 1+, 2+); Oestrogen receptor persistence on rebiopsy of a metastasis; Germline BRCA1 and BRCA2 (PARP inhibitor eligibility); Glycated haemoglobin and glucose before PI3K or AKT inhibitors

## Standard of care

- ESR1-mutant disease after a CDK4/6 inhibitor: Elacestrant (EMERALD), imlunestrant (EMBER-3) or vepdegestrant; where available, a switch to camizestrant at the moment ESR1 appears in plasma while continuing the CDK4/6 inhibitor (SERENA-6). ([Elacestrant](https://onco.cc/drugs/elacestrant/), [EMERALD](https://onco.cc/trials/emerald/), [Imlunestrant](https://onco.cc/drugs/imlunestrant/), [EMBER-3](https://onco.cc/trials/ember-3/), [Camizestrant](https://onco.cc/drugs/camizestrant/), [SERENA-6](https://onco.cc/trials/serena-6/), [Vepdegestrant](https://onco.cc/drugs/vepdegestrant/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/))
- PIK3CA, AKT1 or PTEN alteration: Capivasertib with fulvestrant (CAPItello-291); alpelisib with fulvestrant for PIK3CA (SOLAR-1); inavolisib with palbociclib and fulvestrant for PIK3CA-mutant disease relapsing during or soon after adjuvant endocrine therapy (INAVO120). ([Capivasertib](https://onco.cc/drugs/capivasertib/), [CAPItello-291](https://onco.cc/trials/capitello-291/), [Alpelisib](https://onco.cc/drugs/alpelisib/), [SOLAR-1](https://onco.cc/trials/solar-1/), [Inavolisib](https://onco.cc/drugs/inavolisib/), [INAVO120](https://onco.cc/trials/inavo120/), [Fulvestrant](https://onco.cc/drugs/fulvestrant/))
- No targetable alteration: Fulvestrant with abemaciclib (postMONARCH), everolimus with exemestane, or another endocrine agent; giredestrant with everolimus is emerging (evERA). ([Abemaciclib](https://onco.cc/drugs/abemaciclib/), [postMONARCH](https://onco.cc/trials/postmonarch/), [Everolimus](https://onco.cc/drugs/everolimus/), [Exemestane](https://onco.cc/drugs/exemestane/), [evERA](https://onco.cc/trials/evera/))
- Endocrine-refractory, HER2-low or ultralow: Trastuzumab deruxtecan before chemotherapy (DESTINY-Breast06), then sacituzumab govitecan (TROPiCS-02) or datopotamab deruxtecan (TROPION-Breast01) after chemotherapy. ([Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [DESTINY-Breast06](https://onco.cc/trials/destiny-breast06/), [Sacituzumab govitecan](https://onco.cc/drugs/sacituzumab-govitecan/), [TROPiCS-02](https://onco.cc/trials/tropics-02/), [Datopotamab deruxtecan](https://onco.cc/drugs/datopotamab-deruxtecan/), [TROPION-Breast01](https://onco.cc/trials/tropion-breast01/), [HER2-low and HER2-ultralow](https://onco.cc/terms/her2-low/))
- Germline BRCA carriers: Olaparib (OlympiAD) or talazoparib (EMBRACA) in place of chemotherapy. ([Olaparib](https://onco.cc/drugs/olaparib/), [OlympiAD](https://onco.cc/trials/olympiad/), [Talazoparib](https://onco.cc/drugs/talazoparib/), [EMBRACA](https://onco.cc/trials/embraca/), [Germline BRCA mutation (gBRCA)](https://onco.cc/terms/gbrca-mutation/))

## State of the art

- A plasma ESR1 test now decides treatment, and SERENA-6 showed switching on the blood result before the scan changes works.
- Three oral SERDs and a PROTAC degrader are approved within four years of the first.
- Capivasertib and inavolisib brought the AKT and PI3K pathway under control with less hyperglycaemia than alpelisib.
- Antibody-drug conjugates sit ahead of chemotherapy in HER2-low luminal disease.

## Open problems

- No trial has compared the sequence of oral SERD, pathway inhibitor and antibody-drug conjugate.
- Whether to continue a CDK4/6 inhibitor after progression gives small gains and it is unclear for whom.
- PIK3CA and ESR1 mutations often coexist and the combinations to treat both are unproven.
- Hyperglycaemia, rash and diarrhoea limit pathway inhibitors in older patients.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Breast_cancer
- EMERALD (JCO 2022): https://doi.org/10.1200/JCO.22.00338
- CAPItello-291 (NEJM 2023): https://doi.org/10.1056/NEJMoa2214131
- INAVO120 (NEJM 2024): https://doi.org/10.1056/NEJMoa2404625
- SERENA-6 on ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT04964934

## Connected records

- drugs: [Abemaciclib](https://onco.cc/drugs/abemaciclib/), [Alpelisib](https://onco.cc/drugs/alpelisib/), [Atirmociclib](https://onco.cc/drugs/atirmociclib/), [Camizestrant](https://onco.cc/drugs/camizestrant/), [Capivasertib](https://onco.cc/drugs/capivasertib/), [Datopotamab deruxtecan](https://onco.cc/drugs/datopotamab-deruxtecan/), [Elacestrant](https://onco.cc/drugs/elacestrant/), [Everolimus](https://onco.cc/drugs/everolimus/), [Exemestane](https://onco.cc/drugs/exemestane/), [Fulvestrant](https://onco.cc/drugs/fulvestrant/), [Gedatolisib](https://onco.cc/drugs/gedatolisib/), [Giredestrant](https://onco.cc/drugs/giredestrant/), [Imlunestrant](https://onco.cc/drugs/imlunestrant/), [Inavolisib](https://onco.cc/drugs/inavolisib/), [Ipatasertib](https://onco.cc/drugs/ipatasertib/), [Olaparib](https://onco.cc/drugs/olaparib/), [Sacituzumab govitecan](https://onco.cc/drugs/sacituzumab-govitecan/), [Samuraciclib](https://onco.cc/drugs/samuraciclib/), [Talazoparib](https://onco.cc/drugs/talazoparib/), [Tersolisib](https://onco.cc/drugs/tersolisib/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Vepdegestrant](https://onco.cc/drugs/vepdegestrant/)
- trials: [A Randomised, Open-label, Multicentre Phase III Clinical Study to Evaluate the Efficacy and Safety of JS105 Combined With Dalpiciclib and Fulvestrant Compared With Dalpiciclib and Fulvestrant in Patients With PIK3CA-mutated, HR-positive, HER2-negative Recurrent or Metastatic Breast Cancer](https://onco.cc/trials/nct07207070/), [A Study Evaluating the Efficacy and Safety of Inavolisib Plus Fulvestrant Compared With Alpelisib Plus Fulvestrant in Participants With HR-Positive, HER2-Negative, PIK3CA Mutated, Locally Advanced or Metastatic Breast Cancer Post CDK4/6i and Endocrine Combination Therapy](https://onco.cc/trials/nct05646862/), [A Study of SIM0270 Combined With Everolimus vs. Treatment of Physician's Choice in Patients With ER+/HER2- Advanced Breast Cancer (SIMRISE)](https://onco.cc/trials/simrise/), [A Study of Tersolisib (LY4064809/STX-478) With Other Anti-Cancer Treatments in Participants With Advanced Breast Cancer With a Genetic Change (PIK3CA)](https://onco.cc/trials/pik3ca-2/), [A Study to Evaluate the Effect of GDC-4198 Alone and in Combination With Giredestrant Versus Abemaciclib and Giredestrant in Participants With Locally Advanced or Metastatic Estrogen Receptor-Positive (ER+), Human Epidermal Growth Factor Receptor-Negative (HER2-) Breast Cancer](https://onco.cc/trials/nct07100106/), [A Study to Learn About the Study Medicine Called PF-07248144 in Combination With Fulvestrant in People With HR-positive, HER2-negative Advanced or Metastatic Breast Cancer Who Progressed After a Prior Line of Treatment](https://onco.cc/trials/nct07062965/), [CAMBRIA-1 & CAMBRIA-2](https://onco.cc/trials/cambria/), [CAPItello-291](https://onco.cc/trials/capitello-291/), [DESTINY-Breast06](https://onco.cc/trials/destiny-breast06/), [EMBER-3](https://onco.cc/trials/ember-3/), [EMBRACA](https://onco.cc/trials/embraca/), [EMERALD](https://onco.cc/trials/emerald/), [evERA](https://onco.cc/trials/evera/), [INAVO120](https://onco.cc/trials/inavo120/), [OlympiAD](https://onco.cc/trials/olympiad/), [OP-1250 (Palazestrant) vs. Standard of Care for the Treatment of ER+/HER2- Advanced Breast Cancer](https://onco.cc/trials/nct06016738/), [Phase 3 Study of RLY-2608 + Fulvestrant vs Capivasertib + Fulvestrant as Treatment for Locally Advanced or Metastatic PIK3CA-mutant HR+/HER2- Breast Cancer](https://onco.cc/trials/nct06982521/), [postMONARCH](https://onco.cc/trials/postmonarch/), [Safety and Efficacy of SPH4336 in Combination With Endocrine Therapy in the Treatment of Locally Advanced or Metastatic Breast Cancer](https://onco.cc/trials/nct05860465/), [SERENA-6](https://onco.cc/trials/serena-6/), [SOLAR-1](https://onco.cc/trials/solar-1/), [Study to Assess the Efficacy and Safety of Alpelisib Plus Fulvestrant in Participants With HR-positive (HR+), HER2-negative, Advanced Breast Cancer After Treatment With a CDK4/6 Inhibitor and an Aromatase Inhibitor.](https://onco.cc/trials/nct05038735/), [TROPiCS-02](https://onco.cc/trials/tropics-02/), [TROPION-Breast01](https://onco.cc/trials/tropion-breast01/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- terms: [Germline BRCA mutation (gBRCA)](https://onco.cc/terms/gbrca-mutation/), [HER2-low and HER2-ultralow](https://onco.cc/terms/her2-low/)
- cancers: [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/)

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