Alpelisib or inavolisib?

INAVO120 placed inavolisib + palbociclib + fulvestrant as 1L for PIK3CA-mutant HR+/HER2- metastatic breast cancer in patients who progressed on adjuvant endocrine therapy or within 12 months of completing it. Alpelisib + fulvestrant retains use in later lines or where the inavolisib triplet is not feasible. Inavolisib has a more favorable hyperglycemia profile.

Tissue NGS or ctDNA for PIK3CA testing?

Both are validated. Tissue NGS (FoundationOne CDx, Tempus xT, Caris) gives the broader genomic picture. Plasma ctDNA (Guardant360 CDx, FoundationOne Liquid CDx) is faster and the FDA companion diagnostic pathway for alpelisib eligibility. Use tissue when available; reflex to ctDNA when tissue is exhausted or inadequate.

Capivasertib vs alpelisib?

Different drug targets (capivasertib targets all three AKT isoforms; alpelisib targets PI3Kα). CAPItello-291 covered a broader AKT pathway-altered population (PIK3CA, AKT1, PTEN). Capivasertib's AE profile (diarrhea, rash) differs from alpelisib's (hyperglycemia, rash). Sequencing depends on prior lines and AE history.

Variant cheat sheet · HR+ HER2- breast cancer

PIK3CA mutations in HR+/HER2- breast cancer

Free clinical reference. Educational use only — not a substitute for professional medical advice.

TL;DR

PIK3CA hotspot mutations (H1047R, E545K, E542K) in HR+/HER2- metastatic breast cancer are AMP/ASCO/CAP Tier I-A. Alpelisib + fulvestrant (SOLAR-1) is established after progression on endocrine therapy. Inavolisib + palbociclib + fulvestrant (INAVO120) is the newer 1L metastatic option for endocrine-resistant tumors. Hyperglycemia and rash are class-effect PI3K inhibitor toxicities requiring active management.

Biology

PIK3CA encodes the p110α catalytic subunit of class I PI3K. Hotspot activating mutations (helical domain E542K, E545K; kinase domain H1047R) constitutively activate the PI3K/AKT pathway, driving proliferation and resistance to endocrine therapy. PIK3CA-mutant tumors are vulnerable to alpha-selective PI3K inhibition (alpelisib, inavolisib).

Epidemiology

PIK3CA hotspot mutations occur in ~30-40% of HR+/HER2- breast cancers, one of the most common actionable alterations in this subtype.

Detection

NGS panels (FoundationOne CDx, Tempus xT, Caris) report PIK3CA mutations with hotspot annotation.
Plasma ctDNA (Guardant360 CDx, FoundationOne Liquid CDx) — companion diagnostic for alpelisib.
Single-gene PCR companion diagnostics also exist (therascreen PIK3CA).

FDA-approved targeted therapies

Drug	Indication	Line	Tier
Alpelisib + fulvestrant	PIK3CA-mutant HR+/HER2- metastatic breast post-endocrine (SOLAR-1)	2L+	I-A
Inavolisib + palbociclib + fulvestrant	PIK3CA-mutant HR+/HER2- metastatic, endocrine-resistant 1L (INAVO120)	1L (post-endocrine resistance)	I-A
Capivasertib + fulvestrant	AKT pathway altered (PIK3CA, AKT1, PTEN) HR+/HER2- mBC post-aromatase inhibitor (CAPItello-291)	2L+	I-A

Tier = AMP/ASCO/CAP 2017 (Li MM et al., J Mol Diagn 2017). Drug names link to openFDA labels where available. Synthetic data; consult primary sources before treatment.

Resistance pathways

Loss of PTEN function — bypasses upstream PIK3CA blockade.
ESR1 mutations (endocrine resistance) — combination matters.
Bypass-track activation: AKT amplification, MTOR pathway.

Pharmacogenomics

Alpelisib commonly causes hyperglycemia; baseline HbA1c assessment and active glucose monitoring with proactive metformin initiation are standard. Rash (sometimes severe) requires aggressive prevention/management with antihistamines. Inavolisib has a more selective alpha-PI3K profile with lower hyperglycemia signal in INAVO120.

Frequently asked questions

Alpelisib or inavolisib?: INAVO120 placed inavolisib + palbociclib + fulvestrant as 1L for PIK3CA-mutant HR+/HER2- metastatic breast cancer in patients who progressed on adjuvant endocrine therapy or within 12 months of completing it. Alpelisib + fulvestrant retains use in later lines or where the inavolisib triplet is not feasible. Inavolisib has a more favorable hyperglycemia profile.
Tissue NGS or ctDNA for PIK3CA testing?: Both are validated. Tissue NGS (FoundationOne CDx, Tempus xT, Caris) gives the broader genomic picture. Plasma ctDNA (Guardant360 CDx, FoundationOne Liquid CDx) is faster and the FDA companion diagnostic pathway for alpelisib eligibility. Use tissue when available; reflex to ctDNA when tissue is exhausted or inadequate.
Capivasertib vs alpelisib?: Different drug targets (capivasertib targets all three AKT isoforms; alpelisib targets PI3Kα). CAPItello-291 covered a broader AKT pathway-altered population (PIK3CA, AKT1, PTEN). Capivasertib's AE profile (diarrhea, rash) differs from alpelisib's (hyperglycemia, rash). Sequencing depends on prior lines and AE history.