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Last updated: September 26, 2026
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Find matching trials →The PI3K/AKT/mTOR pathway is a central intracellular signaling cascade that controls cell growth, survival, and metabolism. PIK3CA encodes p110α, the catalytic subunit of the enzyme PI3Kα. When PI3Kα is activated — frequently by an activating PIK3CA mutation — it produces the lipid second messenger PIP3, which recruits and activates AKT; AKT then activates mTOR and other effectors that drive proliferation, block apoptosis, and promote resistance to endocrine therapy. In HR+/HER2- breast cancer, PIK3CA is mutated in about 40% of tumors — the most common actionable alteration in this subtype — and PTEN loss or AKT1 mutations activate the same pathway in additional tumors.
A PI3K/AKT pathway inhibitor is a small-molecule oral drug that blocks one node of this cascade:
These drugs are given in combination with endocrine therapy (usually fulvestrant), and increasingly with a CDK4/6 inhibitor, where they restore sensitivity to hormone blockade and prolong progression-free survival — alpelisib (SOLAR-1), capivasertib (CAPItello-291), and inavolisib (INAVO120) each improved PFS in their pivotal trials, establishing the pathway as the backbone of biomarker-directed therapy after or alongside CDK4/6 inhibitors in HR+/HER2- breast cancer.
| Drug | Sponsor | Class / Target | Regulatory Status |
|---|---|---|---|
| Alpelisib (Piqray, BYL719) | Novartis | PI3Kα inhibitor (first-in-class) | FDA May 2019: PIK3CA-mutant HR+/HER2- metastatic breast + fulvestrant (SOLAR-1). The first PI3Kα inhibitor in breast cancer. |
| Capivasertib (Truqap, AZD5363) | AstraZeneca | Pan-AKT inhibitor (AKT1/2/3) | FDA Nov 2023: HR+/HER2- metastatic breast with PIK3CA / AKT1 / PTEN alterations + fulvestrant (CAPItello-291). |
| Inavolisib (Itovebi, GDC-0077) | Genentech / Roche | PI3Kα inhibitor + mutant-p110α degrader | FDA Oct 2024: PIK3CA-mutant, endocrine-resistant HR+/HER2- advanced breast + palbociclib + fulvestrant (INAVO120). |
| Zovegalisib (RLY-2608) | Relay Therapeutics | Allosteric mutant-selective PI3Kα inhibitor | Investigational — FDA Breakthrough Therapy designation Sep 2026 for PIK3CA-mutant HR+/HER2- advanced breast. Now Phase 3 vs capivasertib + fulvestrant. |
| Tersolisib (LY4064809 / STX-478) | Scorpion Therapeutics / Eli Lilly | Mutant-selective PI3Kα inhibitor | Investigational. Phase 3 in PI3Kα-mutant advanced breast; designed to spare wild-type PI3Kα. |
| Gedatolisib (Revtorpyk) | Celcuity | Pan-PI3K / mTOR inhibitor | Investigational. Phase 3 as 1L treatment in HR+/HER2- advanced breast (VIKTORIA program). |
| TOS-358 · LOXO-783 · ETX-636 | Totus · Lilly · MapKure/others | Next-gen / mutant-selective PI3Kα | Investigational (Phase 1/2). Early-phase PIK3CA-mutant solid-tumor and breast programs. |
Everolimus (Afinitor, mTOR inhibitor) + exemestane (BOLERO-2) is also FDA-approved in HR+/HER2- breast but is not PIK3CA-biomarker-selected, so it sits alongside rather than within this biomarker-directed class. AKT inhibitor ipatasertib and others had limited recruiting breast trials in the September 2026 corpus.
A PI3Kα inhibitor differentiated by also promoting degradation of mutant p110α. FDA October 2024 for PIK3CA-mutant, endocrine-resistant HR+/HER2- locally advanced or metastatic breast cancer in combination with palbociclib (a CDK4/6 inhibitor) and fulvestrant, based on INAVO120, which roughly doubled progression-free survival vs palbociclib + fulvestrant alone in this high-risk, rapidly-relapsing population. Key recruiting trials in the corpus: NCT06790693 (inavolisib + CDK4/6 inhibitor + letrozole vs placebo + CDK4/6i + letrozole in PIK3CA-mutant HR+/HER2- breast, Phase 3 — extending the triplet into 1L); NCT05646862 and NCT05894239 (inavolisib + fulvestrant-based combinations, Phase 3); NCT05306041 (neoadjuvant endocrine therapy ± inavolisib, Phase 2); NCT07054190 (inavolisib in early-stage disease, Phase 2).
A pan-AKT inhibitor (AKT1/2/3) that acts one step downstream of PI3K, so it treats tumors driven by any of a broader biomarker set. FDA November 2023 for HR+/HER2- advanced/metastatic breast cancer with one or more PIK3CA, AKT1, or PTEN alterations, in combination with fulvestrant, based on CAPItello-291 (improved PFS in the biomarker-altered population). Dominant toxicities are diarrhea and rash (less hyperglycemia than alpelisib). Key recruiting trials in the corpus: NCT07281833 (Phase 3 capivasertib combination in advanced breast); NCT05720260 (immunotherapy + hormone therapy + AKT inhibitor in premenopausal ER+ breast, Phase 2); and the head-to-head NCT06982521 (zovegalisib + fulvestrant vs capivasertib + fulvestrant, Phase 3).
The first-in-class PI3Kα inhibitor. FDA May 2019 for PIK3CA-mutant HR+/HER2- advanced/metastatic breast cancer in combination with fulvestrant after progression on endocrine therapy, based on SOLAR-1. Its dose-limiting toxicity — hyperglycemia, from inhibition of wild-type PI3Kα in normal metabolic tissue — is the specific problem the newer mutant-selective agents aim to solve. Key recruiting trials in the corpus: NCT06545682 (alpelisib + pembrolizumab in metastatic breast, Phase 1b); NCT05660083 (alpelisib + iNOS inhibitor + nab-paclitaxel in HER2-negative / triple-negative metastatic breast, Phase 2).
The lead of the emerging wave: an allosteric, pan-mutant, isoform-selective PI3Kα inhibitor that binds a cryptic pocket near the ATP site to preferentially block mutant PI3Kα while largely sparing the wild-type enzyme — the design intended to reduce hyperglycemia and rash. FDA Breakthrough Therapy designation September 2026 for PIK3CA-mutant HR+/HER2- advanced breast cancer, supported by the Phase 1/2 ReDiscover trial (durable progression-free survival with fulvestrant in pretreated patients, including SERD-pretreated and ESR1-mutant subsets). Key recruiting trials in the corpus: NCT06982521 (Phase 3 zovegalisib + fulvestrant vs capivasertib + fulvestrant — the first head-to-head of a mutant-selective PI3Kα inhibitor against an approved AKT inhibitor); NCT05216432 (first-in-human study of RLY-2608 as monotherapy and in combinations). Investigational; not yet FDA-approved.
Another mutant-selective PI3Kα inhibitor engineered to spare wild-type PI3Kα and reduce the metabolic toxicity of first-generation agents. Key recruiting trials in the corpus: NCT07174336 (tersolisib with other anti-cancer treatments in advanced breast cancer with a PI3Kα mutation, Phase 3, including CDK4/6-inhibitor combinations); NCT05768139 (first-in-human study of tersolisib as monotherapy and in combination, Phase 1/2). Other early-phase mutant-selective / next-generation PI3Kα programs in the corpus include TOS-358 (NCT05683418), LOXO-783 (NCT05307705), and ETX-636 (NCT06993844); the pan-PI3K/mTOR inhibitor gedatolisib is in Phase 3 as 1L treatment (NCT06757634). All investigational.
The 55+ recruiting PI3K/AKT-pathway trials are grouped below by clinical setting. Nearly all are in HR+/HER2- breast cancer, where PIK3CA (~40%), AKT1, and PTEN alterations define the treated population; a few extend into neoadjuvant/early-stage and triple-negative disease. Access is biomarker-gated, so a current PIK3CA / AKT1 / PTEN result (tumor NGS or ctDNA) is usually required to screen.
The INAVO120 triplet (inavolisib + palbociclib + fulvestrant) is FDA-approved for endocrine-resistant PIK3CA-mutant disease; the current Phase 3 wave pushes PI3K/AKT-pathway drugs into the 1L combination with a CDK4/6 inhibitor + endocrine backbone, and tests a pan-PI3K/mTOR agent as 1L therapy.
After progression on 1L CDK4/6i + endocrine therapy, PI3K/AKT-pathway inhibition is the leading biomarker-directed option: capivasertib for PIK3CA/AKT1/PTEN-altered tumors, inavolisib for PIK3CA-mutant, and the emerging mutant-selective PI3Kα agents — including the first head-to-head against an approved AKT inhibitor.
A cluster of first-in-human and Phase 1/2 programs is racing to deliver a mutant-selective PI3Kα inhibitor with the efficacy of alpelisib but far less hyperglycemia — the toxicity that limits real-world PI3K-inhibitor use.
Beyond metastatic disease, PI3K/AKT-pathway inhibitors are being tested in the neoadjuvant/early-stage setting and, for AKT and select PI3Kα combinations, in HER2-negative / triple-negative breast cancer.
Showing curated highlights from 55+ RECRUITING PI3K/AKT-pathway interventional breast-cancer trials in the ClinTrialFinder corpus as of September 26, 2026. Trial phase, status, and eligibility change — verify on ClinicalTrials.gov. For the latest searches: inavolisib, capivasertib, alpelisib, zovegalisib (RLY-2608), tersolisib.
The central limitation of first-generation PI3Kα inhibition is on-target, off-tumor toxicity. Wild-type PI3Kα mediates insulin signaling in normal liver, muscle, and fat, so a drug that blocks both mutant and wild-type PI3Kα (like alpelisib) inevitably causes hyperglycemia — often dose-limiting, sometimes requiring anti-diabetic medication, and a frequent reason patients stop treatment. Rash is a second class effect. This toxicity, not lack of efficacy, is the main barrier to real-world PI3K-inhibitor use.
The field's response, and the reason this class is a 2026 frontier:
Resistance and cross-talk also shape how these drugs are sequenced:
The net effect: PIK3CA/AKT1/PTEN status is becoming a routine, decision-critical biomarker in HR+/HER2- breast cancer, and the mutant-selective wave aims to make targeting it far more tolerable.
What is a PI3K/AKT pathway inhibitor and how does it work?
The PI3K/AKT/mTOR pathway is a central growth-and-survival signaling cascade. PIK3CA encodes p110α, the catalytic subunit of PI3Kα; when activated (often by a PIK3CA mutation), PI3K generates PIP3, which activates AKT, which activates mTOR — driving proliferation, survival, and endocrine resistance. In HR+/HER2- breast cancer, PIK3CA is mutated in ~40% of tumors, the most common actionable alteration. A PI3K/AKT inhibitor is an oral drug that blocks one node: a PI3Kα inhibitor (alpelisib, inavolisib, and mutant-selective zovegalisib/tersolisib) blocks the mutant enzyme; an AKT inhibitor (capivasertib) blocks the downstream kinase, covering PIK3CA, AKT1, or PTEN alterations. They are given with endocrine therapy (usually fulvestrant), where they restore hormone-therapy sensitivity and prolong progression-free survival.
Which PI3K/AKT inhibitors are FDA-approved for breast cancer?
Alpelisib (Piqray, Novartis): FDA May 2019, the first PI3Kα inhibitor, PIK3CA-mutant HR+/HER2- metastatic + fulvestrant (SOLAR-1). Capivasertib (Truqap, AstraZeneca): FDA Nov 2023, a pan-AKT inhibitor, HR+/HER2- metastatic with PIK3CA/AKT1/PTEN alterations + fulvestrant (CAPItello-291). Inavolisib (Itovebi, Genentech/Roche): FDA Oct 2024, a PI3Kα inhibitor that also degrades mutant p110α, PIK3CA-mutant endocrine-resistant HR+/HER2- advanced breast + palbociclib + fulvestrant (INAVO120). Everolimus (Afinitor, mTOR inhibitor) + exemestane (BOLERO-2) is also approved but not PIK3CA-selected. A PIK3CA/AKT1/PTEN biomarker test is required for alpelisib, capivasertib, and inavolisib; consult current FDA prescribing information.
What's the difference between a PI3K inhibitor and an AKT inhibitor (inavolisib vs capivasertib vs alpelisib)?
They act at different nodes. Alpelisib and inavolisib are PI3Kα inhibitors — they block PI3K itself and are used in PIK3CA-mutant tumors (inavolisib also degrades mutant p110α and has an FDA-approved triplet with palbociclib + fulvestrant). Capivasertib is a pan-AKT inhibitor — it blocks the kinase downstream of PI3K, covering a broader biomarker group (PIK3CA, AKT1, or PTEN). Toxicity differs: PI3Kα inhibitors (especially alpelisib) cause hyperglycemia and rash because they also hit wild-type PI3Kα; capivasertib causes more diarrhea and less hyperglycemia. The newest mutant-selective PI3Kα inhibitors (zovegalisib, tersolisib) are designed to spare wild-type PI3Kα to reduce hyperglycemia. Choice depends on biomarker, prior therapy, and diabetes risk.
What are mutant-selective PI3Kα inhibitors like zovegalisib and tersolisib, and why do they matter?
First-generation PI3Kα inhibitors (alpelisib) block both mutant and wild-type PI3Kα; inhibiting wild-type PI3Kα (which controls insulin signaling) causes dose-limiting hyperglycemia. Mutant-selective agents preferentially block the mutant enzyme while sparing wild-type, aiming to keep efficacy while cutting hyperglycemia and rash. Zovegalisib (RLY-2608, Relay Therapeutics) is an allosteric, pan-mutant, isoform-selective PI3Kα inhibitor that received FDA Breakthrough Therapy designation in September 2026 for PIK3CA-mutant HR+/HER2- advanced breast (Phase 1/2 ReDiscover, ~11-month median PFS with fulvestrant in pretreated patients) and is now in Phase 3 (NCT06982521) head-to-head vs capivasertib + fulvestrant. Tersolisib (LY4064809/STX-478, Scorpion/Lilly) is another mutant-selective PI3Kα inhibitor in Phase 3 (NCT07174336). Both are investigational, not yet FDA-approved.
What biomarker testing do I need (PIK3CA, AKT1, PTEN)?
Access is biomarker-gated. Alpelisib and inavolisib require a PIK3CA mutation; capivasertib requires a PIK3CA, AKT1, or PTEN alteration (broader). Testing is done on tumor tissue (NGS of an archival or fresh biopsy) or blood (ctDNA liquid biopsy, including FDA-cleared companion diagnostics) — ctDNA is convenient and captures the metastatic clone, though tissue may confirm a negative blood result. PIK3CA is mutated in ~40% of HR+/HER2- breast, AKT1 in ~3-6%, PTEN loss in ~5%. Because these alterations can emerge under prior endocrine/CDK4/6i therapy, re-testing at progression (not relying only on the original biopsy) is often recommended. Bring your most recent NGS or ctDNA report when screening for trials.
How is hyperglycemia from PI3K inhibitors managed?
Hyperglycemia is the signature PI3Kα-inhibitor toxicity (most pronounced with alpelisib) because the drug also inhibits wild-type PI3Kα, which mediates insulin's effect on glucose. Management: check fasting glucose and HbA1c before starting and monitor during treatment; optimize any pre-existing diabetes first (poorly controlled diabetes is often a trial exclusion); prophylactic or reactive metformin as first-line, with SGLT2 inhibitors increasingly used; carbohydrate moderation; and dose interruption/reduction for severe or persistent hyperglycemia. AKT inhibitors (capivasertib) cause less hyperglycemia, and the mutant-selective PI3Kα inhibitors (zovegalisib, tersolisib) are designed to reduce it. Manage hyperglycemia with your oncology team and, when needed, an endocrinologist — never adjust these medicines on your own.
Find Matching PI3K/AKT Pathway Inhibitor Trials
Use ClinTrialFinder's AI-powered matching to find inavolisib (Itovebi), capivasertib (Truqap), alpelisib (Piqray), zovegalisib (RLY-2608), tersolisib, and other PI3K/AKT-pathway trials based on your cancer type, HR/HER2 status, biomarker profile (PIK3CA, AKT1, PTEN), prior CDK4/6-inhibitor and endocrine therapy, and country.
Find Matching PI3K/AKT Pathway TrialsThis page is for information only and is not medical advice. ClinTrialFinder helps you find clinical trials that may match your situation, but enrollment decisions and treatment choices should always be made with your medical oncologist. Trial eligibility, recruitment status, and treatment details can change — verify directly with the trial sponsor or on ClinicalTrials.gov before acting on any information here. FDA approval dates and indications are summarized for context only; consult the current FDA prescribing information for each drug for authoritative regulatory status.