Investigational Drug
Ipatasertib
TrialFetch AI Analysis
Show TrialFetch AI Analysis
Overview
Ipatasertib (RG7440; GDC-0068) is an investigational, orally administered small-molecule AKT inhibitor developed for cancers with activation of the PI3K–AKT pathway, particularly tumors with PTEN loss or PIK3CA/AKT1/PTEN alterations. It has been evaluated in breast, prostate, gastric and other solid tumors. Although some phase II and III studies showed progression-free survival signals, confirmatory trials have not demonstrated consistent efficacy or an overall-survival benefit. Clinical investigation is continuing in selected settings. (aacrjournals.org)
Mechanism of action
Ipatasertib is a selective, ATP-competitive inhibitor of all three AKT isoforms—AKT1, AKT2 and AKT3—with preferential activity against phosphorylated, active AKT. Inhibition reduces signaling through downstream proteins including PRAS40, GSK3β, 4E-BP1, S6 and mTOR, pathways involved in tumor-cell growth, metabolism and survival. First-in-human pharmacodynamic studies confirmed pathway inhibition in tumor biopsies. (aacrjournals.org)
Efficacy
- Metastatic triple-negative breast cancer: In the 124-patient phase II LOTUS trial, ipatasertib plus paclitaxel improved median progression-free survival (PFS) to 6.2 months versus 4.9 months with placebo plus paclitaxel (HR 0.60). Objective response rates were 40% versus 32%. The signal appeared stronger in genomically altered tumors, but subgroup sizes were small. (pmc.ncbi.nlm.nih.gov)
- Confirmatory breast-cancer trial: In the 255-patient phase III IPATunity130 trial restricted to PIK3CA/AKT1/PTEN-altered advanced triple-negative breast cancer, the LOTUS result was not confirmed. Median PFS was 7.4 versus 6.1 months (HR 1.02), and median overall survival was 24.4 versus 24.9 months (HR 1.08). (pubmed.ncbi.nlm.nih.gov)
- Metastatic castration-resistant prostate cancer: In the 1,101-patient phase III IPATential150 trial, adding ipatasertib to abiraterone and corticosteroid increased median radiographic PFS from 16.5 to 18.5 months among patients whose tumors had PTEN loss by immunohistochemistry (HR 0.77). The improvement in the overall population did not meet the prespecified significance threshold. Final analysis found no overall-survival benefit, including in the PTEN-loss population (HR 0.94). Exploratory genomic subgroups remain hypothesis-generating. (pubmed.ncbi.nlm.nih.gov)
- Other settings: Ipatasertib did not improve PFS when added to mFOLFOX6 for advanced gastric or gastroesophageal-junction cancer. In the neoadjuvant FAIRLANE trial, addition to paclitaxel did not increase the pathological complete-response rate in early triple-negative breast cancer. (pubmed.ncbi.nlm.nih.gov)
Safety
The principal toxicities reflect AKT-pathway inhibition and include diarrhea, rash and hyperglycemia, with nausea, fatigue and appetite loss also reported. In IPATunity130, grade 3 or higher diarrhea occurred in 9% versus 2%, and dose reductions in 39% versus 14%, although overall grade 3 or higher adverse-event rates were similar (51% versus 46%). (pubmed.ncbi.nlm.nih.gov)
In IPATential150, grade 3–5 adverse events occurred in approximately 70% of patients receiving ipatasertib–abiraterone versus 39% with control treatment. Treatment discontinuation due to adverse events occurred in 21% versus 5%; severe diarrhea, hyperglycemia and rash were prominent toxicities. Two treatment-related deaths were reported in the ipatasertib group, from hyperglycemia and chemical pneumonitis. (annalsofoncology.org)
Further reading
- First-in-human phase I study
- LOTUS phase II trial
- IPATunity130 phase III trial
- IPATential150 primary phase III results
- IPATential150 final overall-survival analysis
Last updated: Sep 2026
Active trials using Ipatasertib
Found 3 active trials using this drug:
TrialFetch AI summary: Patients with measurable recurrent or persistent endometrial carcinoma after 1–2 prior systemic therapies are assigned to biomarker-matched cohorts. Open cohorts evaluate atezolizumab (anti–PD-L1) plus talazoparib (PARP inhibitor) for high genomic loss of heterozygosity or tiragolumab (anti-TIGIT) for MSI-high/high-TMB tumors, and inavolisib (PI3Kα inhibitor) plus letrozole for PIK3CA-mutant tumors or giredestrant (ER degrader) plus abemaciclib (CDK4/6 inhibitor) for RB1-intact, low-grade ER-positive tumors.
ClinicalTrials.gov ID: NCT04486352
TrialFetch AI summary: For patients with inoperable locally advanced or metastatic ER-positive breast cancer, treatment cohorts include HER2-negative disease after CDK4/6 inhibitor–containing endocrine therapy, HER2-positive disease after trastuzumab–taxane and HER2-directed therapy, and HER2-negative, PIK3CA-mutated disease recurring during or shortly after adjuvant endocrine therapy. Arms test giredestrant, an investigational oral estrogen receptor degrader, alone or with CDK4/6, PI3K, AKT, mTOR, or CDK7 inhibitors, atezolizumab, and/or pertuzumab–trastuzumab, depending on cohort.
ClinicalTrials.gov ID: NCT04802759
TrialFetch AI summary: Adults with metastatic or inoperable locally advanced breast cancer are assigned by subtype and treatment history to regimens for PD-L1-positive or previously treated TNBC, PIK3CA-mutated HR-positive/HER2-negative disease, or PIK3CA-mutated HER2-positive/HER2-low disease. Treatments include atezolizumab-based combinations or capecitabine for TNBC, as well as investigational AKT inhibitor ipatasertib, LIV-1–directed antibody–drug conjugate ladiratuzumab vedotin, or CD40 agonist selicrelumab; PIK3CA-mutated cohorts receive investigational PI3K inhibitor inavolisib with endocrine/CDK4/6 therapy or trastuzumab deruxtecan.
ClinicalTrials.gov ID: NCT03424005
