Investigational Drug
Ipatasertib
TrialFetch AI Analysis
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Overview
Ipatasertib (GDC-0068; RG7440) is an oral, ATP-competitive pan-AKT inhibitor (AKT1/2/3) developed to target tumors with PI3K/AKT pathway activation (e.g., PTEN loss, PIK3CA or AKT1 alterations). It has been studied across solid tumors, with the most advanced data in metastatic castration‑resistant prostate cancer (mCRPC) and triple‑negative breast cancer (TNBC). (aacrjournals.org)
Mechanism of action
- Selective, ATP-competitive inhibitor that preferentially binds active, phosphorylated AKT; pharmacodynamic studies in first‑in‑human biopsies confirmed inhibition of downstream targets (PRAS40, GSK3β, mTOR). (aacrjournals.org)
Efficacy
Prostate cancer (mCRPC) - Phase II (ipatasertib + abiraterone vs placebo + abiraterone, post‑docetaxel): rPFS improved numerically overall; greater effect in PTEN‑loss tumors. (pubmed.ncbi.nlm.nih.gov) - Phase III IPATential150 (first‑line mCRPC): in the prespecified PTEN‑loss (IHC) subgroup, ipatasertib + abiraterone improved radiographic PFS vs placebo + abiraterone (median 18.5 vs 16.5 months; HR 0.77, 95% CI 0.61–0.98; P=0.0335). No rPFS benefit in PTEN‑intact tumors. Exploratory NGS suggested larger benefit in tumors with PIK3CA/AKT1/PTEN alterations. Final overall survival (OS) analysis (median follow‑up 33.9 months) showed no OS improvement in PTEN‑loss or intention‑to‑treat populations. Selected exploratory NGS subsets (e.g., PIK3CA/AKT1/PTEN‑altered) showed signals but require validation. (ascopubs.org)
Triple‑negative breast cancer (TNBC) - Phase II LOTUS (first‑line ipatasertib + paclitaxel vs placebo + paclitaxel): improved PFS in the ITT population (median 6.2 vs 4.9 months; HR 0.60, 95% CI 0.37–0.98) with a larger effect in PIK3CA/AKT1/PTEN‑altered tumors; OS showed a numerical but not statistically significant trend at final reporting. (mdanderson.elsevierpure.com) - Phase III IPATunity130 Cohort A (biomarker‑selected, PIK3CA/AKT1/PTEN‑altered advanced TNBC): negative for PFS (HR 1.02; median 7.4 vs 6.1 months) and OS (HR 1.08). (aacrjournals.org)
Neoadjuvant TNBC (early disease) - Phase II FAIRLANE (ipatasertib + paclitaxel vs placebo + paclitaxel, 12 weeks): no significant improvement in pathologic complete response in the ITT (17% vs 13%), PTEN‑low, or PIK3CA/AKT1/PTEN‑altered subgroups. (pubmed.ncbi.nlm.nih.gov)
Safety
- Class‑consistent adverse events include diarrhea, rash, and hyperglycemia; most were grade 1–2 in early studies, with dose‑dependent increases at higher exposures. (aacrjournals.org)
- In combinations:
- With abiraterone (IPATential150): higher rates of grade 3/4 AEs and drug discontinuations vs placebo; diarrhea, hyperglycemia, rash, and transaminase elevations were more frequent and tended to occur early (median onset 8–43 days). Overall safety considered tolerable with supportive care. (pubmed.ncbi.nlm.nih.gov)
- With paclitaxel (LOTUS): grade ≥3 diarrhea occurred in 23% with ipatasertib vs 0% with placebo; other grade ≥3 events included neutropenia/neutrophil count decreased. (mdanderson.elsevierpure.com)
- Phase I combination work corroborated diarrhea, hyperglycemia, and rash as ipatasertib‑associated events; recommended phase II doses in combinations were 400 mg with paclitaxel and 600 mg with mFOLFOX6. (pubmed.ncbi.nlm.nih.gov)
Development status (as of October 2025)
- In mCRPC, phase III rPFS benefit was limited to the PTEN‑loss subgroup by IHC, but final OS was negative; exploratory genomics may refine selection. (sciencedirect.com)
- In TNBC, the biomarker‑selected phase III study was negative, tempering earlier phase II signals. (aacrjournals.org)
Further reading
- First‑in‑human pharmacology and mechanism: Cancer Discovery 2016. (aacrjournals.org)
- Phase II mCRPC (ipatasertib + abiraterone) with PTEN biomarker analyses: Clinical Cancer Research 2018/2019. (aacrjournals.org)
- IPATential150 biomarker and outcome analyses (ASCO/ESMO abstracts and final OS in European Urology 2025). (ascopubs.org)
- LOTUS phase II TNBC (Lancet Oncology 2017) and final OS update (Breast Cancer Research and Treatment 2021). (mdanderson.elsevierpure.com)
- IPATunity130 phase III TNBC (Clinical Cancer Research 2024). (aacrjournals.org)
- FAIRLANE neoadjuvant TNBC (Annals of Oncology 2019). (pubmed.ncbi.nlm.nih.gov)
Notes: Key quantitative results and safety data above come from peer‑reviewed journals and major conference abstracts. Where exploratory biomarker findings are noted, these require prospective validation.
Last updated: Oct 2025
Active trials using Ipatasertib
Found 4 active trials using this drug:
TrialFetch AI summary: Eligible patients are adults with advanced or metastatic non-breast solid tumors harboring activating PTEN or AKT alterations who have progressed on or within 6 months of taxane-based therapy and have not received prior AKT inhibitors. Participants receive paclitaxel plus ipatasertib, an oral selective pan-AKT inhibitor, until progression or unacceptable toxicity.
ClinicalTrials.gov ID: NCT05554380
TrialFetch AI summary: Biomarker-driven platform for adults with recurrent/persistent endometrial carcinoma after 1–2 prior lines, assigning patients by FoundationOne CDx to targeted doublets with or without the PD‑L1 inhibitor atezolizumab. Active cohorts include atezolizumab plus talazoparib for high genomic LOH, atezolizumab plus anti‑TIGIT tiragolumab for MSI‑H/high TMB tumors, inavolisib (PI3Kα inhibitor) plus letrozole for PIK3CA‑mutant tumors without PTEN/AKT1 alterations, and giredestrant (oral SERD) plus abemaciclib for ER‑positive, RB1‑intact disease.
ClinicalTrials.gov ID: NCT04486352
TrialFetch AI summary: This trial enrolls postmenopausal women with advanced ER+ and/or HER2+ breast cancer who have progressed after standard therapies into multiple cohorts based on subtype, randomizing them to investigational combinations featuring the oral SERD giredestrant (estrogen receptor degrader), CDK7 inhibitor samuraciclib, pan-AKT inhibitor ipatasertib, PI3K inhibitor inavolisib, HER2-targeted agents, immune checkpoint blockade (atezolizumab), and/or standard partners. Patients must have good performance status and meet strict eligibility criteria, with adaptive assignment to novel regimens as new data emerge.
ClinicalTrials.gov ID: NCT04802759
TrialFetch AI summary: This umbrella study enrolls adults with metastatic or inoperable locally advanced breast cancer across molecular subtypes (including first- and second-line triple-negative, HR+ PIK3CA-mutant, and HER2+/HER2-low PIK3CA-mutant disease) to randomized arms of standard therapies or novel combinations featuring agents such as atezolizumab (PD-L1 inhibitor), ipatasertib (pan-Akt inhibitor), inavolisib (PI3K inhibitor), sacituzumab govitecan (Trop-2–directed ADC), ladiratuzumab vedotin (anti-LIV-1 ADC), and selicrelumab (CD40 agonist antibody). Treatments are assigned by subtype and prior therapy, with crossover options for select cohorts upon progression.
ClinicalTrials.gov ID: NCT03424005
