ipatasertib (RG7440) / Roche, Pfizer - LARVOL DELTA

Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy (clinicaltrials.gov) - P1/2 | N=273 | Completed | Sponsor: Genentech, Inc. | Active, not recruiting ➔ Completed

Trial completion • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs • PTEN

CNS distribution and preclinical activity of the PI3K/AKT inhibitors inavolisib and ipatasertib in pediatric-type diffuse high-grade gliomas. (PubMed, Cancer Chemother Pharmacol) - "These findings highlight the therapeutic potential of inavolisib for treating PIK3CA-mutated pHGG. Despite the blood-brain barrier, inavolisib achieved sufficient CNS exposure to prolong survival in preclinical models, whereas ipatasertib efficacy did not translate from in vitro to in vivo settings."

Journal • Preclinical • Brain Cancer • Diffuse Midline Glioma • Glioma • High Grade Glioma • Oncology • Pediatrics • Solid Tumor • PIK3CA

CLINICAL OUTCOMES WITH TRASTUZUMAB EMTANSINE OR IPATASERTIB PLUS PACLITAXEL FOR PERSISTENT/RECURRENT RARE EPITHELIAL OVARIAN CARCINOMAS: ENGOT-GYN2/GOG-3051/BOUQUET PHASE 2 BIOMARKER-DIRECTED STUDY (IGCS 2024) - P2 | "Ipatasertib+paclitaxel demonstrated more encouraging activity. The tolerability of both regimens was consistent with previous experience."

Biomarker • Clinical • Clinical data • P2 data • Oncology • Ovarian Cancer • Solid Tumor • AKT1 • HER-2 • PIK3CA • PTEN

NRG-GY027: Testing the Addition of Ipatasertib to the Usual Chemotherapy Treatment (Paclitaxel and Carboplatin) for Stage III or IV Epithelial Ovarian Cancer (clinicaltrials.gov) - P1 | N=25 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Feb 2026 ➔ Feb 2027

Trial completion date • Epithelial Ovarian Cancer • Fallopian Tube Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • HRD

A phase Ib, open-label study evaluating the safety and efficacy of ipatasertib plus rucaparib in patients with metastatic castration-resistant prostate cancer. (PubMed, Clin Cancer Res) - P1 | "Ipatasertib plus rucaparib was manageable with dose modification but did not demonstrate synergistic or additive antitumor activity in previously treated patients with mCRPC."

Journal • Metastases • Genito-urinary Cancer • Hematological Disorders • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor

A phase 2 study of ipatasertib in combination with pembrolizumab for first-line treatment of recurrent or metastatic squamous cell cancer of the head and neck. (ASCO 2026) - P2 | "I+P demonstrated an acceptable safety profile and shows promising clinical activity in R/M HNSCC."

Clinical • Combination therapy • Metastases • P2 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

The Rome trial from histology to target: The road to personalize targeted therapy and immunotherapy (ESMO 2024) - P2 | "The most frequently assigned TTs were IPI/NIVO (37%), ipatasertib (16%), pemigatinib (8%), TDM1 (8%), and atezo/ipatasertib (6%). The ROME Trial demonstrated that a mutational-based treatment approach based on the MTB discussion of CGP results may significantly improve ORR and PFS compared to SoC in pretreated patients with metastatic solid tumors, particularly with immunotherapy."

IO biomarker • Late-breaking abstract • Tumor mutational burden • Biliary Cancer • Biliary Tract Cancer • Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Glioblastoma • Oncology • Solid Tumor • FGFR • HER-2 • PIK3CA • PTEN

Ipatasertib plus Paclitaxel for patients with PIK3CA/AKT1/PTEN-Altered Locally Advanced Unresectable or Metastatic Triple-Negative Breast Cancer in the IPATunity130 Phase III Trial. (PubMed, Clin Cancer Res) - "Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered advanced TNBC. Biomarkers for benefit from PI3K/AKT pathway inhibition in TNBC remain poorly understood."

Journal • Metastases • P3 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AKT1 • PIK3CA • PTEN

Ipatasertib and atezolizumab in cancers with increased PI3K-AKT pathway activity: First results from the CRAFT trial (ESMO 2023) - P2 | "Conclusions Ipatasertib and atezolizumab were ineffective in this patient population with PI3K-AKT-altered tumors. More stringent molecular selection criteria and an addition trial arm were implemented (arm 5)."

IO biomarker • Brain Cancer • Breast Cancer • Genito-urinary Cancer • HER2 Breast Cancer • Oncology • Prostate Cancer • Solid Tumor • ALK • BRAF • HER-2 • PIK3CA • PTEN

Activation of the AKT pathway and outcomes in patients (pts) treated with or without ipatasertib (ipat) in metastatic castration-resistant prostate cancer (mCRPC): Next-generation sequencing (NGS) data from the phase III IPATential150 trial. (ASCO 2022) - P3 | "Background: Ipat + abiraterone (abi) significantly reduced the risk of radiographic disease progression vs placebo (pbo) + abi in pts with mCRPC and PTEN loss tumors by immunohistochemistry (IHC; HR, 0.77; 95% CI: 0.61, 0.98; P=0.034) but not in ITT pts (HR, 0.84; 95% CI: 0.71, 0.99; P=0.043; Sweeney Lancet 2021)... Pts with mCRPC were randomized 1:1 to ipat (400 mg/d) + abi (1000 mg/d) + prednisone (5 mg bid) or pbo + abi + prednisone... At the second IA, no significant improvement in OS was observed with ipat + abi in pts with PTEN loss by IHC. Exploratory analyses in pts with PIK3CA/AKT1/PTEN alterations by NGS suggest that these patients have poorer prognosis but may derive greater benefit from ipat + abi."

Biomarker • Clinical • Next-generation sequencing • P3 data • Genito-urinary Cancer • Oncology • Pain • Prostate Cancer • Solid Tumor • PIK3CA • PTEN

SOLTI-1507 IPATHER: Primary results of the phase Ib study of ipatasertib (IPAT) and dual anti-HER2 therapy with trastuzumab and pertuzumab (HP) in patients (pts) with PIK3CA mutant (mut) HER2+ advanced breast cancer (ABC) (ESMO-BC 2024) - P1 | "Conclusions Maintenance treatment with IPAT 400mg + HP following CT had an acceptable safety profile and showed promising efficacy in pts with PIK3CAmut HER2+ ABC. Combining a PI3K/AKT pathway inhibitor with anti-HER2 treatment in this setting merits further evaluation."

Clinical • Late-breaking abstract • Metastases • P1 data • Breast Cancer • Fatigue • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • PIK3CA

A double-blind placebo controlled randomized phase III trial of fulvestrant and ipatasertib as treatment for advanced HER2-negative and estrogen receptor positive (ER+) breast cancer following progression on first line CDK 4/6 inhibitor and aromatase inhibitor: The CCTG/BCT MA.40/FINER study (NCT04650581). (ASCO 2025) - P3 | "Ipatasertib plus fulvestrant significantly prolongs PFS compared to placebo/fulvestrant in patients with hormone receptor–positive MBC post progression on 1st line CDK 4/6 inhibitor and AI. Follow-up and additional analyses continue. Supported by Hoffmann-La Roche Ltd, CCS grant #707213."

Clinical • Late-breaking abstract • Metastases • P3 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Fatigue • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA • PTEN

Final Overall Survival and Molecular Data Associated with Clinical Outcomes in Patients Receiving Ipatasertib and Abiraterone in the Phase 3 IPATential150 Trial. (PubMed, Eur Urol) - "Ipatasertib addition to abiraterone did not improve OS for men with mCRPC, regardless of PTEN status on IHC. Exploratory biomarker analyses identified additional genomic alterations of potential clinical relevance for AKT blockade in mCRPC that require further validation in prospective studies."

Clinical data • Journal • P3 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AKT1 • PIK3CA • PTEN

CTEP 10492, a phase 1/1b study of the AKT inhibitor ipatasertib with chemoradiation for locally advanced head and neck squamous cell carcinoma. (ASCO 2024) - P1 | "Preclinical evidence suggests that both radiation therapy (RT) and cisplatin activate the PI3K/AKT pathway, leading to treatment resistance through multiple processes, including increased DNA repair, decreased apoptosis, and modulation of the tumor microenvironment by promoting angiogenesis, immune escape and hypoxia. Additional correlative studies include assessment of the pharmacokinetic profile of ipatasertib with CRT, as well as correlation of efficacy with tumor genotype, based on whole exome sequencing of pre-treatment biopsy specimens. Enrollment is currently at dose level 2 in the escalation phase, and is expected to complete accrual in 2025."

Metastases • P1 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • AKT1S1

Trial in Progress: CTEP 10492, A Phase 1/1b Study of the AKT Inhibitor Ipatasertib with Chemoradiation for Locally Advanced Head and Neck Squamous Cell Carcinoma (ASTRO 2024) - P1 | "Preclinical evidence suggests that both radiation therapy (RT) and cisplatin activate the PI3K/AKT pathway, leading to treatment resistance through multiple processes, including increased DNA repair, decreased apoptosis, and modulation of the tumor microenvironment by promoting angiogenesis, immune escape and hypoxia. Enrollment is currently at dose level 2 in the escalation phase, and is expected to complete accrual in 2025."

Metastases • P1 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • AKT1S1 • PIK3CA • PTEN

Characterization of anticancer drug transport and binding mechanisms through HSA using multi-technique approaches | Poster Board #1161 (ACS-Fall 2026) - "The anticancer drugs investigated include Ipatasertib (IPA), Brigatinib (BRIGA), and Binimetinib (BINI). In addition, clinically relevant combinations such as Cobimetinib with Vemurafenib and Dabrafenib with Vemurafenib are analyzed to assess potential synergistic effects or interactions with HSA. Furthermore, antimelanoma drugs encapsulated in self-assembled nanomicelles are explored using theoretical approaches such as COSMOmic, supporting the development of advanced drug delivery systems."

Oncology • Solid Tumor

Preliminary evidence of antitumor activity of Ipatasertib (Ipat) and Atezolizumab (A) in glioblastoma (GBM) patients (pts) with PTEN loss in the Phase 1 Ice-CAP trial (NCT03673787) (AACR 2023) - P1/2 | "One exceptional responder, a 58yr male refractory to radical chemo-radiotherapy and Bevacizumab had a resection of enhancing disease after 5 cycles that showed >70% depletion of CD4+ T regulatory cells with an increase in CD8+ lymphocyte infiltration and no residual evidence of tumor (pathological CR). In contrast, a non-responding patient who proceeded to debulking surgery had no change in infiltration of CD8+ lymphocytes, but a marked increase (>27-fold) in CD4+ regulatory T cells.Conclusion The RP2D of 400mg Ipa OD + 1200mg A Q3W was well tolerated in GBM pts. Early efficacy signals were detected with PTEN loss being a promising predictive biomarker for response to combination."

Clinical • IO biomarker • P1 data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CD4 • CD8 • FOXP3 • PTEN

Cancer-associated fibroblasts potentiate subcutaneous tumor growth in a novel bladder cancer mouse model with a genotype dependency (AACR 2023) - "We found that Pten-KO base organoids were 9x more sensitive to ipatasertib than Pten WT organoids...IHC staining of 9p21/Trp53 KO tumors for CD206 and CD11c revealed greater recruitment of M2 macrophages than M1 macrophages.Conclusions CAFs remodel the tumor-microenvironment in bladder cancer via the recruitment of pro-tumorigenic M2 macrophages. This may occur in a genotype-specific manner and 9p21 loss may be a requirement for some genotypes to be tumorigenic."

Preclinical • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CAFs • CDKN2A • CDKN2B • ITGAX • MRC1 • MTAP • PTEN • PTPRC • RB1 • TP53

Cancer associated fibroblast dependency in a model of bladder cancer (AACR 2024) - "These organoids were co-edited for Trp53 and Rb1 KO, and further editing of the Pten gene resulted in a nine-fold increase in sensitivity to the kinase inhibitor ipatasertib...While TSC1/TSC2 KO lines exhibited elevated P-S6K signaling, they displayed resistance to Torin 1, Voxtalisib, and Everolimus—kinase inhibitors targeting mTORC1/2. Our research establishes the crucial role of CAFs in bladder tumor formation. Our now established customizable model of bladder cancer is suitable for direct targeting by kinase inhibitors while providing a platform for understanding the genotype-phenotype relationship in bladder cancer."

Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CAFs • PIK3CA • PTEN • RB1 • TSC1 • TSC2

Cancer associated fibroblast dependency in a model of muscle invasive bladder cancer (AACR 2025) - "Further editing of the Pten gene resulted in a nine-fold increase in sensitivity to the kinase inhibitor ipatasertib, while a Pikc3a H1047R hotspot mutation sensitized organoids up to 2000-fold to the Pik3 inhibitor pictilisib. Our research demonstrates the importance of CAFs in bladder cancer progression. Through further examining the mechanistic interplays between CAFs and immunoregulation, we can gain a better understanding of the main drivers and potential targets in bladder tumorigenesis."

Bladder Cancer • Genito-urinary Cancer • Oncology • Skin Cancer • Solid Tumor • CAFs • CSF2 • IL6 • PTEN • RB1 • TGFB1 • TP53

Study of Chemotherapy Plus Ipatasertib for People With Solid Tumors With PTEN/AKT Mutations, A ComboMATCH Treatment Trial (clinicaltrials.gov) - P2 | N=33 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Aug 2026 ➔ Feb 2027 | Trial primary completion date: Aug 2026 ➔ Feb 2027

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • AKT2 • PTEN

Study of Chemotherapy Plus Ipatasertib for People With Solid Tumors With PTEN/AKT Mutations, A ComboMATCH Treatment Trial (clinicaltrials.gov) - P2 | N=33 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Active, not recruiting

Enrollment closed • Oncology • Solid Tumor • AKT2 • PTEN

AKT Inhibitor, Ipatasertib, With Endocrine and CDK 4/6 Inhibitor for Patients With Metastatic Breast Cancer (TAKTIC) (clinicaltrials.gov) - P1 | N=77 | Active, not recruiting | Sponsor: Massachusetts General Hospital | Trial completion date: Jul 2026 ➔ Aug 2027

Trial completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Emerging Strategies Targeting the PI3K/AKT/mTOR Pathway in HR+/HER2- Advanced Breast Cancer. (PubMed, Drugs) - "Isoform-specific PI3K inhibitors, including alpelisib and inavolisib, have demonstrated clinically meaningful progression-free survival benefits in PIK3CA-mutated populations, with inavolisib showing improved tolerability and efficacy. In contrast, pan-PI3K inhibitors such as buparlisib have been constrained by toxicity. Targeting downstream signaling, AKT inhibitors have also shown benefit: capivasertib has demonstrated clinical efficacy leading to US Food and Drug Administration approval, while ipatasertib has yielded encouraging results, particularly in tumors harboring PIK3CA, AKT1, or PTEN alterations. Mammalian target of rapamycin inhibitors, notably everolimus, have shown efficacy irrespective of mutation status. The dual PI3K-mTOR inhibitor (gedatolisib) has also shown promising progression-free survival benefit in a PIK3CA wild-type population...Future directions include rational combination strategies, improved biomarker-driven selection, and novel..."

Journal • Review • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • AKT1 • HER-2 • PIK3CA • PTEN

A spotlight on PTEN alterations in prostate cancer: a narrative review. (PubMed, Crit Rev Oncol Hematol) - "We also discuss current methodologies for PTEN assessment, including immunohistochemistry and genomic techniques, and provide an overview of clinical trials targeting the PI3K/AKT axis in prostate cancer. Understanding PTEN alterations is essential for improving prognostic stratification and guiding precision oncology approaches."

Journal • Review • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • PTEN