Truqap (capivasertib) / Otsuka, AstraZeneca - LARVOL DELTA

COPS5 inhibition synergizes the antitumor effect of trastuzumab by PTEN upregulation in HER2 amplified gastric cancer (AACR 2025) - "Moreover, COPS5 KO cells exhibited increased sensitivity to the proliferative effect and downstream signaling inhibition of AKT inhibitors MK2206 and capivasertib compared to control cells. In conclusion, the synergistic antiproliferative effect of COPS5 inhibition and trastuzumab was attributed to increased PTEN expression via SNAIL ubiquitination, resulting in the AKT downstream inhibition. These findings highlight the potential of COPS5 as a therapeutic target in combination with trastuzumab for HER2-amplified GC, warranting further clinical studies."

Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor • HER-2 • PTEN • SNAI1

Synthesis, X-ray diffraction, and computational studies of acyclovir and HBG analogs derived from Triazolyl-1,4-benzothiazine and their oxidized forms for breast cancer and SARS-CoV-2. (PubMed, Comput Biol Chem) - "Molecular docking studies revealed significant interactions, highlighting compound 11b's favorable binding with the target protein AKT1, achieving a binding energy of -6.43 kcal/mol, which is close to the Capivasertib standard. Similarly, compound 12b showed interactions akin to hydroxychloroquine, with a binding energy of -6.29 kcal/mol for the SARS-CoV-2 target protein...Finally, the two most promising compounds, 11b and 12b, selected from the docking results, were analyzed using Density Functional Theory (DFT). These analyses revealed significant variations in their electronic properties, providing valuable insights into their reactivity, stability, and polarity."

Journal • Breast Cancer • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor

Enhancing chemotherapy efficacy in PTEN-deficient prostate tumors with targeted AKT inhibition (AACR 2025) - "Capivasertib is currently being evaluated in a Phase 3 trial (CAPItello-280) along with docetaxel (Dtx) for the treatment of patients with mCRPC...Mice with tumors treated with Dtx+ capivasertib after progression to androgen deprivation therapy (surgical castration) and apalutamide had longer survival and longer tumor doubling times than those treated with Dtx alone. In conclusion, PTEN-deficient CRPC is less sensitive to Dtx than HSPC. However, our model showed that adding capivasertib to Dtx suppressed tumor growth and improved the therapeutic efficacy of CRPC."

Clinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AKT1S1 • CASP3 • PTEN • TP53

The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer. (PubMed, NPJ Breast Cancer) - "In PIK3CA altered, PTEN protein high models, PI3Kα and AKT inhibition was effective, however ablation and partial PTEN expression reduction attenuated PI3Kαi but not AKTi efficacy, alone or combined with fulvestrant. Downregulating FOXM1 expression reversed resistance to capivasertib, while FOXM1 overexpression reduced capivasertib efficacy. Collectively this suggests the AKT-FOXO3-FOXM1 axis plays a pivotal role in response to AKTi in ER+ breast cancer with PIK3CA mutations with and without expression of PTEN, that FOXO3 expression loss can mediate resistance, and that FOXM1 downregulation is a potential biomarker of response."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • AKT1 • ER • FOXM1 • FOXO3 • PIK3CA • PTEN

Co-alterations in PIK3CA and ARID1A lead to greater sensitivity to PI3K pathway inhibition (AACR 2025) - "Previously we have shown that patients with mutations in both genes are more sensitive to copanlisib (cop) treatment than those with just PIK3CA(PK) mutation...An enhanced response was observed with some other PI3K inhibitors, including sapanisertib (PK=0.13; PKAD=0.014; p < 0.005) everolimus (PK=0.66, PKAD=0.36; p < 0.005) and capivasertib (PK=0.85; PKAD=0.47; p < 0.05). Cancers with PK and AD alterations have enhanced efficacy to PI3K pathway inhibition, especially those inhibitors with downstream activity against AKT or MTOR. Further mechanistic and in vivo studies are warranted in addition to further clinical validation."

Colorectal Cancer • Endometrial Cancer • Oncology • Solid Tumor • ARID1A • IFNG • IL6 • PIK3CA

AKT inhibitor capivasertib combines with dexamethasone and venetoclax to enhance anti-tumor responses in the preclinical models of childhood acute lymphoblastic leukemia (AACR 2025) - "Whereas a 20% increase in survival relative to the vehicle group was observed in a disseminated T-ALL PDX model. Taken together, our results provide preclinical evidence for the rational combination of capivasertib, venetoclax and dexamethasone in the treatment of pediatric patients with relapsed/refractory ALL."

IO biomarker • Preclinical • Acute Lymphocytic Leukemia • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hematological Malignancies • Hormone Receptor Breast Cancer • Leukemia • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • PTEN

Capivasertib-Induced Diabetic Ketoacidosis in a Non-diabetic Patient With Metastatic Prostate Cancer With Bone Involvement: A Case Report of a Rare but Serious Metabolic Complication. (PubMed, Cureus) - "The proposed mechanism involves AKT inhibition leading to impaired insulin signaling, reduced glucose uptake, and increased lipolysis, ultimately resulting in ketogenesis. This case underscores the need for vigilant glucose monitoring in patients receiving capivasertib, especially those with predisposing risk factors for insulin resistance or pancreatic dysfunction."

Journal • Diabetes • Gastrointestinal Disorder • Genito-urinary Cancer • Hepatology • Metabolic Disorders • Oncology • Prostate Cancer • Solid Tumor

Update on CAPItello-280 Phase III trial of Truqap in metastatic castration-resistant prostate cancer (AstraZeneca Press Release) - "AstraZeneca is discontinuing the CAPItello-280 Phase III trial evaluating the efficacy and safety of Truqap (capivasertib) in combination with docetaxel and androgen-deprivation therapy (ADT) compared to docetaxel and ADT with placebo in patients with metastatic castration-resistant prostate cancer (mCRPC). This decision is based on the recommendation of the Independent Data Monitoring Committee (IDMC) following their review of data from a pre-specified interim analysis, which concluded that the Truqap combination was unlikely to meet the dual primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) versus the comparator arm upon trial completion. The safety profile for Truqap was consistent with previous trials. The Company will work with investigators to ensure the necessary follow up with patients. Data from the trial will inform ongoing research."

Trial termination • Castration-Resistant Prostate Cancer

Unanticipated Metabolic Emergency as a Consequence of Akt Pathway Inhibition (ATS 2025) - "Intravenous heparin, vasopressors, vancomycin, and cefepime were started...Propofol, midazolam, and levetiracetam were started...Further, the therapeutic efficacy of conventional antidiabetic medications (metformin, SGLT-2 inhibitors, sulfonylureas) in managing capivasertib-induced hyperglycemia remains uncertain. These findings emphasize the need for systematic glycemic monitoring protocols in patients receiving Akt inhibitor therapy. The importance of early recognition and intervention strategies for hyperglycemic complications cannot be overstated, particularly as capivasertib transitions into broader clinical use."

Acute Kidney Injury • Breast Cancer • Cardiovascular • CNS Disorders • Depression • Diabetes • Diabetic Nephropathy • Epilepsy • Fatigue • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hypotension • Metabolic Disorders • Nephrology • Oncology • Psychiatry • Renal Disease • Solid Tumor • Ventricular Tachycardia • AKT2

Targeting NRF2-responsive kinases for the treatment of esophageal squamous cell carcinoma (AACR 2025) - "Furthermore, NRF2null-KYSE70 cells showed increased sensitivity to EGFR inhibitor (Gefitinib), PIK3CA inhibitor (Alpelisib), and AKT inhibitor (Capivasertib), compared to NRF2W24C-KYSE70 cells. Consistent with these findings, pNRF2 expression correlated with PI3K signaling proteins, including pAKT and p-mTOR, in human ESCC tissues. These studies highlight the potential of combining an NRF2 inibitor with a PI3K pathway inhibitor as a promising therapeutic strategy for ESCC."

Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • AKT2 • DUSP1 • NFE2L2 • PIK3CA • PKM • PTEN

Efficacy and Safety of Capivasertib in HR+/HER2- Advanced Breast Cancer: A Systematic Review and Meta-Analysis (ESMO-BC 2025) - No abstract available

Metastases • Retrospective data • Review • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Inhibition of MEK and AKT synergistically induces melanoma stem cell apoptosis and blocks NRAS-mutant xenograft growth (AACR 2025) - "Similarly, in vivo mouse xenograft studies using Dox-inducible BAKP cells revealed increased rates of tumor growth after induction of CD133 expression in trametinib-treated +Dox mice, an effect that was most effectively suppressed by the combination treatment. Therefore, targeting nodes of the AKT and MAPK survival pathways with trametinib and capivasertib underscores the potential for combination therapies for difficult-to-treat NRAS-mutant melanoma stem cells, paving the path towards improved treatment strategies for patients with high-risk melanoma."

Melanoma • Oncology • Solid Tumor • CASP3 • CD133 • NRAS

Comparison of PI3K Inhibitor Versus AKT Inhibitor on Hyperglycemia with Continuous Glucose Monitoring in Metastatic Breast Cancer (ENDO 2025) - "Clinical Case: A 59-year-old woman with a history of T2DM, diastolic heart failure, and metastatic breast cancer (ER+, PR+, HER2+), was started on alpelisib 250 mg daily in combination with fulvestrant after a liquid biopsy analyzing tumor biomarkers confirmed a PIK3CA (H1047R) mutation. Her diabetes was previously well-managed with metformin extended release, yielding a glucose management indicator (GMI) of 5.6%...Alpelisib was stopped and empagliflozin 10 mg daily was started, and glycemia normalized four days later (average glucose of 120 mg/dL)... This case underscores the pronounced hyperglycemic effects of alpelisib, emphasizing the need for diligent monitoring and management of glycemia. Options to manage hyperglycemia from PI3K inhibitors are limited as medications binding to the insulin receptor can activate the PI3K tissue proliferation cascade. The transition to capivasertib improved her glycemic control and highlights the importance of individualized cancer..."

Metastases • Breast Cancer • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • HER2 Breast Cancer • HER2 Positive Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Type 2 Diabetes Mellitus • HER-2 • IR • PGR • PIK3CA

The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer (AACR 2025) - "Combining fulvestrant (a selective estrogen receptor (ER) degrader) with the PI3K-AKT signalling inhibitors such as alpelisib (PI3Kα inhibitor) or capivasertib (AKT inhibitor) gives benefit to patients with ER+ breast cancer (ER+ BC) harboring PIK3CA mutations (alpelisib) and PIK3CA, PTEN and AKT-1 altered tumors (capivasertib). Furthermore, the study highlights the pivotal role of the AKT-FOXO3-FOXM1 axis in mediating responses to AKT inhibitors in ER+ breast cancer with PIK3CA mutations regardless of PTEN expression. In addition, loss of FOXO3a expression can mediate resistance, and FOXM1 downregulation serves as a crucial biomarker of response to the combination treatment."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • FOXM1 • FOXO3 • PIK3CA • PTEN

Capivasertib (C) + ribociclib (R) + fulvestrant (F) in patients (pts) with HR-positive/HER2-negative advanced breast cancer (ABC): CAPItello-292 Phase 1b (ESMO-BC 2025) - No abstract available

Clinical • Metastases • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Development of Acquired Resistance in Alpelisib-treated Gastric Cancer Cells With PIK3CA Mutations and Overcoming Strategies. (PubMed, Anticancer Res) - "In alpelisib-treated GC cells with PIK3CA mutations, PTEN functional loss and changes in the associated signaling pathway were identified as important mechanisms of acquired alpelisib resistance. The combination of capivasertib and SN38 effectively overcomes acquired resistance to alpelisib in PIK3CA-mutant GC, providing a preclinical rationale for future clinical trials targeting acquired alpelisib-resistant GC with PIK3CA mutations."

Journal • Preclinical • Gastric Cancer • Oncology • Solid Tumor • AKT1S1 • CASP3 • CASP7 • CDC42 • PIK3CA • PTEN • STAT1

Managing Capivasertib Induced Hyperglycemia in a Patient with Pre-Existing Type 2 Diabetes (ENDO 2025) - "The AKT inhibitor, capivasertib, has been approved by the US Food and Drug Administration (FDA) in combination with fulvestrant in the treatment of HR+, HER2- breast cancer...Clinical Case: A 71-year-old woman with class I obesity, type 2 diabetes, and metastatic ER+/PR+/HER2- breast cancer with osseous metastases and PIK3CA mutation, was started on alpelisib... Therapeutic agents that target the PI3K/AKT/mTOR signaling pathway are increasingly common in breast cancer treatment. Hyperglycemia is prevalent with aleplisib, the first FDA approved PI3K inhibitor, occurring in 64% of patients in the SOLAR-1 trial. While management of PI3K inhibitor associated hyperglycemia remains under investigation, low carbohydrate diets and oral antiglycemic agents have been reported."

Clinical • Breast Cancer • Diabetes • Genetic Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Metabolic Disorders • Obesity • Oncology • Solid Tumor • Type 2 Diabetes Mellitus • HER-2 • PGR • PIK3CA

A randomized, open-label, phase 3 study of fulvestrant and CDK4/6 inhibitors with or without gedatolisib as first-line treatment in patients with HR+/HER2- advanced breast cancer (VIKTORIA-2) (AACR 2025) - P3 | "Background: For patients with HR+/HER2- advanced breast cancer (ABC), first-line treatment typically includes a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) combined with endocrine therapy (ET)...Gedatolisib, a potent multi-node PAM inhibitor, has demonstrated superior potency and cytotoxicity in BC cell lines compared to approved single-node PAM inhibitors such as alpelisib, everolimus, and capivasertib (Rosetti S, et al...In a Phase 1b study, gedatolisib combined with palbociclib and letrozole as a 1L treatment for patients with endocrine sensitive HR+/HER2- ABC reported an overall response rate (ORR) of 85.2%, mPFS of 48.4 months, and a median OS of 77.3 months in treatment-naïve patients (Layman R, et al...Secondary endpoints will evaluate OS, safety, and tolerability between treatment arms. Enrollment is ongoing."

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

ME09. Paul Workman: Personalized Molecular Medicine Enabled by Multidisciplinary Approaches to Cancer Drug Discovery and Clinical Development (AACR 2025) - "Examples will include the AKT inhibitor capivasertib and the developmental GCN2 activator and HSF1 pathway inhibitor NXP800. I will also describe our recent progress towards drugging the transcription factor brachyury, the primary driver of the rare bone cancer chordoma, providing an approach that can be applied to drug other oncogenic transcription factors."

Clinical • Chordoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • HSF1

LossFinder: a novel algorithm for detecting PTEN homozygous deletions in cancer (AACR 2025) - "PTEN homozygous deletions, more significant than hemizygous deletions, are key markers in cancer treatment, especially with the approval of the AKT inhibitor capivasertib... The LossFinder algorithm offers high sensitivity and specificity in detecting PTEN homozygous deletions. It accurately identifies both whole and partial homozygous deletions, showing a high level of consistency with IHC."

Breast Cancer • Genito-urinary Cancer • Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • PTEN

AKT inhibition enhances antitumor efficacy of radiation and immune checkpoint blockade in triple-negative breast cancer by modulating tumor-infiltrating myeloid cells (AACR 2025) - "These findings suggest that capivasertib, when combined with RT and ICB, led to less immunosuppressive tumor microenvironment by modulating tumor-infiltrating myeloid cells. Taken together, this combination strategy could be a viable approach to overcome therapeutic resistance of ICB in TNBC patients."

Checkpoint block • Checkpoint inhibition • Clinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD86

The epigenetic regulators KDM5C and KAT6A influence AKT inhibitor response in ER positive breast cancer (AACR 2025) - "For patients with ER+ advanced BC with one or more PIK3CA/AKT1/PTEN tumor alterations, capivasertib (AKT inhibitor) in combination with fulvestrant (selective oestrogen receptor (ER) degrader) is a recommended treatment. In summary, this findings identified and validated KDM5C and KAT6A as novel epigenetic targets, the inhibition of which enhances efficacy of AKTi in PI3K pathway mutated ER+ breast cancer. Inhibitors of KDM5C and KAT6A may be potential combination partners for capivasertib in ER+ breast cancer."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • KAT6A • KDM5C • PIK3CA • PTEN

Single center study of efficacy and safety of capivasertib in hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC). (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • Metastases • 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 • HER-2

In-silico investigation integrated with machine learning to identify potential inhibitors targeting AKT2: Key driver of cancer cell progression and metastasis. (PubMed, Comput Methods Programs Biomed) - "However, future in-vivo research can ascertain whether our proposed drug candidates can pass the standard clinical trials as publicly accessible novel drug targets."

Journal • Breast Cancer • Colorectal Cancer • Gastrointestinal Disorder • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • AKT2

ITGAV is a targetable vulnerability in epithelial ovarian cancer (AACR 2025) - "Using this platform, we have identified genes that regulate integrin signaling as a major mechanism of synthetic lethality against the PI3Ki pictilisib and the AKTi capivasertib. The mechanisms underlying induction of DNA damage and cell death in response to combination treatment are currently under investigation. The ultimate goal is to bring this combination treatment approach to HGSOC patients and shed new light on mechanisms of resistance to PI3K/AKT pathway inhibitors in ovarian cancer."

Epithelial Ovarian Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor