Truqap (capivasertib) / Otsuka, AstraZeneca - LARVOL DELTA

DESTINY-Breast08: a phase 1b study of trastuzumab deruxtecan in combination with other anticancer therapies in patients with HER2-low metastatic breast cancer. (PubMed, Clin Cancer Res) - "Safety results were generally consistent with known individual profiles for T-DXd and combination drugs. T-DXd plus capecitabine, capivasertib, anastrozole, or fulvestrant demonstrated preliminary clinical activity in patients with HER2-low mBC."

Journal • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Interstitial Lung Disease • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • HER-2

Targeted therapy for DNA damage response and homologous recombination repair defects: The Olaparib Combinations trial. (PubMed, Cancer) - "The study failed to meet its primary end point of ORR. DDR and homologous recombination repair defects are not consistently actionable with olaparib as monotherapy or in combination with other targeted therapies in a histology-agnostic manner."

Journal • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • ARID1A • HRD

Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. (PubMed, N Engl J Med) - P3 | "Capivasertib-fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients with hormone receptor-positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor. (Funded by AstraZeneca and the National Cancer Institute; CAPItello-291 ClinicalTrials.gov number, NCT04305496.)."

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

NRG GY012: A randomized phase II study comparing single-agent cediranib with olaparib/durvalumab, cediranib/durvalumab, and olaparib/capivasertib in women with recurrent, persistent or metastatic endometrial cancer (ESMO 2025) - P2 | "Methods Eligible patients (pts) had at least 1 prior line of chemotherapy (no more than 2) with prior endocrine and immunotherapy (prior lenvatinib/pembrolizumab excluded) allowed, ECOG 0-1. Conclusions The combinations of O+D, O+CA and C+D did not meet prespecified endpoints for significance in an unselected population. Further evaluation of molecular subgroups and prior immunotherapy treatment is necessary to determine if there are any signals warranting future investigation."

Clinical • Metastases • P2 data • Endometrial Cancer • Oncology • Solid Tumor

Capivasertib and fulvestrant for patients with hormone receptor-positive advanced breast cancer: characterization, time course, and management of frequent adverse events from the phase III CAPItello-291 study. (PubMed, ESMO Open) - "Frequent AEs associated with PI3K/AKT pathway inhibition occurred early and were manageable. The low rate of treatment discontinuations suggests that, when appropriately managed, these AEs do not pose a challenge to clinical benefit."

Adverse events • Journal • Metastases • P3 data • Breast Cancer • Diabetes • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

ReDiscover-2, a phase 3 study of RLY-2608 + fulvestrant versus capivasertib + fulvestrant as treatment for locally advanced or metastatic PIK3CA-mutant HR+/ HER2- breast cancer following recurrence or progression on or after treatment with a CDK4/6 inhibitor (trial in progress) (SABCS 2025) - P3 | "While the PI3K inhibitors alpelisib and inavolisib and the AKT inhibitor capivasertib have been approved by the FDA to treat this substantial patient population, these therapies cause significant toxicity, notably hyperglycemia, rash, and diarrhea, due to their non-selective targeting of the pathway. Type 1 diabetes, or Type 2 diabetes requiring antihyperglycemic medication are excluded• No prior PI3K, AKT, or mTOR inhibitors or any agent whose mechanism of action is to inhibit the PI3K/AKT/mTOR pathwayReDiscover-2 (NCT06982521) is open for enrollment. For further information, contact: clinicaltrials@relaytx.com."

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 • PTEN

Patient reported outcomes (PRO) and tolerability of capivasertib (capi) plus abiraterone (abi) versus placebo (pbo) plus abi in patients (pts) with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC): CAPItello-281. (ASCO-GU 2026) - P3 | "Common capi-associated AEs occur early and are clinically manageable. While pts in the capi+abi arm had more symptomatic AEs (eg diarrhea, rash) consistent with faster decline in self-reported PWB compared with pts in the pbo+abi arm, this did not affect other functional aspects of life (eg work, sleep) and overall HRQoL, allowing for continued treatment with capi+abi."

Clinical • Metastases • Patient reported outcomes • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • PTEN

Precision: Osimertinib Plus Capivasertib in NSCLC With PIK3CA/AKT1/PTEN Alterations Following Prior 1L Osimertinib (clinicaltrials.gov) - P1/2 | N=53 | Not yet recruiting | Sponsor: Shanxi Province Cancer Hospital

First-in-human • Monotherapy • New P1/2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AKT1 • CD4 • CTLA4 • PD-L1 • PIK3CA • PTEN

A phase III study of capivasertib (capi) + abiraterone (abi) vs placebo (pbo) + abi in patients (pts) with PTEN deficient de novo metastatic hormone-sensitive prostate cancer (mHSPC): CAPItello-281 (ESMO 2025) - P3 | "The safety profile was broadly consistent with the known profiles of capi and abi. Capi in combination with abi represents a potential first-in-class targeted treatment for this poor prognosis population with high unmet need."

Clinical • Metastases • P3 data • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • PTEN

Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 Phase III study. (PubMed, Ann Oncol) - P3 | "Capivasertib plus abiraterone improves rPFS versus placebo plus abiraterone in PTEN-deficient mHSPC, on a background of ADT, with a 7.5-month improvement in median rPFS. AE profile was consistent with that of the individual agents. Patients with PTEN-deficient mHSPC benefit from dual blockade of the PI3K/AKT and AR pathways with capivasertib plus abiraterone."

Journal • P3 data • Diabetes • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • PTEN

Elacestrant in combination with everolimus or abemaciclib in patients with ER+/HER2- locally advanced or metastatic breast cancer (mBC): phase 2 results from ELEVATE, an open-label, umbrella study (SABCS 2025) - " ELEVATE is evaluating elacestrant combined with everolimus, alpelisib, capivasertib, abemaciclib, ribociclib,or palbociclib to address different resistance mechanisms...PFS benefit was consistent across subgroups, including those with visceral metastases, prior fulvestrant or primary ET resistance... Elacestrant in combination shows a consistent PFS benefit irrespective of ESR1m status in pts with ER+/HER2-mBC after progressive disease on ET ± prior CDK4/6i. Elacestrant has the potential to become an ET backbone for combination strategies with targeted agents, supporting an all-oral approach that may delay the need for chemo or ADC-based regimens in this patient population. Table 1:Phase 2 mPFS, mo[95% CI] in all patients and subgroupsNR, not reached"

Clinical • Combination therapy • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER • HER-2 • PIK3CA

Gedatolisib, a multi-target PI3K/AKT/mTOR (PAM) inhibitor, plus fulvestrant with or without palbociclib for second-line (2L) treatment of patients with HR+/HER2-/PIK3CA-wild type (WT) advanced breast cancer (ABC): updated results from the randomized, phase 3 VIKTORIA-1 trial (SABCS 2025) - "In preclinical studies, gedatolisib demonstrated superior potency and cytotoxicity compared to alpelisib, capivasertib, and everolimus, regardless of PI3K-pathway mutation status, and combinations of gedatolisib + fulvestrant, with and without palbociclib, were active in treatment-naive and resistant cell lines. These updated results support gedatolisib combination therapy as a potential new standard of care for the 2L treatment of patients with HR+/HER2-/PIK3CA WT ABC."

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

PRECISION: A first in human, phase Ib/IIa study of osimertinib in combination with capivasertib in EGFRm advanced NSCLC patients with PIK3CA/AKT1/PTEN alterations who had progressed on osimertinib (ELCC 2026) - P1/2 | "Primary endpoints are RCD and safety in phase Ib and confirmed objective response rate (ORR, RECISIT v1.1) in phase IIa. Secondary endpoints include ORR in phase Ib and progression free survival, duration of response, overall survival, and safety in phase IIa."

Clinical • Combination therapy • First-in-human • Metastases • P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • AKT1 • PIK3CA • PTEN

Resistance to the SFK inhibitor NXP900 in cholangiocarcinoma is characterized by IL13RA2-AKT signaling and can be overcome by combination therapy (AACR 2026) - "NXP900 is a highly selective SFK inhibitor with a novel mechanism of action that locks SFKs in a closed, inhibited conformation, providing sustained suppression of catalytic and non-catalytic functions, which is distinct from other SFK inhibitors like dasatinib. These findings confirm the central role of IL13RA2 signaling and the PI3K-AKT pathway in mediating acquired resistance to NXP900, consistent with our previous multiomics analysis. Importantly, this study identifies combination strategies that may be able to overcome NXP900 resistance, supporting the development of combinatorial approaches to restore therapeutic efficacy in resistant tumors."

Combination therapy • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • IL13RA2

AKT inhibition with capivasertib counteracts tumor microenvironment remodeling and enhances AR-targeted therapy in PTEN-deficient prostate cancer (AACR 2026) - "Capivasertib enhances tumor growth inhibition achieved by ADT plus abiraterone and mitigates TME remodeling associated with PTEN loss and AR-targeted therapy. These findings highlight AKT inhibition as a strategy to counteract TME-driven disease progression and improve therapeutic outcomes."

Biomarker • Tumor microenvironment • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AKT1S1 • CD31 • IL6 • PECAM1 • PTEN • TP53

Gene knockout or selective inhibition of AKT-3, but not AKT-1 or AKT-2 isoform, enhances apoptosis in CD133+ melanoma cancer stem cells treated with the MEK inhibitor trametinib (AACR 2026) - "Combinational inhibition of the MAPK and PI3K/AKT pathways with trametinib and the pan-AKT inhibitor capivasertib synergistically induces melanoma cell apoptosis in vitro and inhibits tumor growth in vivo...We next investigated apoptosis induction by selective inhibitors of each of the AKT isoforms; afuresertib for AKT-1, CCT128930 for AKT-2, or uprosertib for AKT-3, as a monotherapy or in combination with trametinib...Future studies will focus on optimizing the effect of selective inhibitors of AKT-3 in dose response experiments, and test its effects in in vivo mouse xenograft studies. Simultaneously targeting the AKT and MAPK survival pathways with trametinib and uprosertib underscores the importance of combination therapies to eliminate recalcitrant melanoma stem cells."

Cancer stem • Brain Cancer • Glioblastoma • Melanoma • Oncology • Solid Tumor • AKT1 • AKT2 • ANXA5 • CD133 • NRAS

The combination of the AR PROTAC AZD9750 and AKT inhibitor capivasertib delivers improved efficacy over monotherapy in prostate cancer (AACR 2026) - P3 | "Consistent with this, in the Phase III CAPItello-281 trial (NCT04493853), capivasertib plus abiraterone and ADT achieved a statistically significant improvement in radiographic progression-free survival versus abiraterone and ADT in patients with PTEN-deficient de novo metastatic hormone-sensitive prostate cancer (mHSPC). In PTEN-null patient-derived xenograft prostate tumor models (both HSPC and CRPC), the combination consistently delivered significantly greater efficacy than either monotherapy, including 73% tumor growth inhibition (TGI) in TM00298 (vs AZD9750 52% TGI and capivasertib 14% TGI) and >100% TGI with 25% regression in MR041 (vs AZD9750 90% TGI and capivasertib 61% TGI), with similar benefits observed in other models. These findings indicate that in PTEN-null prostate cancer AZD9750 mediated AR degradation synergizes with AKT inhibition by capivasertib to enhance antitumor efficacy and support clinical evaluation of the AR-PROTAC-AKT inhibitor..."

Clinical • Monotherapy • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • AKT1S1 • CRBN • KLK3 • PTEN

Application of mechanistic preclinical PK/PD/efficacy modeling to support combination strategy for AZD9750, a novel oral androgen receptor degrader (PROTAC) (AACR 2026) - "AZD9750 is a novel potent oral selective AR Proteolysis-targeting chimera (PROTAC) with a suitable pharmacological profile to be used in combination with a variety of other therapeutics such as capivasertib, a potent pan-AKT kinase inhibitor with anti-tumor activity in tumors with PIK3CA and PTEN mutations, and saruparib, a PARP1-selective inhibitor especially effective against tumors with mutations in genes like BRCA1 and BRCA2. The study enriches our understanding of biomarkers relevant to AR-PROTACs, PARP inhibitors, and AKT inhibitors, informing the selection of biomarkers for monitoring in clinical trials. Additionally, it quantifies the extent of biomarker modulation required to achieve maximal antitumor activity and supports rational combination strategies, as well as dose and schedule optimization for clinical development."

PK/PD data • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • BRCA1 • BRCA2 • PIK3CA • PTEN

Investigating the value of testing for actionable alterations and circulating tumor DNA in breast and colorectal cancers (AACR 2026) - "HR+/HER2- BC samples had AAs associated with approved matched therapy in 13 (54.2%) samples , which included PIK3CA mutations associated with alpelisib, capivasertib, and/or inavolisib (7 samples; 16.7%) and 1 ESR1 alteration. Other AAs associated with FDA-approved therapies are listed in the table. Detection of AAs associated with FDA-approved matched therapy in approximately half of samples tested for ctDNA suggests it may influence therapy selection and disease management."

Circulating tumor DNA • Breast Cancer • Colorectal Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA

Targeting TUBB2B: Exploiting brain metastatic vulnerabilities in triple-negative breast cancer (AACR 2026) - "Ongoing studies are testing the combination effects of siTUBB2B-gold nanoparticles with Akti (GDC-0068 and Capivasertib) in preclinical animal models. TUBB2B plays a critical role in TNBC brain metastasis and represents a promising therapeutic target, particularly in combination with Akt pathway inhibition. TUBB2B plays a critical role in TNBC brain metastasis and represents a promising therapeutic target, particularly in combination with Akt pathway inhibition. These findings may inform future clinical strategies for TNBC patients with brain metastases.This work is supported by National Natural Science Foundation of China (81972781, 82273470) and City University of Hong Kong (9609316, 9680348). This abstract was proofread using AI-assisted tools."

Metastases • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • TUBB2B

Integrative pathway analysis of I-SPY2 HER2+ breast cancers reveals drug-repurposing opportunities (AACR 2026) - "Growth-factor/RTK bypass (PI3K/AKT) and DNA repair & oxidative stress defense were strongly upregulated in non-responders within BP-HER2, revealing actionable nodes involving PI3K/AKT (alpelisib, capivasertib), IGF1R (linsitinib), MET (crizotinib, capmatinib), and DNA repair (PARP inhibitors). Notably, metabolic rewiring and lipid homeostasis—targetable by vismodegib and sonidegib—were upregulated in non-responders across both BP subtypes, reflecting a shared metabolic vulnerability. Luminal biology-linked transcriptional programs may persist within the HER2+ BP-HER2 subtype and contribute to resistance... Luminal biology-linked transcriptional programs may persist within the HER2+ BP-HER2 subtype and contribute to resistance. BP-HER2 non-responders exhibit coordinated activation of RTK-bypass and DNA repair pathways, exposing therapeutic vulnerabilities targetable by existing agents. Furthermore, targeting lipid metabolic reprogramming alongside anti-HER2 therapy..."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

PIK3CA and ARID1A co-altered tumors are sensitive to AKT inhibitor, capivasertib (AACR 2026) - "These cancers had enhanced sensitivity to PI3K inhibition with copanlisib (cop) in the MATCH trial arm Z1F. PIK3CA and ARID1A co-altered tumors have enhanced sensitivity to capi relative to PIK3CA mutant tumors, potentially through induction of Bims. Capi should be investigated further clinically in PIK3CA and ARID1A co-altered cancers. Additionally, further studies identifying novel drug combinations with capi are warranted to further enhance patient response"

Colorectal Cancer • Oncology • Solid Tumor • AKT1S1 • ARID1A • BCL2L1 • CASP3 • MCL1 • PIK3CA • RPS6

Pharmacodynamics of Akt drugs revealed by a kinase-modulatedbioluminescent indicator withBBB-permeable substrate (AACR 2026) - "Remarkably, capivasertib, ipatasertib, and ML-B01 all demonstrated prolonged PD effects that outlasted their pharmacokinetic (PK) profiles. Together, these results establish bioluminescence imaging with the Akt KiMBI as a sensitive and efficient method for real-time, longitudinal visualization of Akt inhibitor and degrader activity in vivo. This platform offers a powerful approach for early-stage drug optimization and for elucidating the pharmacodynamics of kinase-targeted therapies in live animals."

PK/PD data • Oncology

Pro-metastatic kinase network inhibition to treat drug-resistant triple-negative breast cancer (AACR 2026) - "Sequential administration of capivasertib and dasatinib to target the Src family did not reduce organoid viability but did disrupt organoid formation and self-renewal, suggesting effective inhibition of metastatic potential...We further refined this to a three-drug regimen (Ralimetinib, JNK-in-8, and Trametinib) that inhibits stress kinase networks, pro-motility gene expression and TNBC cell invasion in organoid assays...Ongoing studies focus on optimizing treatment efficacy with antibody-drug conjugates, characterizing kinase network targets specific for other metastasis regulators such as transcription factors, and exploring kinase networks as biomarkers for treatment resistance. Our long-term goal is to develop a low-toxicity, multi-kinase inhibitor strategy that reprograms metastatic TNBC cells, enhancing the efficacy and durability of their response to chemotherapy and improving clinical outcomes."

Metastases • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Integrative analysis of capivasertib mediated AKT blockade with AR inhibition in mouse PTEN-deficient prostate cancer (AACR 2026) - "PI3K/AKT activation compensates for AR inhibition, reducing the efficacy of androgen deprivation therapy (ADT) and agents such as abiraterone (Abi). Capiva improved response to ADT and Abi in PTEN-deficient prostate cancer. Favorable outcomes were associated with sustained AKT inhibition, reduced pro-tumor immune infiltration, and decreased vascularization. These findings underscore the importance of targeting PI3K/AKT to overcome AR therapy resistance and highlight the value of integrative approaches for biomarker discovery and optimizing therapeutic outcomes."

Preclinical • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • PTEN