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AKT Inhibitors for Prostate Cancer – Let’s Try Again

The PI3K/AKT/mTOR signaling pathway plays a critical role in regulating cellular growth, survival, metabolism, and proliferation. In prostate cancer, especially in advanced stages, this pathway becomes dysregulated in a significant proportion of patients, most notably through the loss of the tumor suppressor PTEN. PTEN loss, observed in approximately 40–60% of metastatic castration-resistant prostate cancer (mCRPC) cases, results in unchecked AKT activation and tumor progression.1 This biological rationale has prompted the investigation of AKT inhibitors as a therapeutic strategy, particularly in patients with PTEN-deficient prostate cancer.

Early-phase clinical studies of AKT inhibitors showed promise, particularly when used in combination with androgen receptor (AR)-targeting agents. One of the most extensively studied AKT inhibitors is ipatasertib. In a randomized Phase II study (NCT01485861), ipatasertib was combined with abiraterone and prednisone in patients with mCRPC. The trial stratified patients by PTEN status, revealing that those with PTEN-deficient tumors (assessed by immunohistochemistry) derived greater radiographic progression-free survival benefit from ipatasertib. This trial used less stringent criteria for PTEN-deficiency, requiring only a minimum of 50% of the specimen’s tumor area to have no detectable PTEN staining by the Ventana SP218 antibody. The safety profile was acceptable, with common side effects of diarrhea, hyperglycemia, and rash.2

Building on these findings, the IPATential150 trial, a Phase III, randomized, double-blind study, was conducted to further evaluate the combination of ipatasertib with abiraterone in patients with mCRPC. This trial enrolled patients who were asymptomatic or mildly symptomatic and had not received prior chemotherapy for castration-resistant disease. Results showed that in patients whose tumors had PTEN deficiency (again defined by immunohistochemistry), the addition of ipatasertib led to a statistically significant improvement in rPFS.3 Secondary endpoints of confirmed objective response, PSA response, and time to PSA progression all favored the ipatasertib arm. However, in the overall intent-to-treat population, the benefit was less pronounced, and the final analysis did not demonstrate a statistically significant improvement in overall survival (OS).4

Capivasertib, another AKT inhibitor, has also been tested in prostate cancer. In the PROCAID trial, Capivasertib (AZD5363), an oral pan-AKT inhibitor, was combined in a phase 1 clinical trial with docetaxel and prednisolone for patients with mCRPC, and a recommended phase 2 dose was determined for this combination.5 The placebo-controlled, randomized phase II portion of the ProCAID trial evaluated the combination of capivasertib with docetaxel and prednisolone vs. docetaxel and prednisolone in patients with mCRPC, and was unfortunately unable to confirm any benefit in the primary endpoint of composite PFS. However, a key secondary endpoint of overall survival was superior in the capivasertib arm.6 An overall survival update after 66% of events occurred in the intention-to-treat population, revealing median overall survival of 25.3 months for capivasertib plus docetaxel vs. 17.6 months for placebo plus docetaxel (HR 0.70, 95% CI 0.47-1.05; nominal p=0.09).

Most recently, at ESMO 2025, the CAPItello-281 trial was presented, studying men with de novo metastatic castration-sensitive prostate cancer who harbor PTEN deficiency and randomizing them to androgen deprivation therapy and abiraterone with either Capivasertib 400 mg po bid 4 days on and 3 days off or with placebo.7 The definition of PTEN deficiency for eligibility required >90% of viable malignant cells with no specific cytoplasmic staining by immunohistochemistry. Of ~6200 patients submitting tumor tissue, 97% had a valid immunohistochemistry result, and 25% were considered PTEN deficient. The primary endpoint of investigator-assessed radiographic progression-free survival (rPFS) was statistically significantly improved for the capivasertib arm at a median rPFS of 33.2 months compared to 25.7 months for the placebo arm, HR 0.81 (0.66, 0.98), p=0.034. Overall survival is a secondary endpoint, and the data have yet to mature; however, at this interim analysis, the HR is 0.90 (0.71, 1.15), p=0.401. The toxicity profile was as expected, with any grade diarrhea being experienced by 51.9% of patients and grade 3 diarrhea in 6.2%. Next was hyperglycemia experienced at any grade by 38.0% of the study population and reaching grade 3 level in 10.3%. Rash was reported in 35.4%, with 12.3% reaching a grade 3 level.

The toxicity profile of AKT inhibitors presents multiple challenges. Gastrointestinal side effects, such as diarrhea and nausea, are common and can be dose-limiting. Hyperglycemia is also among the most frequently observed adverse events and is attributable to the disruption of insulin signaling pathways downstream of AKT. Of course, fatigue remains a huge issue. Effective management of these side effects, including supportive care and dose adjustments, remains crucial for maintaining quality of life and treatment adherence. Any future consideration of standard use will require a careful balance of the efficacy vs. toxicity ratio.

All of this makes patient selection even more important. Indeed, a recurring theme across trials is the critical role of molecular biomarkers in predicting response to AKT inhibitors. While PTEN loss, as determined by immunohistochemistry, remains the most commonly used biomarker, emerging evidence suggests that it may be insufficient on its own. For instance, exploratory analyses in IPATential150 using next-generation sequencing (NGS) revealed that patients with genomic alterations in PIK3CA or AKT1 may also benefit from AKT inhibition.⁴ Further, recent preclinical studies suggest that phosphorylated AKT (p-AKT) expression may be a more dynamic and predictive biomarker. One such study using patient-derived xenografts and organoids demonstrated that tumors with high p-AKT expression were more sensitive to capivasertib in combination with docetaxel, even when PTEN status was equivocal.8 Finally, the recent CAPitello-281 presentation mentioned more stringent criteria for PTEN deficiency, such as including only patients with >99% of viable malignant cells with no specific cytoplasmic staining by immunohistochemistry.7

It will soon be up to regulators and potentially individual practitioners and patients to determine whether the magnitude of benefit, balanced with the potential toxicity, warrants the introduction of agents like Capivasertib into the treatment paradigm. Further work is needed to refine patient selection through improved biomarker development, to optimize dosing strategies that minimize toxicity, and to develop rational combination regimens that overcome resistance. In the meantime, there are other ongoing trials testing AKT inhibitors for patients with prostate cancer, and select trials are highlighted below.

Highlighted trials testing AKT inhibitors in patients with prostate cancer

  • SNARE – Neoadjuvant androgen deprivation therapy with abiraterone and capivasertib (NCT05593497)
  • IACS-6274 with capivasertib for malignant solid tumors (NCT05039801)
  • Combomatch – ipatasertib and paclitaxel for AKT mutation (NCT05564377)
  • ATV-1601 for patients with AKT1 E17K mutation (NCT07038369)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11-22.
  2. de Bono JS, De Giorgi U, Rodrigues DN, et al. Randomized Phase II Study Evaluating Akt Blockade with Ipatasertib, in Combination with Abiraterone, in Patients with Metastatic Prostate Cancer with and without PTEN Loss. Clin Cancer Res. 2019;25(3):928-936.
  3. Sweeney C, Bracarda S, Sternberg CN, et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2021;398(10288):131-142.
  4. De Bono JS, He M, Shi Z, et al. Final Overall Survival and Molecular Data Associated with Clinical Outcomes in Patients Receiving Ipatasertib and Abiraterone in the Phase 3 IPATential150 Trial. Eur Urol. 2025;87(6):672-682.
  5. Crabb SJ, Birtle AJ, Martin K, et al. ProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer. Invest New Drugs 2017;35(5):599-607.
  6. Crabb SJ, Griffiths G, Marwood E, et al. Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID). J Clin Oncol 2021;39(3):190-201.
  7. Fizazi K, Clarke NW, De Santis M, et al. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 Phase III study. Ann Oncol 2025; epub October 19, 2025.
  8. Gomes HW, Lister NL, Keerthikumar S, et al. p-AKT Protein Expression Predicts Response to AKT Inhibitor Combined with Docetaxel Therapy in Adenocarcinoma and Neuroendocrine Prostate Cancer. Clin Cancer Res 2025;31(13):2727-2740.