Background: In metastatic hormone-sensitive prostate cancer (mHSPC), abiraterone combined with androgen deprivation therapy (ADT) is highly effective in improving patient outcomes. However, around 20% of patients progress to castration-resistant disease within 12 months of treatment; these patients have shorter survival and limited treatment options. Aberrant activation of the PI3K/AKT pathway, predominately due to PTEN loss, is common in prostate cancer, especially in later-stage disease. The androgen receptor signaling and AKT pathway are reciprocally cross-regulated such as that inhibition of one leads to upregulation of the other. Therefore, combining abiraterone therapy with AKT inhibition may be beneficial in patients with mHSPC who have PTEN deficiency. In preclinical studies, capivasertib, a selective oral pan-AKT inhibitor, inhibited proliferation of models of hormone-sensitive and castration-resistant prostate cancer with PTEN loss. The results of the IPATential150 phase 3 study (NCT03072238) demonstrated that another oral AKT inhibitor, ipatasertib, prolonged radiographic progression-free survival (rPFS) when combined with abiraterone compared with placebo plus abiraterone in metastatic castration-resistant prostate cancer, particularly among patients with PTEN loss. CAPItello-281 (NCT04493853) is a global, multicenter, phase 3 trial to evaluate capivasertib in combination with abiraterone, on a background of ADT, as a treatment for de novo mHSPC patients with PTEN-deficient tumors. Methods: Eligible patients for this double-blind, randomized trial are men aged 18 years or older with confirmed newly diagnosed previously untreated metastatic hormone-sensitive prostate adenocarcinoma with immunohistochemically confirmed PTEN deficiency and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Following screening, approximately 1000 patients will be randomized 1:1 to receive either capivasertib (400 mg) or placebo (twice daily; 4 days on, 3 days off) in combination with abiraterone (1000 mg once daily) and ADT until radiographic progression or intolerable toxicity. The primary endpoint is rPFS. Secondary endpoints include overall survival, time to start of first subsequent therapy or death, symptomatic skeletal event-free survival, time to pain progression and safety profile. Enrolment started in July 2020. Acknowledgments: We thank Julia Grigorieva, PhD, of Oxford PharmaGenesis, Philadelphia, USA, for providing medical writing assistance. Funding: The CAPItello-281 trial is funded and overseen by AstraZeneca. Clinical trial information: NCT04493853