The oral AKT inhibitor capivasertib (Truqap) combined with standard-of-care therapy significantly extended radiographic progression-free survival in patients with PTEN-deficient de novo metastatic hormone-sensitive prostate cancer, according to results from the pivotal CAPItello-281 trial presented at the 2025 European Society for Medical Oncology Congress.
After a median follow-up of 18.4 months, patients receiving capivasertib plus abiraterone acetate, prednisone, and androgen deprivation therapy achieved a median radiographic progression-free survival (rPFS) of 33.2 months (95% CI, 25.9-44.2) compared with 25.7 months (95% CI, 22.0-29.9) for those receiving placebo plus standard therapy (HR, 0.81; 95% CI, 0.66-0.98; P = .034).
"The primary end point was met, showing a statistically significant rPFS benefit with the combination of capivasertib and abiraterone, with consistent benefits observed across clinical end points," said lead investigator Karim Fizazi, MD, PhD, a medical oncologist at Institut Gustave Roussy and Centre Oscar Lambret. "The rPFS in the control arm was only 25.7 months, highlighting the poor prognosis of a PTEN population."
Trial Design and Patient Population
The randomized, double-blind, placebo-controlled phase 3 trial enrolled 1,012 patients with PTEN-deficient de novo metastatic hormone-sensitive prostate cancer. All patients received abiraterone acetate at 1,000 mg with prednisone at 5 mg daily plus ADT. Patients were randomly assigned to receive either capivasertib at 400 mg twice daily for 4 days on and 3 days off (n = 507) or matched placebo (n = 505).
PTEN deficiency was defined as more than 90% of malignant cells with no specific cytoplasmic staining by immunohistochemistry. Of those screened, approximately 25% met these requirements, underscoring the selective nature of this patient population.
The baseline characteristics reflected a high-risk population consistent with PTEN-deficient disease. In the capivasertib and placebo arms respectively, median ages were 67 and 68 years, with Gleason scores of 8 or higher in 78.5% and 79% of patients. High-risk disease was present in 61.3% and 65.9% of patients, while bone metastases occurred in 91.1% and 92.5% of cases. Nearly three-fourths of patients had high-volume disease.
Secondary Efficacy Outcomes
While median overall survival was not yet reached in either arm at the time of analysis, there were 267 events recorded, with 129 in the capivasertib arm and 138 in the placebo group (HR, 0.90; 95% CI, 0.71-1.15; P = .401).
The time to castration resistance was 29.5 months in the capivasertib group compared with 22.0 months for placebo (HR, 0.77; 95% CI, 0.63-0.94). Castration resistance was defined as radiographic disease progression, PSA progression, and development of a skeletal event.
Time to next treatment was extended to 37.0 months with capivasertib versus 28.5 months with placebo (95% CI, 0.75-1.11). The median symptomatic skeletal event-free survival was 42.5 months with capivasertib compared with 37.3 months for placebo, with events including pathological fracture, spinal cord compression, radiation use, surgical intervention, and death.
PTEN Expression Level Analysis
Additional analyses examining different PTEN expression levels revealed increasing treatment benefit with greater PTEN deficiency. Among patients with PTEN loss in 95% or more of cells, median rPFS was 33.2 months with capivasertib versus 22.7 months with placebo (HR, 0.75; 95% CI, 0.60-0.94).
The benefit was most pronounced in patients with complete PTEN loss. When PTEN loss was 100%, median rPFS reached 34.1 months compared with 22.1 months for capivasertib and placebo, respectively (HR, 0.68; 95% CI, 0.48-0.96).
"In the capivasertib arm, we see strongly consistent rPFS irrespective of the degree of PTEN deficiency; however, with increasing PTEN deficiency there is worsening prognosis in the control arm," Fizazi explained. "The same phenomenon of increasing treatment effect was also seen for overall survival."
Safety Profile
Grade 3 or higher adverse events occurred in 67% of patients treated with capivasertib compared with 40.4% of those in the placebo arm. Serious adverse events were experienced by 42.5% of patients in the capivasertib group versus 26% in the placebo arm. There were 36 adverse events leading to death in the investigational arm compared with 26 in the placebo group.
Adverse events led to discontinuation of capivasertib or placebo in 18.3% and 4.8% of patients, respectively. Dose interruptions were required for 62.8% versus 26.8% of patients, and dose reductions were needed for 29% versus 3.6% of patients in the capivasertib and placebo arms, respectively.
The most common adverse events in the capivasertib versus placebo arms were diarrhea (51.9% vs 8.0%), hyperglycemia (38% vs 12.9%), rash (35.4% vs 7%), anemia (23.9% vs 12.7%), and hypokalemia (22.1% vs 12.7%). "Adverse events typical of abiraterone, such as hypertension, hypokalemia, and transaminase increase, were even between arms," Fizazi noted.
Clinical Context
The results come as another capivasertib prostate cancer study, CAPItello-280, was halted in early 2025 following an interim analysis showing potential lack of efficacy. That study was exploring capivasertib in combination with docetaxel and ADT.
Capivasertib has already gained FDA approval in combination with fulvestrant for treating patients with hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer harboring PIK3CA, AKT1, or PTEN alterations following progression on at least one endocrine-based regimen.
