Daniel George, MD, on capivasertib plus abiraterone in PTEN-deficient mHSPC

In this interview, Daniel J. George, MD, discusses the design and key efficacy findings from the phase 3 CAPItello-281 trial (NCT04493853) evaluating capivasertib (Truqap) plus abiraterone (Zytiga) vs placebo plus abiraterone in patients with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC).¹ George is a medical oncologist at Duke Cancer Center in Durham, North Carolina.

George explains that CAPItello-281 was designed to build on prior evidence from breast cancer demonstrating that in the absence of HER2, there is an alternative pathway—the PI3K/AKT pathway—that can be activated. In prostate cancer, activation of this pathway is often driven by PTEN loss, which is associated with a worse prognosis. The investigators sought to determine if dual inhibition of the PI3K/AKT and AR pathways may delay progression and improve outcomes.

Thus, the CAPItello-281 trial enrolled patients with de novo mHSPC whose tumors exhibited at least 90% PTEN loss by immunohistochemistry. Approximately 1000 patients were randomized to receive capivasertib plus abiraterone (n = 507) vs placebo plus abiraterone (n = 505) on a background of androgen deprivation therapy, with radiographic progression-free survival (rPFS) as the primary end point.

Overall, the study met its primary end point, demonstrating a statistically significant improvement in rPFS with the addition of capivasertib. The median rPFS improved from 25.7 months with placebo plus abiraterone and ADT to 33.2 months with the combination, representing a clinically meaningful 7.5-month benefit (HR, 0.81; 95% CI, 0.66 to 0.98, P = .034).

On the 25.7-month median rPFS in the control arm, George noted, “That's way lower than what we have seen historically in other trials of unselected patient populations, and really reinforces the poor prognosis of this PTEN deficient population.”

Further analyses suggested that the benefit of capivasertib may be particularly pronounced in tumors with more complete PTEN loss. While rPFS in the capivasertib arm remained consistent regardless of PTEN-loss threshold, outcomes in the control arm worsened as PTEN loss approached 100%, with rPFS declining to approximately 18 months. This translated into an even larger treatment effect—up to roughly a 14-month difference in rPFS.

According to the authors, these findings highlight the potential of dual PI3K/AKT and AR pathway inhibition to overcome the adverse biology associated with profound PTEN deficiency.

REFERENCE

1. Fizazi K, Clarke NW, Santis MD, et al. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study. Ann Oncol. 2026;37(1):53-68. doi:10.1016/j.annonc.2025.10.004