Capivasertib plus abiraterone produced superior efficacy outcomes vs abiraterone alone in PTEN-deficient mHSPC.
Capivasertib (Truqap) in combination with abiraterone improved radiographic progression-free survival (rPFS) compared with abiraterone in patients with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC), according to data from the phase 3 CAPItello-281 trial (NCT04493853) published in Annals of Oncology.1
Patients who received capivasertib plus abiraterone (n = 507) experienced a median rPFS of 33.2 months (95% CI, 25.8-44.2) compared with 25.7 months (95% CI, 22.0-29.9) among those treated with abiraterone alone (n = 505; HR, 0.81; 95% CI, 0.66-0.98; P = .034). Patients with 100% PTEN deficiency in the investigational (n = 169) and placebo (n = 162) arms had a median rPFS of 34.1 months (95% CI, 22.1-not calculable) and 22.1 months (95% CI, 14.7-26.5), respectively (HR, 0.68; 95% CI, 14.7-26.5).
“Patients with PTEN-deficient mHSPC benefit from dual blockade of the PI3K/AKT and [androgen receptor (AR)] pathways with capivasertib plus abiraterone,” Karim Fizazi, MD, PhD, a medical oncologist at Institut Gustave Roussy and Centre Oscar Lambret, and professor of oncology at Paris-Saclay University, in France, and his coauthors wrote in the publication.
CAPItello-281 was a global, double-blind, placebo-controlled, prospective study that enrolled adult patients with de novo mHSPC.1,2 Patients were required to have an ECOG performance status of 0 or 1 and adenocarcinoma tumors with PTEN deficiency per histology. Prior treatment with androgen deprivation therapy (ADT) with or without abiraterone, plus prednisone/prednisolone for de novo disease from 0 days up to a maximum of 93 days prior to random assignment was permitted. Those who received any other therapy for prostate cancer before random assignment were excluded from the study.
Eligible patients were randomly assigned 1:1 to receive capivasertib at 400 mg twice daily for 4 days on, 3 days off or matching placebo, both in combination with abiraterone at 1000 mg once daily plus prednisone/prednisolone and ADT until disease progression, unacceptable toxicity, withdrawal of consent, or death.1 Capivasertib or placebo dose reduction was permitted from 400 mg twice daily to 320 mg twice daily, then to 200 mg twice daily if indicated; dose re-escalation was not allowed. Dose reduction of abiraterone was performed according to local prescribing information, and dose re-escalation was permitted per local practice.
The primary end point was investigator-assessed rPFS per RECIST 1.1 criteria and/or Prostate Cancer Clinical Trials Working Group 3 criteria. Key secondary end points included overall survival (OS), time to first subsequent therapy (TFST), symptomatic skeletal event-free survival (SSE-FS), and time to pain progression.
At baseline, the median ages in the capivasertib and placebo arms were 67 years (range, 42-87) and 68 years (range, 43-88), respectively. Most patients in both arms were White (52.5% vs 51.3%), had an ECOG performance status of 0 (64.9% vs 63.4%), had bone metastases (91.1% vs 92.5%), had a total Gleason score of at least 8 (78.5% vs 79.0%), had high-risk disease (61.3% vs 65.9%), and had high metastatic volume of disease (73.8% vs 74.9%). The median times from prostate cancer diagnosis to random assignment were 2.5 months (range, 0.3-12.8) and 2.5 months (range, 0.6-27.4), respectively.
The median OS in the investigational arm was not calculable (NC; 95% CI, 42.5 months-NC) and NC (95% CI, NC-NC) in the placebo arm (HR, 0.90; 95% CI, 0.71-1.15; P = .401); these data were at 26.4% maturity at the time of the primary OS analysis and did not meet statistical significance. Numerical improvements in TFST (HR, 0.91; 95% CI, 0.75-1.11) and SSE-FS (HR, 0.82; 95% CI, 0.66-1.02) in favor of the investigational arm at 39.3% and 32.2% maturity, respectively, were reported.
In the safety populations of the investigational and placebo arms (both n = 503), any-grade adverse effects (AEs) occurred at rates of 98.8% and 92.0%, respectively. Grade 3 or higher AEs were reported at rates of 67.0% and 40.4%, respectively. Deaths attributed to an AE were reported in 7.2% and 5.2% of patients, respectively. The most common any-grade AEs in the combination arm were diarrhea (51.9%), hyperglycemia (38.0%), and rash (35.4%).
“These novel results are the first to validate the PI3K/AKT pathway as a clinically relevant and actionable target in mHSPC and to demonstrate that patients with PTEN-deficient tumors, a population with high unmet need and poor outcomes on standard-of-care treatments, benefit from dual blockade of the PI3K/AKT and AR pathways with capivasertib plus abiraterone,” Fizazi and his coauthors wrote.
