Ipatasertib/Abiraterone Data Published in Lancet Underscore the Combo’s Frontline Potential in PTEN-Loss mCRPC

Christopher Sweeney, MBBS

Ipatasertib plus abiraterone acetate (Zytiga) and prednisone demonstrated a significant improvement in radiographic progression-free survival (rPFS) vs placebo plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) with PTEN loss, according to findings from the ongoing phase 3 IPATential150 trial (NCT03072238) that were presented at the 2020 ESMO Virtual Congress and now published in The Lancet.¹

At a median follow-up of 19 months (range, 0-33) the median rPFS was 18.5 months (95% CI, 16.3-22.1) in patients with PTEN-loss mCRPC who received ipatasertib/abiraterone vs 16.5 months (95% CI, 13.9-17.0) in those who were given placebo/abiraterone (HR, 0.77; 95% CI, 0.61-0.98; P = .034; significant at α = 0.04).

In the intention-to-treat (ITT) population, the median rPFS was 19.2 months (95% CI, 16.5-22.3) in the ipatasertib/abiraterone arm vs 16.6 months (95% CI, 15.6-19.1) in the placebo/abiraterone arm (HR, 0.84; 95% CI, 0.71-0.99; P = .043; not significant at α = 0.01).

“Ipatasertib plus abiraterone significantly improved rPFS compared with placebo plus abiraterone among patients with mCRPC with PTEN-loss tumors, but there was no significant difference between the groups in the ITT population,” Christopher Sweeney, MBBS, an institute physician at Dana-Farber Cancer Institute, and coauthors, wrote in the study publication.

The PI3K/AKT and androgen-receptor (AR) pathways are not well regulated in mCRPC, and tumors with functional PTEN loss have overactive AKT signaling. Dual pathway blockade with the AKT inhibitor ipatasertib plus abiraterone could elicit more benefit than abiraterone alone.

To that end, investigators evaluated the combination of ipatasertib and abiraterone vs placebo plus abiraterone in patients with previously untreated mCRPC with and without PTEN loss.

In the randomized, double-blind, phase 3 trial, patients aged 18 years or older with previously untreated asymptomatic or mildly symptomatic mCRPC who had progressive disease and an ECOG performance status of 0 or 1 were randomized to receive 400 mg of oral ipatasertib once daily plus 1000 mg of oral abiraterone once daily and 5 mg of oral prednisone twice daily, or placebo plus abiraterone and prednisone in the same dosing schedule.

Treatment was continued until disease progression, intolerable toxicity, patient withdrawal, or study completion.

Patients were stratified by previous taxane-based therapy for hormone-sensitive prostate cancer, type of progression, presence of visceral metastasis, and PTEN-loss status by immunohistochemistry (IHC).

The co-primary end points of the trial were investigator-assessed rPFS in the PTEN-loss population and in the ITT population.

Between June 30, 2017, and January 17, 2019, 1611 patients were screened for eligibility and 1101 (68%) were enrolled to the trial. Half of patients (n = 547) were assigned to the ipatasertib/abiraterone arm and half of patients (n = 554) were assigned to the placebo/abiraterone arm.

A total of 521 (47%) patients had tumors with PTEN loss by IHC; 260 of these patients were in the ipatasertib/abiraterone arm and 261 were in the placebo/abiraterone arm.

Regarding safety, the adverse effects (AEs) were in line with the known safety profiles of each agent alone.

Grade 3 or higher AEs occurred in 386 (70%) of 551 patients in the ipatasertib/abiraterone arm vs 213 (39%) of 546 patients in the placebo/abiraterone arm. AEs leading to discontinuation of ipatasertib or placebo occurred in 116 patients (21%) in the ipatasertib/abiraterone arm vs 28 patients (5%) in the placebo/abiraterone arm.

Treatment-related AEs leading to death occurred in 2 patients (<1%; hyperglycemia [n = 1] and chemical pneumonitis [n = 1]) in the ipatasertib/abiraterone arm vs 2 patients (<1%; acute myocardial infarction [n = 1] and lower respiratory tract infection [n = 1]) in the placebo/abiraterone arm.

“These data suggest that combined AKT and AR signaling pathway inhibition with ipatasertib and abiraterone is a potential treatment for men with PTEN-loss mCRPC, a population with a poor prognosis,” Sweeney and coauthors concluded.

Reference

1. 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(10295):131-142. doi:10.1016/S0140-6736(21)00580-8