Adding the AKT inhibitor ipatasertib to abiraterone improved radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) and PTEN loss, according to a phase 3 trial published in The Lancet.
The study authors noted that patients with mCRPC often have deregulation of the PI3K/AKT and androgen-receptor pathways, and tumors with functional PTEN loss have hyperactivated AKT signaling.
In the IPATential150 trial (ClinicalTrials.gov Identifier: NCT03072238), researchers evaluated the impact of dual inhibition of AKT and androgen-receptor pathways with ipatasertib plus abiraterone. They compared this combination with placebo plus abiraterone in patients with previously untreated mCRPC, with or without tumor PTEN loss. The trial was conducted at 200 sites in 26 countries.
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The study enrolled 1101 patients. They were randomly assigned 1:1 to receive ipatasertib in combination with abiraterone and prednisolone (n=547) or placebo plus abiraterone and prednisolone (n=554).
Overall, 521 patients (47%) had tumors with PTEN loss. Of these, 261 patients were in the placebo group, and 260 were in the ipatasertib group.
At a median follow-up of 19 months, the median rPFS among the PTEN-loss cohort was 18.5 months for the ipatasertib group and 16.5 months for the placebo group (hazard ratio [HR], 0.77; 95% CI, 0.61-0.98; P =.034; significant at α=0.05).
In the overall intention-to-treat population, the median rPFS was longer in the ipatasertib group (19.2 months) than in the placebo group (16.6 months), but the difference was not statistically significant (HR, 0.84; 95% CI, 0.71-0.99; P =.043; did not reach prespecified significance at α=0.01).
The rate of grade 3 adverse events (AEs) was 57% in the ipatasertib group and 32% in the placebo group. The rate of grade 4 AEs was 8% and 3%, respectively.
The most common grade 3/4 AEs in the ipatasertib group were rash (16%), aminotransferase increase (16%), hyperglycemia (14%), and diarrhea (10%). Aminotransferase increase (7%) was the most common grade 3/4 AE in the placebo group.
Grade 5 AEs occurred in 4% of patients in both groups. There were 2 fatal treatment-related AEs in the ipatasertib group (hyperglycemia, chemical pneumonitis) and 2 in the placebo group (acute myocardial infarction, lower respiratory tract infection).
“This study did not reveal a benefit with ipatasertib in the overall population but confirmed that combined AKT and androgen-receptor signaling pathways blockade
with ipatasertib and abiraterone provided a significantly reduced risk of radiographical disease progression or death and improved clinical outcomes compared with androgen-receptor blockade alone with abiraterone in men with mCRPC with PTEN loss — a large subgroup of patients who have poor prognosis,” the study authors wrote.
Disclosure: This research was supported by F Hoffmann-La Roche and Genentech. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Reference
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
