In a phase III trial (IPATential150) reported in The Lancet, Christopher Sweeney, MD, of Dana-Farber Cancer Institute, and colleagues, found that the addition of the AKT inhibitor ipatasertib to abiraterone and prednisolone produced a significant improvement in radiographic progression-free survival among patients with metastatic castration-resistant prostate cancer with PTEN loss by immunohistochemistry, with no significant benefit observed in the intention-to-treat (ITT) population (ie, patients with and without PTEN loss combined).1
Christopher Sweeney, MD
As stated by the investigators: “The PI3K/AKT and androgen-receptor pathways are dysregulated in … [metastatic castration-resistant prostate cancers]; tumours with functional PTEN-loss status have hyperactivated AKT signalling. Dual pathway inhibition with [the] AKT inhibitor ipatasertib plus abiraterone might have greater benefit than abiraterone alone.”
In the double-blind trial, the ITT population of 1,101 patients with previously untreated asymptomatic or mildly symptomatic progressive castration-resistant prostate cancer from sites in 26 countries or regions were randomly assigned between June 2017 and January 2019 to receive oral ipatasertib at 400 mg (n = 547) or placebo (n = 554) once daily with abiraterone at 1,000 mg once daily and prednisolone at 5 mg twice daily. Randomization stratification factors included in the stratified analysis were previous taxane-based therapy, type of disease progression at study entry (prostate-specific antigen [PSA] alone vs other), presence of visceral metastasis in the liver or lung, and tumor PTEN-loss status by immunohistochemistry. Treatment was continued until disease progression or intolerable toxicity.
The population of patients with PTEN loss by immunohistochemistry (PTEN-loss population) consisted of 260 patients in the ipatasertib group and 261 in the control group. The co-primary endpoints were investigator-assessed radiographic progression-free survival in the PTEN-loss population and in the ITT population.
In the PTEN-loss population, for the ipatasertib vs control group, median patient age was 70 years (range = 48–92 years) vs 70 years (range = 47–87 years), 18% vs 18% had received taxane-based therapy for metastatic disease, and 48% vs 48% had PSA progression alone. All patients had an Eastern Cooperative Oncology group performance status of 0 (77% vs 76%) or 1. Gleason score was up to 8 in 42% vs 32% and at least 8 in 55% vs 64% (unknown in 3% vs 5%). Metastatic sites were lung or liver in 11% vs 13%, bone in 82% vs 85%, lymph node in 36% vs 42%, and other in 7% vs 6%.
At the data cutoff (March 2020), median follow-up was 19 months (range = 0–33 months). In the PTEN-loss population, median progression-free survival was 18.5 months (95% confidence interval [CI] = 16.3–22.1 months) in the ipatasertib group vs 16.5 months (95% CI = 13.9–17.0 months) in the control group (stratified hazard ratio [HR] = 0.77, 95% CI = 0.61–0.98, P = .034; significant at prespecified α = .04). In the ITT population, median progression-free survival was 19.2 months (95% CI = 16.5–22.3 months) in the ipatasertib group vs 16.6 months (95% CI = 15.6–19·1 months) in the control group (stratified HR = 0.84, 95% CI = 0.71–0.99, P = .043; not significant at prespecified α = .01).
In the PTEN-loss population, hazard ratios for the ipatasertib vs control group for progression-free survival according to stratification subgroups were 1.00 (95% CI = 0.58–1.74) with and 0.74 (95% CI = 0.57–0.96) without prior taxane-based therapy, 0.77 (95% CI= 0.54–1.11) for PSA only as progression factor and 0.77 (95% CI = 0.56–1.06) for other factors, and 0.66 (95% CI = 0.37–1.18) with and 0.80 (95% CI = 0.62–1.04) without liver or lung metastases.
Median time to PSA progression was longer in the ipatasertib group in the PTEN-loss population (12.6 vs 7.6 months, HR = 0.69, 95% CI = 0.55–0.87) and ITT population (12.9 vs 8.4 months, HR = 0.73, 95% CI = 0.62–0.85). Objective response rates were higher in the ipatasertib group in the PTEN-loss population (61% vs 39%; difference = 22.1%, 95% CI = 7.4%–36.8%) and ITT population (61% vs 44%; difference = 17.1%, 95% CI = 7.3%–27.0%).
At the time of analysis, overall survival data were immature. Death had occurred in 25% vs 29% of the PTEN-loss population and in 23% vs 26% of the ITT population.
Grade ≥ 3 adverse events occurred in 70% of the ipatasertib group vs 39% of the control group. The most common grade 3 or 4 adverse events were rash (16%), aminotransferase increases (16%), hyperglycemia (14%), and diarrhea (10%) in the ipatasertib group and aminotransferase increases (7%) in the control group. Serious adverse events occurred in 40% vs 23% of patients. Adverse events leading to discontinuation of ipatasertib or placebo occurred in 21% vs 5%. Grade 5 adverse events occurred in 4% of each group. Death considered related to study treatment occurred in two patients in the ipatasertib group, due to hyperglycemia and chemical pneumonitis, and in two patients in the control group, due to acute myocardial infarction and lower respiratory tract infection.
The investigators concluded: “Ipatasertib plus abiraterone significantly improved radiographical progression-free survival compared with placebo plus abiraterone among patients with [metastatic castration-resistant prostate cancer] with PTEN-loss tumours, but there was no significant difference between the groups in the intention-to-treat population. Adverse events were consistent with the known safety profiles of each agent. These data suggest that combined AKT and androgen-receptor signalling pathway inhibition with ipatasertib and abiraterone is a potential treatment for men with PTEN-loss [metastatic castration-resistant prostate cancer], a population with a poor prognosis.”
DISCLOSURE: The study was funded by F. Hoffmann–La Roche and Genentech. Dr. Sweeney holds stock or other ownership interests in Leuchemix; has served as a consultant or advisor to Amgen, Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, Janssen Biotech, Lilly, Pfizer, and Sanofi; has received research funding from Dendreon; has received institutional research funding from Astellas Pharma, Bayer, Janssen Biotech, Pfizer, and Sanofi; and holds intellectual property in “Leuchemix, Parthenolide, Dimethylaminoparthenolide. Exelixis: Abiraterone plus cabozantinib combination.”
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 398:131-142, 2021.
Inhibition of the androgen receptor pathway (AR) with novel hormonal therapies such as abiraterone acetate has greatly improved outcomes for patients with metastatic castration-resistant prostate cancer in recent years. However, through numerous mechanisms, tumors ultimately develop resistance...