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Addition of AKT Inhibitor Ipatasertib to Abiraterone/Prednisolone in Metastatic Castration-Resistant Prostate Cancer With PTEN Loss


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In the phase III IPATential150 trial reported in The Lancet, Christopher Sweeney, MD, and colleagues found that the addition of the AKT inhibitor ipatasertib to abiraterone and prednisolone produced a significant improvement in progression-free survival among patients with metastatic castration-resistant prostate cancer with PTEN loss, with no significant difference observed in the intention-to-treat (ITT) population.

As stated by the investigators, “The PI3K/AKT and androgen-receptor pathways are dysregulated in metastatic castration-resistant prostate cancer; tumors with functional PTEN-loss status have hyperactivated AKT signaling. Dual pathway inhibition with [the] AKT inhibitor ipatasertib plus abiraterone might have greater benefit than abiraterone alone.”

Christopher Sweeney, MD

Christopher Sweeney, MD

Study Details

The double-blind trial included 1,101 patients with previously untreated asymptomatic or mildly symptomatic progressive disease from sites in 26 countries or regions. They 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. 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-by-immunohistochemistry population and in the ITT population.

Progression-Free Survival

At data cutoff (March 2020), median follow-up was 19 months (range = 0–33 months). In 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 (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 (HR = 0.84, 95% CI = 0.71–0.99, P = .043; not significant at prespecified α = .01).

Median time to prostate-specific antigen 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 greater in the ipatasertib group in the PTEN-loss population (61% vs 39%) and ITT population (61% vs 44%). At 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.

KEY POINTS

  • Median progression-free survival was 18.5 months in the ipatasertib group vs 16.5 months in the control group in the PTEN-loss population.
  • Median progression-free survival was 19.2 vs 16.6 months in the ITT population.

Adverse Events

Grade ≥ 3 adverse events occurred in 70% of patients in 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 patients in 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 tumors, but there was no significant difference between the groups in the ITT population. Adverse events were consistent with the known safety profiles of each agent. These data suggest that combined AKT and androgen-receptor signaling 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.”

Johann S. de Bono, MD, of the Division of Clinical Studies, The Institute of Cancer Research, London, is the corresponding author for The Lancet article.

Disclosure: The study was funded by F. Hoffmann-La Roche and Genentech. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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