ASCO GU 2021: PI3K/AKT Pathway Biomarkers Analysis from the Phase III IPATential150 Trial of Ipatasertib plus Abiraterone in Metastatic Castration-Resistant Prostate Cancer

(UroToday.com) In IPATential150 (NCT03072238), ipatasertib plus abiraterone as first-line treatment for metastatic castration-resistant prostate cancer (mCRPC) significantly reduced the risk for disease worsening or death versus placebo plus abiraterone in patients with tumors with PTEN loss by immunohistochemistry (HR 0.77, 95% CI 0.61-0.98) but not in the intention-to-treat population. In patients with PTEN loss tumors by immunohistochemistry, median radiographic progression-free survival was 16.5 months (95% CI 13.9-17.0) with placebo plus abiraterone and 18.5 months (95% CI 16.3-22.1) with ipatasertib plus abiraterone. At the GU ASCO 2021 annual meeting, Dr. Johann De Bono presented results of exploratory analyses evaluating putative biomarker associations with radiographic progression free survival.


The IPATential150 study had the following trial design:

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Before randomization, tumor samples (> 90% archival) were tested for PTEN loss by VENTANA PTEN (SP218) IHC assay (n = 1101). PTEN loss was pre-defined as ≥ 50% of tumor cells with no specific cytoplasmic immunohistochemistry staining. The exploratory analysis evaluated different immunohistochemistry staining cutoffs. Tumor genomic alterations were profiled with next-generation sequencing using the Foundation Medicine FoundationOne CDx NGS assay (n = 743 evaluable by next-generation sequencing, of which n = 518 were PTEN evaluable). Radiographic progression free survival was determined by the investigator.

There was a consistent benefit with the combination arm placebo plus abiraterone observed when PTEN loss by immunohistochemistry was defined more stringently: radiographic progression free survival at ≥ 60% tumor cells with PTEN loss: HR 0.72, 95% CI 0.56-0.92; ≥ 70%: HR 0.72, 95% CI 0.56-0.93; ≥ 80%: HR 0.71, 95% CI 0.54-0.92; ≥ 90%: HR 0.72, 95% CI 0.53-0.97; 100%: HR 0.65, 95% CI 0.39-1.08:

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In contrast, ipatasertib plus abiraterone was not associated with improved radiographic progression free survival in patients with PTEN intact by IHC tumors:

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The median radiographic progression free survival was 19.1 months (95% CI 16.4-21.9) with placebo plus abiraterone and 19.7 months (95% CI 16.4-26.3) with ipatasertib plus abiraterone. By next-generation sequencing assessment, patients with tumors with PTEN loss and with genomic alterations in PIK3CA/AKT1/PTEN had a larger magnitude of radiographic progression free survival benefit with ipatasertib plus abiraterone than patients with no detectable alterations (HR 0.63, 95% CI 0.44-0.88):

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Dr. De Bono concluded this updated analysis of the IPATential150 phase 3 trial with the following conclusions:

  • A proportion of advanced prostate cancers without PTEN loss have other PI3KT/AKT pathway alterations
  • PI3K/AKT pathway alterations are associated with a worse prognosis
  • There were consistent radiographic progression free survival benefits with ipatasertib plus abiraterone over placebo plus abiraterone using immunohistochemistry cutoffs more stringent than the pre-specified >50% cutoff
  • The improved radiographic progression free survival with combination therapy was also demonstrated in mCRPC with PTEN loss by next-generation sequencing and with PIK3CA/AKT1/PTEN alterations
  • These data further support ipatasertib plus abiraterone as a treatment option for first-line mCRPC with PIK3/AKT/PTEN pathway alterations
Presented by: Johann de Bono, MB, ChB, FRCP, MSc, PhD, FMedSci, The Institute of Cancer Research and the Royal Marsden Hospital, London, United Kingdom

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021


Related Content:

IPATential150: Phase III Study of Ipatasertib plus Abiraterone vs Placebo plus Abiraterone in Metastatic Castration-Resistant Prostate Cancer - Cora Sternberg

ESMO Virtual Congress 2020: IPATential150: Phase III Study of Ipatasertib plus Abiraterone vs Placebo plus Abiraterone in Metastatic Castration-Resistant Prostate Cancer

Clinical Trial Information: NCT03072238