The IPATential150 study had the following trial design:
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:
In contrast, ipatasertib plus abiraterone was not associated with improved radiographic progression free survival in patients with PTEN intact by IHC tumors:
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):
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
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
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Clinical Trial Information: NCT03072238