Biomarker analysis of metastatic castration-resistant prostate cancer patients who received ipatasertib plus abiraterone in the phase III IPATential150 trial

The phase III IPATential150 trial previously reported a decrease in the risk of progression with the administration of ipatasertib and abiraterone in metastatic castration-resistant prostate cancer (mCRPC) who also had PTEN loss. In an exploratory analysis reported at ASCO GU 2021, PTEN loss was found to be proportional to risk of progression

Introduction

Reported at ESMO 2020, the phase III IPATential150 trial found that ipatasertib (IPAT) plus abiraterone (ABI) decreased the risk of progression in a first-line setting for patients with metastatic castration resistant prostate cancer (mCRPC) with PTEN loss (HR[95%CI]: 0.77[0.61-0.98], P= 0.0335). This benefit was not observed in the intention-to-treat population, however. In this study, PTEN loss was defined as ≥50% loss of cytoplasmic staining on immunohistochemistry (IHC). Presented at ASCO GU 2021, an exploratory analysis now investigates the impact of different IHC PTEN loss cut-offs on treatment efficacy, the concordance between IHC and next-generation sequencing (NGS) PTEN assessment, and the role of other genomic alterations on treatment efficacy.

This study randomised (1:1) 1101 treatment-naïve mCRPC patients to receive ipatasertib (400 mg, 4 times daily) plus abiraterone (1000 mg, 4 times daily) or placebo plus abiraterone to the same dosing schedule. The primary endpoint of this study was radiographic progression-free survival (rPFS). The exploratory analysis of this trial assessed PTEN loss via IHC staining in 10% increments from 10% to 100% loss. Tumour genomic profiling was assessed with NGS.

Combination benefit was proportional to PTEN loss

In this exploratory analysis, the benefit with IPAT plus ABI was consistent across all IHC-assessed PTEN loss increments, with the risk of progression decreasing with each 10% increment increase (10% PTEN loss HR[95%CI]: 0.84[0.69-1.02]. 100% PTEN loss HR[95%CI]: 0.65[0.39-1.08]). Furthermore, above 50% PTEN loss, a distinct benefit with the combination was also observed. 70% (N= 518) of patients were PTEN NGS evaluable. In contrast, patients with PTEN intact did not receive an rPFS benefit with IPAT plus ABI (60% PTEN intact HR[95%CI]: 0.97[0.77-1.22]).

Concordance between IHC and NGS in the evaluation of PTEN loss was comparable between the two modalities, with an overall agreement of 85.5%. Of the 208 samples with PTEN loss via NGS, 91.3% had PTEN loss by IHC. Conversely, of the 247 samples with PTEN loss via IHC, 76.9% had PTEN loss by NGS. The study combination of IPAT plus ABI also provided an rPFS improvement over ABI alone when PTEN loss was assessed by NGS (19.1 months vs. 14.2 months; HR[95%CI]: 0.65[0.45-0.95]). Assessed by NGS, patients with genomic alterations to PIK3CA/AKT1/PTEN derived a comparable benefit (19.3 months vs. 14.1 months; HR[95%CI]: 0.63[0.44-0.88]), more so than those who did not have genomic alterations (17.7 months vs. 16.6 months; HR[95%CI]: 0.93[0.72-1.18]). Previously reported, compared to PTEN intact patients, PIK3CA/AKT1 alterations were associated with a worse prognosis.

Conclusion

This exploratory analysis demonstrated a consistent rPFS benefit with IPAT plus ABI, compared to ABI alone with more stringent IHC PTEN loss cut-offs. Furthermore, this analysis found good concordance between IHC and NGS PTEN loss assessment, and identified a subgroup of patients with PIK3CA/AKT1/PTEN alterations that also benefitted from the therapeutic combination. These results further support the use of IPAT plus ABI as a first-line treatment option for mCRPC patients, extending this recommendation to mCRPC patients with PIK3CA/AKT1 alterations.

Reference

De Bono JS et al., PI3K/AKT pathway biomarkers analysis from the phase III IPATential150 trial of ipatasertib plus abiraterone in metastatic castration-resistant prostate cancer. Presented at ASCO GU 2021; Abstract 13.