NGS, RNA-Seq, TIL, and PTEN analyses in prostate cancer specimens from patients enrolled in the study of the Akt inhibitor ipatasertib (Ipat) combined with abiraterone acetate (AA).

Abstract

310 Background: In Phase III studies, ipilimumab did not extend OS in unselected populations with metastatic castration-resistant prostate cancer (mCRPC) (Kwon, 2014; Beer, 2014), suggesting that successful cancer immunotherapy development strategies require the evaluation of treatment effects in biomarker-driven segments. In addition, PTEN loss has been identified as a potential mechanism of resistance to immunotherapy (Peng, 2016). Therefore, we explored possible associations between cancer immunity (CI)-related biomarkers and PTEN loss in mCRPC samples. Methods: Tumor samples obtained in the Phase II study of AA ± Ipat in patients with mCRPC (de Bono, ESMO 2016) were retrospectively profiled. DNA alterations and tumor mutational burden (TMB) were assessed by FoundationOne. RNA-seq analysis of multiple CI-related expression signatures was performed. Tumor-immune lymphocyte (TIL) scores were analyzed in 3 compartments (stromal, sTIL; intratumoral, iTIL; peritumoral, pTIL) based on H&E stained specimens. Up to 10 evenly distributed fields were examined; the average of these fields was used to estimate the %TILs for each compartment. Results: Strong associations were observed between multiple CI-related signatures (e.g., INFγ-induced, immune checkpoints, Treg, checkpoint inhibitors). Fewer than 10% of the samples had a high level (≥ 10% of the tumor area) of TIL infiltration in any compartment (Table). TIL scores, TMB values, PTEN status and Gleason score all appeared to be independently associated, and none were associated with CI-related gene signatures, except for a possible association between pTILs and the B-cell signature (ρ = 0.49, P < 0.0001). Conclusions: Comprehensive high-content profiling of prostate cancer samples suggests that PTEN status and CI-related biomarkers were independently associated, while TMB and TIL values were generally not associated with CI-related signatures. Clinical trial information: NCT01485861. [Table: see text]