Role of the receptor for advanced glycation end products (RAGE) in blood as a potential biomarker for progression to olaparib: A post hoc analysis of patients with platinum-resistant ovarian cancer (PROC) treated in the ROLANDO-GEICO 1601 trial.
Authors: Perez-Fidalgo Jose Alejandro , Tavira Beatriz , Peña Carlos J , Guerra Eva , Martínez-Pretel Juan José , García Yolanda , Pineda Begoña , Iglesias María , Hernández-Sosa María , Estévez-García Purificación , Santaballa Ana , Manso Sánchez Luis , González-Martín Antonio 
Published: June 2024

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Background: Olaparib (OLA) has shown significant activity in combination with pegylated liposomal doxorubicin (PLD) regardless of BRCA status in the ROLANDO-GEICO 1601 trial with an overall disease control rate of 77% and a median PFS at 6 months of 47% (Perez-Fidalgo et al ESMO Open 2021). Here we report the results from a translational analysis to determine the potential predictive role for progression to PLD and olaparib of immune and apoptotic proteins in PROC patients treated within the ROLANDO trial. Methods: ROLANDO was a single-arm phase II trial including patients with high-grade PROC. Patients received 6 cycles of PLD every 28 days + OLA 300 mg b.i.d. followed by OLA 300 mg b.i.d. monotherapy until progression or unacceptable toxicity. Patients consented for translational analysis of blood samples. The protein expression levels in blood samples of 12 proteins levels (AURKA, MERTK, AXL, PAI-1, TYRO3, CD36, RAGE, GAS-6, MBL, UPAR, CD31, CALR, LOX-1) were compared at two timing points (at baseline vs +/- 1 month after progression) analyzed Protein levels were analyzed by Luminex using the Immuno-oncology checkpoint 14-plex human and the apoptotic cell clearance ProcartaPlex Panels. A PCA biplot for comparison among the expression of all 12 proteins was constructed. Impact on survival of expression levels at baseline of those proteins significantly different were assessed by Kaplan-Meier test and Cox regression models. Results: From 2017 to 2020, 31 patients were included and 22 patients had analyzable blood samples at baseline and 9 had paired samples. Among the determined biomarkers, in the paired comparison between baseline and progression only RAGE expression was significantly reduced at progression when compared to baseline, mean expression levels of 99,3 pg/ml (standard deviation [SD]: 31.4) vs 82,2 pg/ml (SD: 26.6) ( p=0.015, paired t test). Patients with RAGE >100 pg/mL at baseline showed better survival outcomes, with a median OS 20.5 months (95% CI: 9.6NR) vs 10.1 months (95% CI: 8.2-NR) ( p=0.049, Cox). The median PFS was 6.1 months (95% CI: 3.6-NR) and 5 months (95% CI: 4-NR) for patients with RAGE >100 and ≤100, respectively ( p=0.275). Patients with higher RAGE levels were older (median age 59 years), and had less previous treatment lines (<=2 in 80% of patients). In the PCA biplot expression of RAGE at baseline was positively correlated with CD31, GAS6, PAI1, CALR and MERTK and negatively related with AURKA. Conclusions: Progressive reduction of levels of RAGE in blood could be a predictive biomarker of progression to OLA in the PROC setting. Higher levels of RAGE at baseline in blood is a potential favorable prognostic factor for survival. Clinical trial information: NCT03161132 .