Prognostic value of the modeled CA-125 kinetics parameter KELIM-PARP in patients with advanced ovarian cancer (AOC): analysis of the phase II BOLD study
Aurore Carrot (1) ; Olivier Colomban (1) ; Michele Lamuraglia (2) ; Christophe Sajous (3) ; Pauline Corbaux (3) ; Aymeric Favre (3) ; Benoit You (1)(3) ; Gilles Freyer (3)
(1) EA3738 CICLY, UCBL - HCL Faculté de Médecine Lyon-Sud, Université Claude Bernard Lyon 1, univ Lyon, Oullins, France ; (2) Oncologie médicale, Institut de Cancérologie du CHU de St Etienne, France ; (3) Institut de cancérologie des Hospices Civils de Lyon (IC-HCL), Oncologie médicale, CITOHL, Lyon, France
Objectives:
In patients with recurrent High Grade Ovarian Cancer (HGOC), the combination of durvalumab (anti-PL1 monoclonal antibody), olaparib (PARP inhibitor) and bevacizumab (anti-VEGF monoclonal antibody) was associated with promising efficacy and safety antitumor effects in MEDIOLA and BOLD trials [1].
The CA-125 modeled ELIMination rate contant K (KELIMTM) is a reproducible indicator of the tumor chemosensitivity [2]. In recurrent HGOC patients treated by rucaparib (another PARP inhibitor), the modeled KELIM-PARP score was associated with radiological response and Progression-Free Survival (PFS) [3].
The objective of the present study was to assess the prognostic value of KELIM-PARP, adjusted to BOLD trial data, in terms of PFS and Overall Survival (OS), in patients with recurrent HGOC treated with this chemotherapy-free regimen.
Methods:
Data: The data came from the phase II clinical trial BOLD (NCT04015739) [1], evaluating the safety and efficacy of the combination of olaparib, bevacizumab and durvalumab in 74 patients with recurrent high-grade AOC. Patients with at least three CA-125 titers were selected.
Model: A K-PD model was used to fit CA-125 kinetics with an inhibition of CA-125 production by the treatment through an indirect effect model. This model was previously described [3]. Model validation criteria were the Relative Standard Errors (RSE), shrinkage values, basic Goodness-Of-Fits (GOF) plots, Normalised Prediction Distribution Errors (NPDE) and Visual Predictive Checks (VPC) using NONMEM 7.5.0.
Survival analyses: Individual KELIM-PARP parameters, extracted from the K-PD model, were standardized (Std KELIM-PARP) by the median and defined as a 2-classes score: Unfavorable KELIM-PARP patient (Std KELIM-PARP < 1) and Favorable KELIM-PARP patients (Std KELIM-PARP ≥ 1). The survival analyses were performed with a 100-day landmark time point analysis using Kaplan-Meier curves and cox regression.
Results:
Out of 74 enrolled patients, with at least three CA-125 measurements, 62 were selected. The platinum-sensitivity status (platinum–sensitive relapse (PSR) or platinum-resistant relapse (PRR)) was used as a baseline covariate impacting the CA-125 kinetics, as it allowed to decrease the Objective Function Value of the model [3]. CA-125 values were log-transformed. GOF plots and VPC suggested good predictions of CA-125 kinetics. Most of RSE were lower than 50%, except those for K (kinetic rate constant of treatment) and EC50 (treatment concentration to obtain 50% of maximal effect) (< 150%). High RSE value could be explained by the lack of treatment concentrations information, the low number of patients, and the high inter-individual variability. Median KELIM-PARP was 0.01 day-1 in PRS patients and 0.02 day-1 in PSR patients.
KELIM-PARP score exhibited prognostic value regarding PFS, with a median of 1.5 months (95%CI 0.7-6.2) for unfavorable KELIM-PARP score versus 6.2 months (95%CI 3.5-9.0) for favorable KELIM-PARP score (p=0.03; HR 0.47, 95%CI 0.24-0.92). Such as in PFS, KELIM-PARP score showed prognostic value in terms of OS, with a median OS was 10.6 months (95%CI 6.3-not reached) for unfavorable KELIM-PARP score and was not reached in the favorable group (p=0.005 ; HR 0.29, 95%CI 0.12-0.69).
Conclusions:
This model were effective to characterize individually CA-125 kinetics in AOC patients during the first 100 days of treatment with durvalumab, olaparib and bevacizumab. Like for patients treated with chemotherapy, KELIM-PARP score exhibited a strong prognostic value regarding PFS and OS in patients treated with this chemotherapy-free regimen.
References:
[1] Freyer, G., et al., 733P Bevacizumab (Bev), olaparib (Ola) and durvalumab (Durva) in patients with recurrent advanced ovarian cancer (AOC): The GINECO BOLD study. Annals of Oncology, 2021. 32: p. S734-S735.
[2] Lauby, A., et al., The Increasing Prognostic and Predictive Roles of the Tumor Primary Chemosensitivity Assessed by CA-125 Elimination Rate Constant K (KELIM) in Ovarian Cancer: A Narrative Review. Cancers, 2022. 14(1): p. 98.
[3] Colomban, O., et al., Mathematical modeling of the early modeled CA-125 longitudinal kinetics (KELIM-PARP) as a pragmatic indicator of rucaparib efficacy in patients with recurrent ovarian carcinoma in ARIEL2 & STUDY 10. eBioMedicine, 2023. 89.
