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
; 89: 104477, 2023 Mar.
Article
en En
| MEDLINE
| ID: mdl-36801617
BACKGROUND: PARP inhibitors (PARPi) have revolutionized the management of advanced ovarian carcinoma, and were investigated as forefront treatment in recurrent disease. The objective was to explore if mathematical modeling of the early longitudinal CA-125 kinetics could be used as a pragmatic indicator of the subsequent rucaparib efficacy, like it is for platinum-based chemotherapy. METHODS: The datasets of ARIEL2 and Study 10 involving recurrent HGOC patients treated with rucaparib were retrospectively investigated. The same strategy as those successfully developed for platinum chemotherapy, based on CA-125 ELIMination rate constant K (KELIM™), was implemented. Individual values of rucaparib-adjusted KELIM (KELIM-PARP) were estimated based on the longitudinal CA-125 kinetics during the first 100 treatment days, and then scored as favorable (KELIM-PARP ≥1.0) or unfavorable (KELIM-PARP <1.0). The prognostic value of KELIM-PARP regarding treatment efficacy (radiological response, and progression-free survival (PFS)) was assessed using univariable/multivariable analyses, with respect to platinum-sensitivity and homologous recombination deficiency (HRD) status. FINDINGS: The data from 476 patients were assessed. The CA-125 longitudinal kinetics during the first 100-treatment days could be accurately assessed using the KELIM-PARP model. In patients with platinum-sensitive diseases, BRCA mutational status KELIM-PARP score and were associated with subsequent complete/partial radiological responses (KELIM-PARP: odds-ratio = 2.81, 95% CI 1.86-4.52), and PFS (KELIM-PARP: hazard-ratio = 0.67, 95% CI 0.50-0.91). The patients with BRCA-wild type cancer and favorable KELIM-PARP experienced long PFS with rucaparib regardless of HRD. In platinum-resistant disease patients, KELIM-PARP was associated with subsequent radiological response (odds-ratio = 2.80, 95% CI 1.82-4.72). INTERPRETATION: This proof-of-concept study confirms the early CA-125 longitudinal kinetics during rucaparib in recurrent HGOC patients are assessable by mathematical modeling, to generate individual a KELIM-PARP score associated with the subsequent efficacy. This pragmatic strategy might be useful for selecting the patients for PARPi-based combination regimens, when identifying efficacy biomarker is challenging. Further assessment of this hypothesis is warranted. FUNDING: The present study was supported by Clovis Oncology with a grant to academic research association.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Ováricas
Tipo de estudio:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Female
/
Humans
Idioma:
En
Revista:
EBioMedicine
Año:
2023
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Países Bajos