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. 2025 May 2:220:115329.
doi: 10.1016/j.ejca.2025.115329. Epub 2025 Feb 26.

Immunotherapy and PARP inhibitors as first-line treatment in endometrial cancer: A systematic review and network meta-analysis

Guillermo Villacampa  1 , Gemma Eminowicz  2 , Victor Navarro  3 , Lorenzo Carità  3 , David García-Illescas  4 , Ana Oaknin  4 , J Alejandro Pérez-Fidalgo  5
Affiliations

Immunotherapy and PARP inhibitors as first-line treatment in endometrial cancer: A systematic review and network meta-analysis

Guillermo Villacampa et al. Eur J Cancer. .

Abstract

Background: Several first-line therapeutic strategies have been evaluated alongside platinum-based chemotherapy in advanced or recurrent endometrial cancer (a/rEC). However, the optimal approach remains unclear.

Methods: A systematic review was conducted to identify randomized control trials (RCTs) that evaluate first-line therapeutic strategies in a/rEC involving immune checkpoint inhibitors (ICI) and PARP inhibitors (PARPi). A network meta-analysis with a frequentist framework using random-effects and an extracted individual patient data meta-analysis were performed. The primary endpoint was progression-free survival (PFS) by MMR status, p53 status within the MMRp population and PD-L1 status.

Results: A total of 3210 patients with EC were included. In the MMRp population, the combination (ICI and PARPi) showed a not statistically significant PFS benefit compared with each agent alone. In MMRp p53-abnormal patients (n = 590), combining PARPi and ICI statistically improved PFS compared to ICI alone (HR=0.47, 95 %CI 0.40-0.94) with a numerically better outcome compared to PARPi alone (HR=0.63, 95 %CI 0.26-1.57). No benefit from PARPi was observed in the p53 wild-type MMRp population. PD-L1-positivity (n = 1121) appears to predict more benefit from the addition of ICI and PARPi, with a larger benefit of combination therapy. In the MMRd population (n = 769), the best outcomes were observed with ICI alone, with no additional benefit of PARPi. Grade 3 or greater treatment-related adverse events were seen in 75.1 % patients treated with the combination.

Conclusions: The addition of the combination of ICI and PARPi to platinum-based chemotherapy provides greatest benefit to p53-abnormal MMRp patients. PD-L1 is a potentially useful biomarker with PD-L1-positive tumors more likely to respond to ICI. Implementation of biomarkers is crucial to redefine the treatment paradigm in a/rEC.

Keywords: Endometrial cancer; Immune checkpoint inhibitors; Molecular classification; P53; PARPi; PD-L1.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: G. Villacampa has received a speaker’s fee from Pfizer, MSD, GSK and Pierre Fabrer, has held an advisory role with AstraZeneca and received consultant fees from Reveal Genomics, outside the submitted work. G. Eminowicz reports consulting fees from MSD and Eisai; payment or honoraria from Eisai and GSK; support for attending meeting from MSD; and participation on Data Safety Monitoring Board or Advisory Board for GSK, MSD, and Eisai, outside the submitted work. V. Navarro declares no conflict of interest. L. Carità declares no conflict of interest. D. García-Illescas has received travel, accommodation, expenses, educational meetings from MSD, AstraZeneca, GSK, Speakers' bureau from AstraZeneca and GSK, research funding from Fundación La Pedrera. A. Oaknin reports personal fees for participation in the advisory boards of AstraZeneca, Clovis Oncology, Deciphera, Genmab, GSK, Immunogen, Mersana Therapeutics, PharmaMar, MSD de España, Agenus, Sutro, Corcept Therapeutics, EMD Serono, Novocure, Shattuck Labs, iTeos, and Eisai; travel and accommodation support from AstraZeneca, PharmaMar, and Roche; and funding paid to institution from AbbVie Deutschland, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Clovis Oncology, Eisai, F Hoffmann-La Roche, Regeneron Pharmaceuticals, Immunogen, MSD de España, Takeda, PharmaMar, Tesaro, and Bristol Myers Squibb, outside the submitted work. A. Pérez-Fidalgo has received a speaker’s fee from GSK, Astrazeneca, MSD, Clovis, Seagen, Karypharm, PharmaAnd, advisory board from GSK, Astrazenca, MSD, Clovis, institutional grant from GSK and Astrazeneca.

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