Abstract
Background: The year 2025 witnessed paradigm-shifting advances in gynecologic oncology, with pivotal clinical trial results redefining therapeutic standards across cervical, ovarian, endometrial, and vulvar cancers. Objectives: This systematic review aimed to comprehensively identify, synthesize, and critically evaluate pivotal phase II and III randomized controlled trials and major studies presented at the major annual meetings, alongside significant peer-reviewed publications from 2025 that introduce innovative therapeutic strategies across gynecologic malignancies. Methods: Conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, this review involved exhaustive searches of electronic databases (PubMed/MEDLINE, Embase), conference proceedings (ASCO 2025, ESMO 2025), and major oncology journals for records from January to December 2025. Inclusion criteria encompassed: (1) Phase II or III randomized controlled trials (RCTs) and (2) Non-randomized studies (including phase I and II trials), reporting on novel therapeutic approaches in gynecologic oncology. All studies were required to report primary survival endpoints (overall survival or progression-free survival) or key efficacy outcomes. Study selection, data extraction, and methodological quality assessment were performed independently by two reviewers, with disagreements resolved through consensus or third-party adjudication. Results: From 1842 records, 23 studies met inclusion criteria (17 phase-III RCTs and 6 non-phase III RCTs/early-phase studies), distributed as follows: cervical cancer (9 studies, 39%), ovarian cancer (9 studies, 39%), endometrial cancer (4 studies, 17.5%), and vulvar cancer (1 study, 4.5%). The major advances identified include: (1) In cervical cancer, the KEYNOTE-A18 trial established pembrolizumab combined with chemoradiotherapy as a new standard for high-risk locally advanced disease, while the PHENIX trial validated sentinel lymph node biopsy as a safe surgical de-escalation strategy. (2) In ovarian cancer, the ENGOT-ov65/KEYNOTE-B96 trial demonstrated the first statistically significant overall survival improvement with an immune checkpoint inhibitor in platinum-resistant recurrent disease, establishing pembrolizumab plus weekly paclitaxel as a new standard of care. Novel therapeutic mechanisms, including glucocorticoid receptor modulation (ROSELLA trial) and cadherin-6-targeted antibody-drug conjugates (REJOICE-Ovarian01), showed remarkable efficacy. (3) In endometrial cancer, updated analyses from NRG GY018 and RUBY trials solidified the role of first-line immuno-chemotherapy, with differential benefits according to mismatch repair status. (4) In vulvar cancer, a pivotal phase II study demonstrated meaningful clinical activity of anti-PD-1 therapy in advanced disease. (5) The extensive circulating tumor DNA analysis from the CALLA trial provided crucial insights into biomarker dynamics in cervical cancer. Conclusions: The convergence of high-impact data from 2025 established multiple new standards of care, emphasizing biomarker-driven approaches, immunotherapy integration across disease stages, and novel mechanisms to overcome resistance, while highlighting challenges in treatment sequencing and global access.