Randomized controlled trials remain fundamental to evidence generation in oncology but are increasingly complex, costly, and often misaligned with real-world practice. Traditional explanatory trials, designed under ideal, controlled conditions, frequently enroll highly selected populations, limiting generalizability and underrepresenting key groups such as older adults, patients with comorbidities, and those from low- and middle-income countries. Pragmatic clinical trials offer an alternative by evaluating interventions under routine care conditions, with broader eligibility, simplified procedures, and patient-centered outcomes. To address these challenges, the Gynecologic Cancer InterGroup convened an international brainstorming meeting in May 2025 with multi-disciplinary experts, patients, and advocates to define priorities and develop a roadmap for pragmatic trials in gynecologic oncology. Key discussions emphasized embedding trial design within routine care, aligning eligibility criteria and procedures with standard practice, minimizing non-essential data collection, and prioritizing outcomes meaningful to patients, including quality of life. Innovative designs such as registry-based randomized trials, trials-within-cohorts, and cluster randomization were highlighted as feasible approaches to improve efficiency while preserving internal validity. Integration of patient-reported outcomes and real-world data was considered achievable when carefully streamlined. Major challenges identified included regulatory heterogeneity, consent complexity, data interoperability, and funding limitations, particularly in multi-national settings. Proposed solutions include simplified consent models, centralized ethics processes, hybrid funding strategies, and the responsible use of artificial intelligence to enhance patient identification, recruitment, and potential development of synthetic control arms. Patient engagement was recognized as essential to ensure relevance, feasibility, and equity. Incorporation of patient-reported outcomes was discussed as key to informing acceptance and tolerability. In summary, pragmatic trials within Gynecologic Cancer InterGroup represent a critical pathway to generate efficient, inclusive, and practice-changing evidence in gynecologic cancers across diverse health care settings.

OBJECTIVE:To evaluate the long-term effectiveness and patient satisfaction following endometrial ablation for abnormal uterine bleeding (AUB), with a focus on radiofrequency ablation. METHODS:This retrospective cross-sectional single-center study aims to assess the efficacy and patient satisfaction after endometrial ablation. We analyzed data from 1,757 patients treated for AUB at the Medical University of Innsbruck between 2004 and 2022, including 609 patients who underwent radiofrequency ablation (NovaSure) between 2014 and 2018. Patient-reported outcome were evaluated through standardized telephone interviews. RESULTS:NovaSure was the most commonly used method (63%, 1115/1757), followed by ThermaChoice balloon ablation (29%, 512/1757) and hydrothermoablation (1.6%, 29/1757). The median patient age was recorded as 46 years. Hysterectomy was required in 13% (229/1757) of cases, of which 6.9% (122/229) were due to persistent or recurrent AUB, while 6.1% (107/229) were performed for unrelated indications, including uterine prolapse, adnexal cysts, or endometrial hyperplasia/neoplasia. Among 431 patients with long-term check-up, 90% reported satisfaction, 64% (276/431) achieved amenorrhea, while 83% (358/431) required no further surgery. In multivariate analysis, increasing age was associated with a lower risk of hysterectomy (OR 0.97, p = 0.025) but a higher risk of treatment failure (OR 1.06, p = 0.016). Outcomes were mainly influenced by fibroid-related bleeding, with overall results confirming sustained bleeding reduction and high patient satisfaction. CONCLUSION:Endometrial ablation is a highly effective and well-tolerated treatment for AUB, achieving high patient satisfaction and significant bleeding reduction over a long-term period. Careful patient selection and preoperative assessment are crucial to optimizing outcomes and minimizing the need for secondary interventions.

Importance A subset of patients with platinum-sensitive recurrent ovarian cancer (PS-ROC) treated with maintenance poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have exceptional response. Although licensing recommends continuing PARP inhibitors until progression or unacceptable toxic effects, the optimal duration of PARP inhibitors, and the risks of late progression, myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML) in patients with exceptional response are unknown. Objective To determine the long-term outcomes of patients with PS-ROC who have exceptional response to PARP inhibitors, and to explore genotype-phenotype associations. Design, Setting, and Participants This was an international, multicenter, retrospective cohort study of patients with exceptional response to PARP inhibitors, defined as patients with PS-ROC and progression-free survival (PFS) of 5 years or longer from PARP inhibitor commencement. The study was conducted across 41 sites in 14 countries from January 11, 2023, to November 10, 2025. Exposures Treatment with PARP inhibitors. Main Outcomes and Measures The primary end point was PFS, and secondary end points included overall survival, toxic effects, and dose reductions. Results A total of 320 patients with exceptional response (mean [SD] age, 56.4 [9.4] years) were included, with a median follow-up of 6.8 years (95% CI, 6.6-7.0 years). The median (IQR) PARP inhibitor duration was 75.0 (64.0-91.0) months. Of patients with exceptional response, 211 (65.9%) received continuous PARP inhibitors, but 109 (34.1%) discontinued: 34 (10.6%) due to physician recommendation, 2 (7.5%) had disease progression beyond 5 years, 22 (6.9%) had toxic effects, 17 (5.3%) for patient preference, and 12 (3.8%) for another reason. The 7.5-year and 10-year PFS rates were 88.8% (95% CI, 84.5%-93.3%) and 78.7% (95% CI, 70.5%-87.9%), respectively. Among the patients, 85 (26.6%) discontinued PARP inhibitors for reasons other than disease progression, with a 10-year PFS of 90.1% (95% CI, 80.6%-100%) vs 72.5% (95% CI, 60.3%-87.2%) for those who continued taking PARP inhibitors. Five patients (1.6%) were diagnosed with late-onset MDS/AML. Patients with exceptional response were enriched for variants in the BRCA1 RING domain and the BRCA2 DNA-binding domain. Conclusions and Relevance In this cohort study, most patients with exceptional response to PARP inhibitors remained progression free, including those who discontinued PARP inhibitors without progression. The risk of late-onset MDS/AML was low. These results can guide counseling on the duration of maintenance PARP inhibitors in patients with exceptional response and suggest that functional cure may be possible in patients with PS-ROC and exceptional response to PARP inhibitors.

OBJECTIVE:In BRCA-mutated (BRCAmut) patients, while sensitivity to platinum has been assessed, the efficacy of other chemotherapy drugs, such as paclitaxel, in the recurrent setting is less defined. To this purpose, a single-center retrospective study was designed to evaluate the effects of paclitaxel monotherapy in patients with platinum-resistant ovarian cancer based on BRCA status. METHODS:We collected data on patients with recurrent high-grade epithelial ovarian cancer treated with paclitaxel monotherapy between November 2017 and October 2024. Only patients who received 2 to 4 previous lines of chemotherapy before paclitaxel were selected. BRCAmut patients were compared with BRCA wild-type (BRCAwt) patients. The primary outcome was the impact of paclitaxel monotherapy on overall survival in both groups separately. The secondary outcomes were progression-free survival, response rate, and toxicity profile. RESULTS:Of 175 patients who received paclitaxel, 155 met the inclusion criteria: 50 (32.3%) BRCAmut and 105 (67.7%) BRCAwt patients. Median progression-free survival was 5 months (95% confidence interval [CI] 3.58 to 6.42) in the BRCAwt group compared with 4 months (95% CI 2.29 to 5.71) in the BRCAmut group (p = .013). In BRCAmut patients, median overall survival was 11 months (95% CI 8.28 to 13.72) compared with 18 months for the BRCAwt group (95% CI 16.04 to 19.96) (p < .001). In the 93 patients who had previously received poly (ADP-ribose) polymerase (PARP) inhibitors, overall survival remained significantly longer in BRCAwt patients (p = .004), but not progression-free survival (p > .05). CONCLUSIONS:Treatment with paclitaxel monotherapy seems to be less effective in patients with recurrent platinum-resistant BRCAmut ovarian cancer compared with the BRCAwt population. Further clinical studies are needed to confirm these data and investigate potential mechanisms of paclitaxel resistance in BRCAmut carriers.

Definitive radiochemotherapy with external beam radiotherapy and brachytherapy is standard for locally advanced cervical cancer (LACC). Advanced techniques like intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) have replaced 3D-conformal radiotherapy (3DCRT). This study compares two institutional definitive radiotherapy treatment pathways implemented in different time periods: 3DCRT with five BT fractions and IMRT/VMAT with four BT fractions. This retrospective single-center study included 145 patients with FIGO 2018 stage IB3–IVA LACC treated during 2008–2023. Patients received 3DCRT+5BT (2008–2016; n = 77) or IMRT/VMAT+4BT (2017–2023; n = 68) with concurrent chemotherapy. Histopathological biopsies at final BT evaluated tumor response. Dosimetric parameters (HRCTV-D90–EQD2₍₁₀₎ and OAR-D2cc for bladder, rectum, sigmoid) were analyzed. Endpoints included treatment duration, residual tumor, progression-free survival (PFS), overall survival (OS), and toxicity. After a median follow-up of 60 months, no significant differences were seen in PFS (HR 0.68, 95

Background: The 2025 ESGO/ESTRO/ESP guideline for endometrial carcinoma (EC) integrates molecular classification into clinical decision-making and, for the first time, recommends the subdivision of carcinomas with no specific molecular profile (NSMP) according to estrogen receptor (ER) status and histological grading. However, NSMP carcinomas remain a highly heterogeneous subgroup, posing challenges in terms of diagnosis and therapy. Case presentation: We report the case of a 71-year-old female patient with low-grade NSMP EC. Due to ER-negativity and strong L1 cell adhesion molecule (L1CAM) expression, the German/Austrian/Swiss S3 guideline at that time required comprehensive histopathological reassessment, which reclassified the tumor as mesonephric-like adenocarcinoma. Extended molecular profiling further identified a KRAS mutation and the absence of common alterations in PTEN, PIK3CA, and PIK3R1. These features correspond to the aggressive “Cluster 3” subgroup of NSMP tumors, characterized by ER-negativity, L1CAM positivity, KRAS mutations, and frequent chromosome 1q gain. The patient therefore underwent adjuvant carboplatin/paclitaxel chemotherapy followed by vaginal brachytherapy and has remained recurrence-free for five years. Conclusion: This case demonstrates molecular classification of an unusual histological type of EC exhibiting an extremely short-term risk of early distant metastasis and its implication on aggressive adjuvant therapeutical approach. It, furthermore, exemplifies the pronounced heterogeneity of the NSMP subgroup.

Background: The prognostic role of the Systemic Immune-Inflammation Index (SII) in patients with endometrial cancer (EC) treated with pembrolizumab plus lenvatinib (Len-Pem) is unknown. In this study, the association between baseline SII and progression-free survival (PFS) was evaluated. Methods: This is a monocentric, observational, retrospective/ambispective study including patients with advanced, recurrent, or metastatic mismatch repair proficient (pMMR) EC treated with Len-Pem. Results: Fifty-three patients were enrolled, with a median age of 64 years. Median PFS in the overall population was 7.1 months; median OS was 15 months. Patients with baseline SII ≤ 540 had significantly longer PFS (12.5 months) compared to those with SII > 540 (5.5 months; HR 2.94, p = 0.004). Higher SII was also significantly associated with increased risk of specific toxicities, including nausea, anorexia, and vomiting. The Overall Response Rate (ORR) was 42%, and Disease Control Rate (DCR) was 71%. Conclusion: Our real-world study supports the hypothesis-generation of a prognostic role for SII in predicting outcomes and toxicity in EC patients treated with Len-Pem. SII may serve as a cost-effective, accessible biomarker to stratify patients and hypothetically guide clinical decision-making. Further prospective studies are warranted to validate its clinical utility and to optimize dosing strategies that balance efficacy and tolerability.

BACKGROUND:To clarify the prevalence and clinical utility of molecular biomarkers in vulvar cancer, we performed a review of systematic and high-quality narrative reviews, complemented by interrogation of public repositories containing genomic datasets. Our objectives were to (i) quantify biomarker prevalence across vulvar cancer subtypes, (ii) evaluate their prognostic and predictive value, and (iii) identify actionable therapeutic targets. METHODS:A review of reviews following the Joanna Briggs Institute's Manual for Evidence Synthesis was conducted using MEDLINE, Scopus, Web of Science, and ProQuest from inception to October 1, 2025 (PROSPERO CRD420251080015). Additional genomic data were obtained from cBioPortal, SRA, GEO, EGA, Zenodo. Eligible publications were systematic or high-quality narrative reviews (SANRA ≥8/12) reporting the prevalence or clinical associations of molecular biomarkers in primary or recurrent vulvar malignancies. Systematic reviews were appraised with AMSTAR-2 and narrative reviews with SANRA by two blinded reviewers, with arbitration by a third when needed. Biomarkers' pooled prevalence estimates were generated, and prognostic or predictive associations were synthesized. Public sequencing datasets were examined to identify clinically actionable alterations. RESULTS:Thirteen reviews (four systematic with meta-analysis, and nine narrative) met the inclusion criteria. HPV-independent vulvar tumors showed high pooled prevalences of TP53 mutations (0.57, 95% CI 0.43-0.71) and CDKN2A alterations (0.16, 95% CI 0.09-0.25), both linked to poorer survival and increased recurrence. HPV-associated vulvar squamous cell carcinomas demonstrated strong p16^INK4A overexpression (0.84, 95% CI 0.72-0.94), correlating with more favorable outcomes. Recurrent PIK3CA, HRAS, and FGFR3 variants emerged as potential therapeutic targets. Activating BRAF and c-KIT mutations were frequent in vulvar melanoma, while ERBB2/HER2 amplification was noted in invasive Paget disease. CONCLUSIONS:Molecular profiling underscores the biological heterogeneity of vulvar cancer and suggests opportunities for improved risk stratification and targeted therapy. Validation in prospective biomarker-driven trials is needed before routine clinical adoption.

OBJECTIVE:We report outcomes for the sub-group of participants who only received neoadjuvant, adjuvant, or neoadjuvant+adjuvant platinum-based chemotherapy before enrollment in the phase 3 Study 309/KEYNOTE-775 (NCT03517449) and ENGOT-en9/LEAP-001 (NCT03884101). METHODS:Study 309/KEYNOTE-775 enrolled participants with advanced/recurrent/metastatic endometrial cancer with disease progression after 1 previous line of platinum-based chemotherapy (2 allowed if initially given as [neo]adjuvant therapy). ENGOT-en9/LEAP-001 enrolled participants with stage III-IV or recurrent, radiographically apparent endometrial cancer and no previous chemotherapy or disease progression ≥6 months after (neo)adjuvant platinum-based chemotherapy. In both trials, participants were randomized 1:1 to lenvatinib 20 mg once daily+pembrolizumab 200 mg every 3 weeks or chemotherapy (doxorubicin or paclitaxel in Study 309/KEYNOTE-775, carboplatin+paclitaxel in ENGOT-en9/LEAP-001). Overall survival and progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review) were primary endpoints. RESULTS:In Study 309/KEYNOTE-775 (n = 300), median (95% confidence interval) overall survival was 17.4 (14.0 to 22.8) months with lenvatinib+pembrolizumab and 13.3 (10.9 to 15.5) months with chemotherapy (hazard ratio [95% confidence interval], 0.67 [0.52 to 0.87]). Median (95% confidence interval) progression-free survival was 7.2 (5.6 to 8.0) and 3.9 (3.6 to 5.4) months (hazard ratio [95% confidence interval], 0.52 [0.40 to 0.68]). Objective response rates were 34.3% versus 16.6%. In ENGOT-en9/LEAP-001 (n = 121), median (95% confidence interval) overall survival was 35.4 (26.6 to not reached) months with lenvatinib+pembrolizumab and 22.1 (16.4 to 34.8) months with chemotherapy (hazard ratio [95% confidence interval], 0.66 [0.42 to 1.03]). Median (95% confidence interval) progression-free survival was 15.0 (8.3 to 21.0) and 8.3 (6.2 to 10.2) months (hazard ratio [95% confidence interval], 0.52 [0.33 to 0.81]). Objective response rates were 63.5% versus 43.1%. In both trials, the most common treatment-related adverse events with lenvatinib+pembrolizumab were hypertension (62.4%/60.3%) and hypothyroidism (58.2%/60.3%). CONCLUSIONS:In this sub-group analysis of participants who only received neoadjuvant, adjuvant, or neoadjuvant+adjuvant platinum-based chemotherapy before enrollment, lenvatinib+pembrolizumab demonstrated better anti-tumor activity and favorable outcomes versus chemotherapy with manageable safety. Lenvatinib+pembrolizumab is approved for patients with advanced endometrial cancer and could be considered an effective treatment option in this sub-group.

JARID1A is a histone demethylase involved in cell cycle regulation, epigenetic remodeling, and cancer progression. While it has been associated with tumor-promoting processes such as epithelial-to-mesenchymal transition and chemoresistance in several cancer types, its exact role in ovarian cancer remains poorly defined. In this study, we analyzed JARID1A mRNA-expression in a well-characterized cohort of 179 epithelial ovarian cancers (OC), with a focus on advanced high-grade serous and endometrioid subtypes (HGOC). High JARID1A expression was significantly associated with unfavorable tumor features, including advanced FIGO stage (P=0.016), high tumor grade (P<0.001) and adverse molecular markers. However, prognostically it was linked to improved progression-free and overall survival (P=0.001 and P=0.001, respectively) and remained an independent predictor of favorable prognosis in multivariate analysis (HR=0.44 for PFS (P=0.001), HR=0.49 for OS (P=0.006). This was also corroborated by validation with external data sets. It is tempting to speculate that in advanced HGOC high JARID1A expression may contribute to growth-inhibitory mechanisms or less proliferative tumor states, despite its association with established markers of aggressiveness. Taken together, our findings identify JARID1A mRNA-expression as a favorable prognostic marker, whose therapeutic inhibition should, at present, be approached with caution in high-grade ovarian cancer.

The identification of novel molecular drivers and the development of new state-of-the-art therapies are critical challenges in ovarian cancer (OC) treatment. Cyclin-dependent kinase 12 (CDK12) is a promising target, as it’s functional activity promotes genomic stability. Here, we examined the anticancer efficacy of the dual CDK12/13-inhibitor SR-4835 in platinum-sensitive and -resistant OC cell lines, as well as its potential as a drug partner for platinum or olaparib combination therapy. SR-4835 exhibited potent anti-proliferative effects on most OC cell lines with IC50 values within the nanomolar range. A tendency for increased sensitivity of the cisplatin-resistant compared to their sensitive, parental cell lines was observed. Transcriptome analyses indicated gross changes in gene expression in numerous signaling pathways by SR-4835. Gene downregulation was in part due to alternative exon usage, which correlated with the number of intronic polyadenylation sites per gene and gene length. Furthermore, SR-4835 lead to the downregulation of key homologous recombination pathway genes rendering a BRCAness phenotype. However, the combination of SR-4835 with cisplatin or olaparib primarily exhibited an additive, not synergistic, effect. In summary, the present findings indicate that CDK12/13 inhibitor SR-4835 has potent anti-cancer effects accompanied by a BRCAness induction, but fails to achieve synergistic effects with cisplatin or olaparib in OC cells.

Objective: Squamous cell carcinoma antigen (SCC-A) is a widely used biomarker for squamous cell cervical carcinoma and pretreatment elevation is associated with poor prognosis. Normalization during chemoradiation correlates with PET-CT response and survival. This study assessed the prognostic value of SCC-A normalization for biopsy-proven pathological response and survival outcomes. Materials and Methods: This retrospective single-center cohort study included patients with locally advanced or node-positive squamous cell cervical cancer treated with definitive chemoradiation at the Medical University Innsbruck between 2008 and 2023. Eligible patients had baseline SCC-A ≥ 2 ng/mL and at least two additional measurements within 42 days of treatment. SCC-A normalization was evaluated at predefined weekly time points. Associations with biopsy-assessed residual disease, PFS, and OS were assessed. Results: Of 186 screened patients, 83 met the inclusion criteria. Within 42 days, 70% achieved SCC-A normalization, with a median time of 21 days (IQR 19-32). Among predefined time points, normalization by day 28 was associated with reduced odds of residual disease (OR 0.14; 95% CI 0.04-0.44) and improved PFS (HR 0.28; 95% CI 0.12-0.63) and OS (HR 0.37; 95% CI 0.14-0.96), remaining independently significant after multivariate adjustments. Conclusions: SCC-A normalization during chemoradiation is a non-invasive independent biomarker of treatment response. Normalization within 28 days identifies patients at low risk of residual disease, progression, and death, supporting its use for early risk stratification and response monitoring for potential treatment adaptations.

INTRODUCTION:Despite response to up-front treatment, patients with ovarian cancer remain at high risk of recurrence, with poor survival. Immunotherapy plus chemotherapy, alone or in combination with poly(ADP-ribose) polymerase inhibitors (PARPi) or VEGF inhibitors, has been investigated in ovarian cancer, with heterogeneous results. METHODS:A meta-analysis of randomized phase III trials was conducted. PubMed, EMBASE, ClinicalTrials.gov, and congress proceedings were systematically searched. Two comparisons were performed: i) mono-immunotherapy throughout and the relative control arm; ii) immunotherapy plus PARPi and the relative control arm. The primary endpoint was the progression-free survival (PFS) and was analyzed in the overall population and by bevacizumab use, BRCA/homologous recombination deficiency (HRD) status, and PD-L1 expression. RESULTS:Six trials, involving 6465 patients, were analyzed. In the overall population, immunotherapy did not affect PFS, alone [Hazard ratio (HR) 0.94, 95% Confidence Interval (CI) 0.85-1.05] or with PARPi (HR 0.83, 95% CI 0.62-1.12). Potential benefits are suggested in selected populations. Immunotherapy plus PARPi and bevacizumab significantly improved PFS (HR 0.71, 95% CI 0.58-0.85). A PFS benefit was observed in the HRD-positive, BRCA wild-type and PD-L1-negative populations receiving immunotherapy plus PARPi (HR 0.71, 95% CI 0.52-0.97 and HR 0.72, 95% CI 0.57-0.91, respectively) compared to control groups. Mono-immunotherapy showed a slight advantage in HRD-negative patients (HR 0.87, 95% CI 0.78-0.98). CONCLUSION:In first-line treatment of advanced ovarian cancer, immunotherapy ± PARPi does not provide PFS benefits in unselected patients. However, efficacy signals in specific subgroups support the need for biomarker-driven strategies and optimized trials.

Background:Patients with osseous metastatic breast cancer receive bone-modifying agents (BMAs) as part of their standard care. Medication-related osteonecrosis of the jaw (MRONJ) is one of the most important toxicities of this class of drugs. MRONJ heavily impacts patients' quality of life and represents a major medical burden necessitating a discontinuation of treatment. Currently, the diagnosis of MRONJ is established upon the manifestation of clinical symptoms like exposed necrotic jawbone, pain, swelling or signs indicative of infection of the jaw. The objective of this study was to assess the potential of imaging modalities, specifically FDG-PET/CT (positron emission tomography with computed tomography) in the early detection of MRONJ. Methods:This cohort study in Austria included all patients with metastatic breast cancer who were receiving denosumab and regular PET/CTs, diagnosed with MRONJ between 2000 and 2022 at the Department of Obstetrics and Gynecology Innsbruck. For each of the patients in the study cohort, two control patients with comparable clinical characteristics were matched to serve as a control group. Control patients with metastasized breast cancer did not develop MRONJ but did receive denosumab and regular FDG-PET/CTs. Imaging data were independently assessed by two experienced nuclear medicine physicians. Findings:Baseline characteristics were well balanced. Patients received 120 mg denosumab once per month subcutaneously without de-escalation of therapy. The median time to develop MRONJ was 23 months (range 5-71, lower Quartile (Q1), upper Quartile (Q3) 16, 40 months). Nuclear medicine physicians detected jaw alterations in 91% (19/21) of MRONJ cases (sensitivity, 95% CI: 70%-98.8%) and in 29% (12/42) of controls, corresponding to a specificity of 71% (30/42; 95% CI: 55%-84%). Median lead time of imaging by demonstrating lesion in the jaw was 238 days (range 11-1118, Q1, Q3 106,494) prior to MRONJ diagnosis. In 68% (13/19) of MRONJ cases the nuclear medicine physicians were able to predict the exact tooth location of MRONJ with a deviation of no more than two teeth. Interpretation:The high sensitivity and negative predictive value of imaging for early detection of MRONJ underscore its significance for clinical practice. Given that the majority of patients receive regular PET/CTs, our results provide an excellent opportunity for early intervention when MRONJ is detected with a considerable lead time. Funding:This study received no external funding.

OBJECTIVE:Evidence on the clinical utility of baseline human epididymis protein 4 levels and their kinetics in recurrent ovarian cancer remains limited. This study evaluated longitudinal human epididymis protein 4 dynamics in real-world patients treated with platinum-based chemotherapy, aiming to determine the prognostic significance of human epididymis protein 4 kinetic parameters compared with CA125 response and established prognostic factors for progression-free and overall survival. METHODS:This retrospective analysis included 220 patients with recurrent epithelial ovarian cancer treated with second-line platinum-based chemotherapy between 2000 and 2020. Four mathematical models were tested to describe human epididymis protein 4 kinetics, with model selection based on goodness of fit, visual predictive checks, and prognostic performance. The prognostic value of the most informative human epididymis protein 4 kinetic parameter (the modeled residual human epididymis protein 4 level), was assessed in univariable and multi-variable analyses. RESULTS:Among the 93 assessable patients, no clear associations were observed between baseline human epididymis protein 4 levels and disease characteristics. Longitudinal human epididymis protein 4 kinetics differed from those of CA125 and showed an initial decline followed by a plateau at approximately 40 days. The best-fitting model was a mono-exponential decline incorporating the modeled residual human epididymis protein 4 parameter, which was subsequently evaluated as a prognostic factor. Baseline human epididymis protein 4 levels lacked prognostic significance for progression-free or overall survival. In contrast, a higher modeled residual human epididymis protein 4 level was significantly associated with shorter progression-free and overall survival in univariable analyses (residual human epididymis protein 4 ≥median vs <median; median progression-free survival: 7.2 vs 12.6 months, p =.002; median overall survival: 16.5 vs 34.9 months; p =.001) and in multi-variable models (overall survival: hazard ratio 2.65; 95% confidence interval 1.23 to 5.71, p =.012) alongside CA125 response. CONCLUSIONS:In this study, we identified residual HE4 levels in patients treated with second-line platinum-based chemotherapy as an independent dynamic marker of overall survival, with higher levels indicating poorer outcomes and potential chemoresistance.