Philipp Harter’s research while affiliated with Vitos Gießen-Marburg and other places

LBA5500 Background: Optimal timing of cytoreduction in non-frail patients (pts) with seemingly resectable stage IIIB-IVB ovarian, tubal, and peritoneal carcinoma (OC) remains controversial. Methods: TRUST is an international randomized multicenter phase III trial in pts with stage IIIB-IVB OC and good performance status (ECOG 0/1) comparing primary cytoreductive surgery (PCS) followed by 6 cycles of intravenous (iv) chemotherapy to 3 cycles of neoadjuvant iv chemotherapy (NACT) followed by interval cytoreductive surgery (ICS) and 3 further iv cycles. Maintenance treatment with bevacizumab and/or PARP inhibitors was allowed if selection criteria was similar for both arms. Pts were eligible for the study if preoperative clinical and radiologic assessment identified them as potential candidates for PCS. To ensure surgical quality, participating centers complied with an onsite surgery quality assurance audit, had adequate infrastructure, surgical proficiency (complete resection rates ≥50% in PCS) and sufficient volume (≥36 PCS/year). The intent to treat analysis population included all eligible pts with confirmed stage IIIB-IVB disease. The primary endpoint was overall survival (OS). Superiority was tested using a two-sided stratified log-rank test with significance level 0.05. Secondary endpoints were progression-free survival (PFS) and surgical complications. Results: A total of 688 eligible pts (median age: 63y; range: 32-83) underwent randomization: 345 were assigned to PCS and 343 to NACT/ICS. 91% had high-grade serous histology. Complete resection was achieved in 61.7%/62.9% of all randomized/all operated pts in the PCS group and 72%/76.6% in the ICS group. Median PFS was 22.2 months in the PCS group, and 19.7 months in the ICS group (HR 0.80 95%CI: 0.66-0.96; p=0.02). Median OS was 54.3 months in the PCS group and 48.3 months in the ICS group (HR 0.89 95%CI: 0.74-1.08; p=0.24). Pts with complete cytoreduction after PCS had the most favorable outcome, with a median PFS and OS of 27.9 and 67.0 months, respectively. A long-term benefit from PCS was seen in all analyzed subgroups. The benefit of PCS was most prominent in stage III pts (n=468): median PFS for PCS vs ICS, 26.3 vs 21.4 mos; median OS for PCS vs ICS, 63.7 vs 53.2 months. Major postoperative complication rates were acceptable, with a 30-day postoperative mortality rate of < 1% in both groups. Conclusions: In expert centers with proven surgical quality, PCS followed by iv chemotherapy resulted in a significantly longer median PFS and a numerically longer OS compared to NACT/ICS in non-frail OC pts. Although statistical significance in the primary endpoint was not reached, this is the first randomized trial to show a benefit of PCS over ICS. This benefit is likely to be associated with the high complete resection rate, reinforcing PCS as a standard of care in non-frail pts with seemingly resectable advanced OC. Clinical trial information: NCT02828618 .

TPS5618 Background: Sacituzumab tirumotecan (sac-TMT; formerly MK-2870/SKB264) is an antibody‒drug conjugate comprising a trophoblast cell-surface antigen 2 (TROP2)–antibody, a hydrolytically-cleavable linker, and the cytotoxic drug KL610023 (average drug/antibody ratio, 7.4). In an ongoing phase 1/2 study (MK-2870-001), sac-TMT monotherapy showed promising antitumor activity in participants with locally advanced unresectable/metastatic solid tumors that were refractory to standard therapies. This phase 3, randomized, open-label, multicenter study (NCT06459180) evaluates the efficacy and safety of sac-TMT monotherapy vs treatment of physician’s choice (TPC) as second-line treatment in participants with recurrent/metastatic cervical cancer. Methods: Eligible participants are aged ≥18 years with progressive recurrent/metastatic cervical cancer, measurable per RECIST version 1.1 by the investigator, and had received 1 prior line of platinum doublet chemotherapy (±bevacizumab) and anti‒PD-1/anti‒PD-L1 therapy as a part of cervical cancer regimens. Participants must provide tissue from a core or excisional biopsy of a not previously irradiated tumor lesion. Approximately 666 participants will be randomly assigned 1:1 to receive either sac-TMT 4 mg/kg intravenously (IV) Q2W or TPC (pemetrexed 500 mg/m ² IV Q3W; tisotumab vedotin 2 mg/kg IV Q3W; topotecan 1 or 1.25 mg/m ² on days 1–5 of each 3-week treatment cycle; vinorelbine 30 mg/m ² on days 1 and 8 of each 3-week treatment cycle; gemcitabine 1000 mg/m ² on days 1 and 8 of each 3-week treatment cycle; or irinotecan 100 or 125 mg/m ² on days 1, 8, 15, and 22 of each 6-week treatment cycle). Tumor imaging will be performed ≤28 days before treatment allocation/randomisation, then Q9W until week 54 and Q12W thereafter. The primary endpoint is OS; secondary endpoints include PFS assessed by blinded independent central review, objective response, duration of response, safety, time to deterioration, and patient-reported outcomes. Enrollment began in Q3 2024. Clinical trial information: NCT06459180 .

e17548 Background: Low-grade serous ovarian cancer (LGSOC), a rare ovarian malignancy, exhibits a very limited responsiveness to chemotherapy. There is a pressing need for new therapeutic combinations with modern agents to enhance response rates and prognosis in this patient subgroup. Immune checkpoint inhibitors offer a promising pathway, having shown effectiveness in various malignant diseases, including selected cases of ovarian cancer. If our trial should show pembrolizumab effectivity in LGSOC, it would be a signal and impulse for future clinical studies in this rare disease. Methods: This multi-center, single-arm phase II study evaluates pembrolizumab in combination with platinum-based chemotherapy (carboplatin plus pegylated liposomal doxorubicin [PLD] or carboplatin plus gemcitabine) and as maintenance therapy in recurrent LGSOC. Eligible patients include those with disease progression or recurrence ≥6 months post prior platinum-based therapy and ECOG performance status 0-1. The primary endpoint is the 12-month progression-free survival (PFS) rate. Secondary endpoints include overall survival (OS), response rate (RR), PFS and RR based on Ki67 expression, time to first subsequent therapy and response, safety, and quality of life (QoL). Using Simon’s two-stage design, up to 33 patients will be enrolled. The null hypothesis is a 12-month PFS rate of 20%. In stage 1, 18 patients were enrolled, and since 5 achieved the primary endpoint, the study advanced to stage 2, enrolling 15 additional patients. Success is defined as ≥11 patients achieving 12-month PFS. Assuming a true PFS rate of 40%, the study has 5% type I error and 80% power. Results: Data from 18 patients enrolled at interim analysis were evaluated. Of these, 5 patients met the primary endpoint, while 6 patients progressed or died before achieving 12-month PFS. Ten patients remain on treatment, and 7 may still achieve the endpoint. Median patient age was 60 years (range: 43-81), with ECOG 0 in 16 patients (88.9%). Most patients had one prior chemotherapy line (61.1%; range: 1-5). Chemotherapy regimens included carboplatin + PLD (77.8%) and carboplatin + gemcitabine (22.2%). SAEs were reported in 10 patients (55.6%), with 3 (16.7%) deemed treatment-related. One SAE resulted in death but was not related to study treatment. Conclusions: Interim analysis supports the hypothesis that pembrolizumab, in combination with chemotherapy, may extends PFS in recurrent LGSOC. These promising results warrant further investigation in this rare patient population. Clinical trial information: 2023-508155-40-00 .

Purpose: Mutant TP53 stabilized by heat shock protein 90 (HSP90) is a novel target in oncology. The open-label randomized phase II GANNET53 trial is the first to evaluate the HSP90 inhibitor Ganetespib (G) with Paclitaxel (P) in platinum-resistant epithelial ovarian cancer (EUDRACT 2013-003868-31; EU FP7 #602602). Patients and Methods: Patients were randomized 2:1 to receive G+P or P alone until progression. Primary endpoints were progression-free survival (PFS) and PFS rate at six months. Exploratory endpoints were biomarkers based on p53 and HSP90. Results: A total of 133 patients were enrolled. Median PFS was 3.5 (G+P) and 5.3 months (P) (HR 1.3, 95% CI: 0.897-1.895, P = 0.16), PFS rates at six months were 22% (G+P) and 33% (P). No significant differences were found in overall survival, objective response rate and post progression PFS between arms. Most frequent adverse events (AEs) were diarrhea (79% vs. 26%), anemia (46% vs. 51%), nausea (41% vs. 40%), and peripheral neuropathy (36% vs. 47%). Serious AEs were more common in G+P (39.5% vs. 23.3%). Gastrointestinal perforation was a new safety finding. Despite of a high TP53 mutation frequency, HSP90-p53 complexes were detected in only 39.6% of the cases and were also detected stably during treatment. In-vitro, no synergistic effects of G+P were observed, and mutp53 depletion did not sensitize ovarian cancer cells to treatment. Conclusions: Although no major safety findings were observed, G+P did not lead to survival benefit. Our companion diagnostic programme confirmed that G+P do not favorably cooperate in killing ovarian cancer cells.

Surgical therapy is a cornerstone of ovarian cancer treatment. The quality of surgery is a decisive prognostic factor for patients. In early ovarian cancer (Fédération Internationale de Gynécologie et d’Obstétrique, FIGO: I-II), this is determined by complete surgical staging. In advanced stages (FIGO: III-IV), the aim is complete macroscopic resection. The operation should always be performed by midline laparotomy to allow complete inspection and palpation of the abdominal cavity. Even in the event of recurrence, the use of secondary cytoreductive surgery can achieve an advantage in overall survival in a selected group of patients.

Real-world data on treatment patterns and outcomes in recurrent or metastatic cervical cancer (r/mCC) are lacking. This first national quality assurance initiative was a retrospective analysis of patients with r/mCC diagnosed between 2018 and 2022, who were identified from medical records of 31 gynecologic cancer centers in Germany. Patient demographic and clinical characteristics, treatment patterns, and clinical outcomes were assessed descriptively. Progression-free (PFS) and overall survival (OS) were calculated using Kaplan-Meier analysis. A total of 503 eligible patients (median age 55 years) were analyzed for r/mCC. 276/503 patients (55%) received first-line (1L) chemotherapy (platinum combination: 247/276; 79%) followed by targeted antibody therapy with bevacizumab (177/247; 72%), immunotherapy (19/247; 8%), or both combined (50/247; 20%). 111/503 (22%) received chemotherapy only (platinum combination: 64/111; 58%, platinum mono: 35/111; 31%, or platinum-free: 12/111; 11%), and 110/503 (22%) did not receive any systemic treatment (the remaining 6/503 patients received immunotherapy only). For these subgroups after a median follow-up of 16 months, the PFS was 12 months (95% CI 11–14), 8.8 months (95% CI 7.1–11), and 3 months (95% CI 2.3–4.8), and OS was 25 months (95% CI 21–31), 17 months (95% CI 14–22), and 3.6 months (95% CI 2.8–5.3), respectively. 176/283 (62%) patients who developed progressive disease (PD) were treated with second-line (2L) therapy. Only half of the patients with r/mCC were treated 1L with platinum-combination therapy including antibody therapy according to national guidelines. Moreover, 22% at initial diagnosis and 38% of patients at PD were not treated with systemic therapy at all. This might reflect poor general performance status, patients’ preference, and/or lack of effective therapies especially in 2L treatment.

Purpose This is an official, recently updated guideline published and coordinated by the German Society of Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG) together with the Austrian Society of Gynecology and Obstetrics (Österreichische Gesellschaft für Gynäkologie und Geburtshilfe, OEGGG) and the Swiss Society of Gynecology and Obstetrics (Schweizerische Gesellschaft für Gynäkologie und Geburtshilfe, SGGG) as part of the guidelines program. Because of their rarity and heterogeneous histopathology, uterine sarcomas are challenging in terms of their clinical management, and treatment requires a multidisciplinary approach. Methods This S2k guideline was first published in 2015. The update published here is again the result of a structured consensus of a representative interdisciplinary group of mandate holders and experts who carried out a selective search of the literature on uterine sarcomas. Members of the participating professional societies achieved a formal consensus on recommendations and statements after a structured consensus process. Recommendations Recommendations were made about the epidemiology, classification, staging of uterine sarcomas, symptoms, general diagnostic workup, general pathology and genetic predisposition for uterine sarcomas, leiomyosarcomas, endometrial stromal sarcomas (low-grade and high-grade), undifferentiated uterine sarcomas, adenosarcomas, and rhabdomyosarcoma of the uterus in children and adolescents. The guideline also discusses the follow-up of uterine sarcomas, the management of morcellated uterine sarcomas, and the information provided to patients.

Introduction Homologous recombination deficiency (HRD) is a key biomarker in the management of high-grade serous ovarian cancer (HGSOC), guiding treatment decisions, particularly regarding the use of poly(ADP-ribose) polymerase inhibitors (PARPi). As multiple HRD assays are available, each with distinct methodologies and cutoff values, the interpretation and clinical application of HRD testing remain complex. This intergroup statement, endorsed by the German Ovarian Cancer Commission, NOGGO, AGO Austria, and AGO Swiss, aims to provide guidance on the indications, appropriate use, and limitations of HRD testing in ovarian cancer. Materials and methods The statement is based on an interdisciplinary review of available literature, clinical trial data, and expert consensus. The recommendations focus on the current landscape of HRD assays, their clinical applicability, and practical considerations regarding the optimal timing and indications for testing. Results and discussion Various HRD assays, including established commercial tests and emerging academic-clinical approaches, are reviewed in this statement. The document outlines key eligibility criteria for HRD testing in ovarian cancer, emphasizing its relevance in specific histological subtypes and clinical scenarios. Additionally, exclusion criteria are defined, highlighting cases where HRD testing may not be appropriate due to insufficient clinical validation or lack of therapeutic implications. Finally, the statement discusses the pathological minimum requirements for tissue samples used in HRD testing, ensuring adequate sample quality and tumor content for reliable results. Conclusion HRD testing is a valuable tool for personalizing ovarian cancer treatment, particularly in identifying patients who may benefit from PARPi therapy. However, assay selection, timing, and result interpretation require careful consideration. This statement provides a structured approach to optimize HRD testing, aiming to improve clinical decision-making and patient outcomes.