Domenica Lorusso

European training requirements for gynecological oncology: the European Society of Gynaecological Oncology Curriculum

Surgical timing in advanced ovarian cancer during the TRUST trial era: A systematic review, meta-analysis and study-level meta-regression of randomized controlled trials

The best surgical timing for advanced epithelial ovarian cancer, whether primary debulking surgery or interval debulking surgery, remains debated. Recent data, including the preliminary ones from TRUST trial, necessitates an updated critical evaluation. A systematic search of PubMed identified only randomized controlled trials comparing interval debulking surgery versus primary debulking surgery in patients with newly diagnosed advanced ovarian cancer. Primary outcomes included overall survival (OS) and progression-free survival (PFS). A random-effects meta-analysis, meta-regression, cumulative synthesis, and leave-one-out influence analysis were performed. A total of 2303 patients were included. Compared to primary debulking surgery, interval debulking surgery was associated with lower rates of postoperative complications (OR = 0.37; 95 % CI: 0.18-0.79; P = 0.01) and mortality (OR = 0.23; 95 % CI: 0.09-0.57; P = 0.002). Meta-analysis showed higher rates of complete cytoreduction with interval debulking surgery (OR = 3.84; 95 % CI: 2.14-6.91; P < 0.00001) and lower rates of macroscopic residual disease (OR = 0.20; 95 % CI: 0.13-0.30; P < 0.00001). Pooled data revealed no significant difference in OS (HR = 0.95; 95 % CI: 0.87-1.04; P = 0.26) or PFS (HR = 0.94; 95 % CI: 0.85-1.03; P = 0.16). Subgroup analyses by stage and residual disease confirmed similar survival outcomes. The meta-regression results suggested that even in trials with very high complete cytoreduction rates, no clinically meaningful OS benefit was observed for upfront surgery. In conclusion, interval debulking surgery offers comparable survival outcomes to primary debulking, with reduced perioperative morbidity and mortality, supporting its role as a valid surgical alternative. PROSPERO REGISTRATION NUMBER: CRD420251105308.

Preclinical Activity of Datopotamab Deruxtecan (Dato-DXd), an Antibody–Drug Conjugate Targeting TROP2, in Poorly Differentiated Endometrial Carcinomas

Abstract Datopotamab deruxtecan (Dato-DXd) is a novel antibody–drug conjugate (ADC) targeting trophoblast antigen-2 (TROP2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver DXd, a potent topoisomerase I inhibitor. We evaluated TROP2 expression in primary endometrial cancer cell lines and the activity of Dato-DXd against endometrial cancer cell lines with different TROP2 expression in vitro and in vivo. TROP2 expression was assessed in nine primary tumor cell lines by flow cytometry. Cell viability after exposure to Dato-DXd was evaluated using flow cytometry–based assays to calculate the IC50. Bystander effect assay assessed the viability of TROP2-negative cells when cocultured with high TROP2-expressing cells. Fluorescent anti–phosphorylated histone H2AX antibody was used to demonstrate double-strand DNA breaks. Antibody-dependent cell cytotoxicity was tested in vitro using 4-hour chromium release assays. In vivo activity of Dato-DXd was evaluated against TROP2-positive endometrial cancer xenografts. A total of 78% (seven of nine) of the primary endometrial cancer cell lines expressed TROP2. Endometrial cancer cell lines expressing TROP2 were significantly more sensitive to Dato-DXd compared with control ADC. Dato-DXd–exposed, TROP2-positive endometrial cancer demonstrated increased double-strand DNA breaks compared with non-binding conjugate exposure. Dato-DXd mediated antibody-dependent cell cytotoxicity against TROP2-positive cell lines and induced significant bystander killing of TROP2-negative tumors when admixed with TROP2-positive tumors. In vivo, injection of Dato-DXd was well tolerated and demonstrated impressive tumor growth inhibition against chemotherapy-resistant poorly differentiated endometrial cancer xenografts (P &amp;lt; 0.0001). In conclusion, Dato-DXd is a novel ADC with remarkable preclinical activity against poorly differentiated endometrial cancer cell lines overexpressing TROP2. Clinical trials with Dato-DXd in patients with recurrent endometrial cancer are warranted. Significance: Targeted treatment of aggressive forms of endometrial cancer using the biomarker TROP2 is a significant opportunity for the development of treatments when patients are resistant to other lines of treatment. Here, we present data showing preclinical evidence of effectiveness of this biomarker-targeted therapy in endometrial cancer.

Mirvetuximab soravtansine in folate receptor alpha (FRα)–high platinum-resistant ovarian cancer: final overall survival and post hoc sequence of therapy subgroup results from the SORAYA trial

Objective The single-arm, phase II SORAYA trial ( NCT04296890 ) of mirvetuximab soravtansine-gynx in folate receptor alpha (FRα)–high platinum-resistant ovarian cancer (n=105 (efficacy-evaluable)) met its primary endpoint with an objective response rate of 32.4% (95% CI, 23.6 to 42.2). Here we report final SORAYA trial results for overall survival and post hoc objective response rates in subgroups by sequence and number of prior therapies. Methods Eligible patients had high-grade serous platinum-resistant ovarian cancer with high FRα expression and one to three prior therapies (prior bevacizumab required). Enrolled participants received 6 mg/kg mirvetuximab soravtansine-gynx adjusted ideal body weight intravenously once every 3 weeks until progressive disease, unacceptable toxicity, withdrawal of consent, or death. Final overall survival and post hoc objective response rates were assessed in efficacy-evaluable participants. The safety population included all patients who received ≥1 dose of mirvetuximab soravtansine-gynx. Results At data cut-off (December 22, 2022; n=105), final median overall survival was 15.0 months (95% CI, 11.5 to 18.7). Median overall survival in participants with one to two prior therapy lines was 18.7 months (95% CI, 13.8 to not estimable (NE)) and 11.6 months (95% CI, 7.1 to 16.7) with three prior therapy lines. Median overall survival was 15.0 months (95% CI, 11.5 to NE) in participants with prior poly (ADP-ribose) polymerase inhibitor (PARPi) treatment versus 14.0 months (95% CI, 7.1 to NE) in those without. Objective response rate (data cut-off: November 17, 2021) differed among participants who received mirvetuximab soravtansine-gynx as their first treatment in the platinum-resistant setting (34.8%; 95% CI, 23.5 to 47.6) versus a different first treatment (28.2%; 95% CI, 15.0 to 44.9) or had received prior bevacizumab in a platinum-sensitive (34.0%; 95% CI, 24.6 to 44.5) versus platinum-resistant setting (17.6%; 95% CI, 3.8 to 43.4). No new safety signals were observed. Conclusion These results support the clinically meaningful efficacy of mirvetuximab soravtansine-gynx in FRα-expressing platinum-resistant ovarian cancer, irrespective of prior treatment or sequence.

Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial

In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status. Patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This Of 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk. This

Genomic instability analysis in DNA from Papanicolaou test provides proof-of-principle early diagnosis of high-grade serous ovarian cancer

Late diagnosis and the lack of screening methods for early detection define high-grade serous ovarian cancer (HGSOC) as the gynecological malignancy with the highest mortality rate. In the work presented here, we investigated a retrospective and multicentric cohort of 250 archival Papanicolaou (Pap) test smears collected during routine gynecological screening. Samples were taken at different time points (from 1 month to 13.5 years before diagnosis) from 113 presymptomatic women who were subsequently diagnosed with HGSOC (pre-HGSOC) and from 77 healthy women. Genome instability was detected through low-pass whole-genome sequencing of DNA derived from Pap test samples in terms of copy number profile abnormality (CPA). CPA values of DNA extracted from Pap test samples from pre-HGSOC women were substantially higher than those in samples from healthy women. Consistently with the longitudinal analysis of clonal pathogenic TP53 mutations, this assay could detect HGSOC presence up to 9 years before diagnosis. This finding confirms the continual shedding of tumor cells from fimbriae toward the endocervical canal, suggesting a new path for the early diagnosis of HGSOC. We integrated the CPA score into the EVA (early ovarian cancer) test, the sensitivity of which was 75% (95% CI, 64.97 to 85.79), the specificity 96% (95% CI, 88.35 to 100.00), and the accuracy 81%. This proof-of-principle study indicates that the early diagnosis of HGSOC is feasible through the analysis of genomic alterations in DNA from endocervical smears.

ENDOESTRO score: Where is the dark side? Evaluation of estrogen receptor expression cutoff in endometrial cancer molecular classification, an ambispective study

Estrogen receptor (ER) expression has prognostic value in endometrial cancer (EC), also in the context of molecular classification. However, a standardized cutoff to define ER positivity is lacking. To identify the ER expression cutoff that best correlates with survival outcomes overall and within each molecular subgroup. We conducted an ambispective study comprising a retrospective phase (Feb 2017-Feb 2022) and a prospective phase (Mar 2022-Jan 2024), including patients with EC who underwent surgery at our institution. In the retrospective cohort, molecular subgroups were defined by immunohistochemistry (IHC): 1) MMRp Among 2084 patients, ER < 10 % was the strongest cutoff for prognosis based on disease-free survival (DFS). Patients with ER < 10 % and < 1 % shared similar unfavorable clinicopathological and molecular features, while ER ≥ 10 % was associated with more favorable profiles. ER < 10 % was an independent adverse prognostic factor in uni- and multivariate analyses for DFS and overall survival, particularly in MMRp ER < 10 % expression is a robust prognostic indicator, associated with worse outcomes and may serve as a clinically meaningful cutoff in endometrial cancer risk stratification. Further prospective validation is warranted.

Predictive factors for adnexal involvement in endometrial cancer FIGO stage IIIA

Understanding ovarian involvement incidence and risk factors in women with endometrial cancer may inform the decision of ovary preservation. Our retrospective study included all consecutive fully surgically staged patients with endometrial cancer who underwent primary surgery between January 2005 and November 2021, assessing the incidence of ovarian metastasis, its role as a prognostic factor for recurrence and death, and evaluated predictors of adnexal involvement. Women with International Federation of Gynecology and Obstetrics (FIGO) 2009 IIIA endometrial cancer comprised 2.3% of the population (36 of 1535 included patients), 23 (63.9%) with endometrioid histology, and a median age of 57.0 years (range 47.7-66.7). A higher body mass index, post-menopausal status, endometrioid histotype, and β-catenin expression were associated with a lower risk of adnexal involvement. Conversely, dMMR phenotype, p53 expression, myometrial infiltration >50%, lymphovascular space invasion, and cervical stromal invasion were independent predictors of an increased risk of adnexal involvement. A total of 145 (9.5%) patients had adnexal involvement, with an incidence rate of 0.27/100 person-days. Overall survival for FIGO (2009) stage IIIA was 88.9%. Our study showed that ovarian preservation may be considered for younger patients with low-risk endometrial cancer (G1 and G2 tumors, absence of lymphovascular space invasion, no cervical involvement, and myometrial invasion <50%), adding a favorable predictive role to higher body mass index and high β-catenin expression.

Genome tumor profiling in endometrial cancer and clinical relevance in endometrial cancer management: a retrospective single-center experience

Next-generation sequencing (NGS) analysis has become an essential tool for endometrial carcinoma management. Moreover, molecular-driven therapies play an increasingly remarkable role in the era of precision oncology. This study aims to determine the clinical relevance of NGS testing in endometrial carcinoma management by analyzing the clinical benefit of NGS-driven targeted therapies. A single-center retrospective study was conducted on 25 endometrial carcinoma patients who underwent Foundation Medicine CDx assay at Fondazione Policlinico Universitario Agostino Gemelli, IRCCS (Rome, Italy). Tumor samples were analyzed by Foundation One CDx. A descriptive analysis of tumor genome profiles was performed. Assessment of clinical benefit according to RECIST 1.1 criteria was analyzed for patients who received a tailored treatment according to actionable targets identified by NGS testing. Out of 25 endometrial carcinoma patients, 11 received targeted therapy. One patient was excluded from the clinical benefit assessment because of COVID-19-related death 1 month after starting the treatment. Eight of the remaining 10 patients benefited from targeted therapies, with an overall clinical benefit rate of 80%. A targeted agent belonging to the PI3K pathway was given to seven patients, with evidence of three partial responses (42.9%), three stable diseases (42.9%), and one progressive disease (14.2%) according to RECIST 1.1 criteria. One complete response (33.3%), one stable disease (33.3%), and one progressive disease (33.3%) were observed in the three patients treated with poly(ADP-ribose) polymerase (PARP) inhibitors according to their homologous recombination deficiency (HRD) status. This study highlights the importance of characterizing the mutation profile of patient tumors through NGS. Our findings suggest a clinical benefit of using NGS-driven targeted therapies in endometrial carcinoma patients. However, this personalized approach could benefit the health system in terms of cost-effectiveness by reducing the costs of inappropriate, ineffective, and often expensive treatments.

Recent progress in the use of pharmacotherapy for endometrial cancer

Endometrial cancer (EC) is the most common gynecological cancer in developed countries. The ESGO/ESTRO/ESP updated evidence-based guidelines in 2020, introducing molecular classification to guide EC treatment. The genomic-based approach has identified four prognostic subgroups of EC. Each of these may benefit from a tailored treatment depending on the molecular profile, the histotype, and stage of disease for the adjuvant and the metastatic/recurrent setting. Several clinical trials are now ongoing to identify the best treatment according to the molecular profile of EC. This review analyzes tailored treatment for EC according to the molecular profile, both in the adjuvant and in the metastatic/recurrent setting. The authors review the results of clinical studies and highlight ongoing trials. Several new agents are under evaluation in order to personalize EC treatment according to specific molecular profiles in the adjuvant, advanced, and recurrent settings. Clinical trials investigating the impact of molecular classification have yielded encouraging results. EC can no longer be considered a single tumor entity susceptible to a single treatment modality but rather be split into four distinct types, requiring tailored treatments.

Management of stage III and IVa uterine cancer

The prognosis of patients with advanced endometrial cancer is poor with limited therapeutic options. Nevertheless, the integration of molecular features in the clinico-pathological classification of endometrial cancer has significantly refined prognostic risk groups, representing a major breakthrough not only in the management of the disease but also in treatment perspectives. New therapeutic compounds such as target therapies, immunotherapy, and hormonal therapies have emerged for this clinical setting. Furthermore, molecular-driven clinical trials may improve significantly the efficacy of new treatments selecting those patients who are highly likely to respond. This review aims at describing the state of the art of advanced stage III-IVa endometrial cancer management, providing also the most interesting clinical perspectives.

Effects of niraparib dose reduction on short-term outcomes in ovarian cancer patients

Despite the individualized starting dose for maintenance therapy in ovarian cancer, the niraparib dose reduction rate remains high. The aim of this study was to evaluate the impact of niraparib dose reduction on progression-free survival in newly diagnosed primary advanced ovarian cancer and recurrent ovarian cancer patients. We also aimed to compare the reduction rates and the safety of niraparib on primary and relapse groups, and identify which factors may predict dose reduction. Patients with primary or recurrent ovarian cancer in maintenance who received niraparib between 2019 and 2022 were retrospectively evaluated. Niraparib dosing was based on individualized starting dose of 300 or 200 mg/day. The impact of niraparib dose reductions was focused on patients treated with 200 or 100 mg in both groups. Reduction rates, adverse events and predictive factors of reduction were assessed in each study group. The primary endpoint was progression-free survival in primary and relapse groups; the secondary endpoints were the reduction rates, the safety and tolerability of niraparib in both groups. Of 215 patients identified, 124 (57.7%) primary and 91 (42.3%) recurrent ovarian cancer patients were included. The majority of patients started niraparib at 200 mg/day (92.7% primary and 80.2% relapse group); dose reductions from 300 or 200 mg/day to 200 or 100 mg/day occurred more frequently within cycles 1-3 (67% primary and 45% relapse group, p=0.001). Grade≥3 adverse events were lower in the relapse group (54.8% primary and 35.1% relapse, p=0.001). In both groups, dose modifications over the treatment did not significantly impair median progression-free survival. Univariate and multivariate analysis demonstrated that weight and platinum-doublets were possible risk factors for dose reduction. Niraparib dose reduction occurs in almost half of patients within cycles 1-3, although it is significantly more common in the first-line setting. Survival outcomes seem not to be impaired by dose reduction.

Pembrolizumab plus chemotherapy for advanced and recurrent cervical cancer: final analysis according to bevacizumab use in the randomized KEYNOTE-826 study

In KEYNOTE-826 (NCT03635567), pembrolizumab plus chemotherapy (±bevacizumab) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with persistent, recurrent, or metastatic cervical cancer. This exploratory analysis examined outcomes in patient subgroups defined by bevacizumab use. Eligible adult patients had persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix not previously treated with chemotherapy and not amenable to curative treatment; measurable disease per RECIST v1.1; and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomly allocated 1 : 1 to pembrolizumab 200 mg every 3 weeks or placebo for up to 35 cycles plus chemotherapy (±bevacizumab 15 mg/kg). Dual primary endpoints were OS and PFS per RECIST v1.1 by investigator assessment. Outcomes were assessed in subgroups defined by bevacizumab use. Hazard ratios (HRs) and 95% confidence intervals (CIs) were based on a stratified Cox regression model. A total of 617 patients were randomly assigned [pembrolizumab arm, n = 308 (63.6% with bevacizumab); placebo arm, n = 309 (62.5% with bevacizumab)]. The most common reason for bevacizumab exclusion was medical contraindication (75.9%). Among patients who received bevacizumab, HRs (95% CIs) for PFS favored the pembrolizumab arm in the programmed cell death-ligand 1 combined positive score ≥1 [0.56 (0.43-0.73)] and all-comer [0.57 (0.45-0.73)] populations; OS results were 0.60 (0.45-0.79) and 0.61 (0.47-0.80), respectively. Among patients who did not receive bevacizumab, HRs (95% CIs) for PFS also favored the pembrolizumab arm in the programmed cell death-ligand 1 combined positive score ≥1 [0.61 (0.44-0.85)] and all-comer [0.69 (0.50-0.94)] populations; OS results were 0.61 (0.44-0.85) and 0.67 (0.49-0.91), respectively. Among patients who received bevacizumab, grade ≥3 treatment-related adverse events occurred in 74.0% of patients in the pembrolizumab arm and 66.8% in the placebo arm. Pembrolizumab plus chemotherapy prolonged PFS and OS and had manageable safety compared with placebo plus chemotherapy in patient subgroups defined by bevacizumab use.

Oregovomab: an investigational agent for the treatment of advanced ovarian cancer

Relacorilant + Nab-Paclitaxel in Patients With Recurrent, Platinum-Resistant Ovarian Cancer: A Three-Arm, Randomized, Controlled, Open-Label Phase II Study

PURPOSE Despite therapeutic advances, outcomes for patients with platinum-resistant/refractory ovarian cancer remain poor. Selective glucocorticoid receptor modulation with relacorilant may restore chemosensitivity and enhance chemotherapy efficacy. METHODS This three-arm, randomized, controlled, open-label phase II study (ClinicalTrials.gov identifier: NCT03776812 ) enrolled women with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer, or ovarian carcinosarcoma treated with ≤4 prior chemotherapeutic regimens. Patients were randomly assigned 1:1:1 to (1) nab-paclitaxel (80 mg/m2) + intermittent relacorilant (150 mg the day before, of, and after nab-paclitaxel); (2) nab-paclitaxel (80 mg/m2) + continuous relacorilant (100 mg once daily); or (3) nab-paclitaxel monotherapy (100 mg/m2). Nab-paclitaxel was administered on days 1, 8, and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) by investigator assessment; objective response rate (ORR), duration of response (DOR), overall survival (OS), and safety were secondary end points. RESULTS A total of 178 women were randomly assigned. Intermittent relacorilant + nab-paclitaxel improved PFS (hazard ratio [HR], 0.66; log-rank test P = .038; median follow-up, 11.1 months) and DOR (HR, 0.36; P = .006) versus nab-paclitaxel monotherapy, while ORR was similar across arms. At the preplanned OS analysis (median follow-up, 22.5 months), the OS HR was 0.67 ( P = .066) for the intermittent arm versus nab-paclitaxel monotherapy. Continuous relacorilant + nab-paclitaxel showed numerically improved median PFS but did not result in significant improvement over nab-paclitaxel monotherapy. Adverse events were comparable across study arms, with neutropenia, anemia, peripheral neuropathy, and fatigue/asthenia being the most common grade ≥3 adverse events. CONCLUSION Intermittent relacorilant + nab-paclitaxel improved PFS, DOR, and OS compared with nab-paclitaxel monotherapy. On the basis of protocol-prespecified Hochberg step-up multiplicity adjustment, the primary end point did not reach statistical significance ( P &lt; .025). A phase III evaluation of this regimen is underway (ClinicalTrials.gov identifier: NCT05257408 ).

Progression-free survival and safety at 3.5 years of follow-up: results from the randomised phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib maintenance treatment in patients with newly diagnosed ovarian cancer

To report updated long-term efficacy and safety from the double-blind, placebo-controlled, phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). Patients with newly diagnosed advanced ovarian cancer with complete or partial response (CR or PR) to first-line platinum-based chemotherapy received niraparib or placebo once daily (2:1 ratio). Stratification factors were best response to first-line chemotherapy regimen (CR/PR), receipt of neoadjuvant chemotherapy (yes/no), and homologous recombination deficiency (HRD) status (deficient [HRd]/proficient [HRp] or not determined). Updated (ad hoc) progression-free survival (PFS) data (as of November 17, 2021) by investigator assessment (INV) are reported. In 733 randomised patients (niraparib, 487; placebo, 246), median PFS follow-up was 3.5years. Median INV-PFS was 24.5 versus 11.2months (hazard ratio, 0.52; 95% confidence interval [CI], 0.40-0.68) in the HRd population and 13.8 versus 8.2months (hazard ratio, 0.66; 95% CI, 0.56-0.79) in the overall population for niraparib and placebo, respectively. In the HRp population, median INV-PFS was 8.4 versus 5.4months (hazard ratio, 0.65; 95% CI, 0.49-0.87), respectively. Results were concordant with the primary analysis. Niraparib-treated patients were more likely to be free of progression or death at 4years than placebo-treated patients (HRd, 38% versus 17%; overall, 24% versus 14%). The most common grade ≥ 3 treatment-emergent adverse events in niraparib patients were thrombocytopenia (39.7%), anaemia (31.6%), and neutropenia (21.3%). Myelodysplastic syndromes/acute myeloid leukaemia incidence rate (1.2%) was the same for niraparib- and placebo-treated patients. Overall survival remained immature. Niraparib maintained clinically significant improvements in PFS with 3.5years of follow-up in patients with newly diagnosed advanced ovarian cancer at high risk of progression irrespective of HRD status. No new safety signals were identified.

Phase I Study of Rucaparib in Combination with Bevacizumab in Ovarian Cancer Patients: Maximum Tolerated Dose and Pharmacokinetic Profile

Targeted agents, such as antiangiogenic drugs (e.g., bevacizumab) and poly(ADP-ribose) polymerase inhibitors (e.g., rucaparib), have been shown to improve outcomes in patients with newly diagnosed or recurrent ovarian cancer. Evidence suggests that combinations of these two classes of targeted agents may result in synergistic antitumor activity. The phase I portion of MITO 25 was designed to determine the maximum tolerated dose, pharmacokinetics, and the safety profile of rucaparib when administered in combination with bevacizumab as maintenance treatment for patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. This was a single-arm, phase I dose-escalation study. Cohorts of three patients were recruited to receive increasing rucaparib doses of 400 mg, 500 mg, or 600 mg twice daily for 28 days. Bevacizumab 15 mg/kg was administered at day 1 every 21 days. We enrolled nine patients. Two patients in the rucaparib 600-mg group had four grade 3 treatment-emergent adverse events: increased in alanine aminotransferase and aspartate aminotransferase levels, depression, and hallucinations. These were deemed to be dose-limiting toxicities related to rucaparib. Because these dose-limiting toxicities occurred in the 600-mg group and affected more than one in three patients, the maximum tolerated dose for rucaparib was considered 500 mg twice daily when combined with bevacizumab 15 mg/kg at day 1 every 21 days. There were no new safety concerns from using the combination. No substantial difference in pharmacokinetic parameters was found between the cohorts or in the pharmacokinetic profiles of rucaparib administered alone or with bevacizumab with respect to historical controls. The maximum tolerated dose of rucaparib is 500 mg twice daily when co-administered with bevacizumab. The plasma concentration-time profiles of rucaparib in combination with bevacizumab suggest no pharmacokinetic interactions between the drugs. The randomized phase II portion of MITO 25 will further investigate rucaparib maintenance treatment with or without bevacizumab in patients with newly diagnosed stage III-IV ovarian cancer who responded to carboplatin-paclitaxel chemotherapy with or without bevacizumab. ClinicalTrials.gov identifier NCT03462212; registered March 2018.

Rucaparib maintenance treatment for recurrent ovarian carcinoma: the effects of progression-free interval and prior therapies on efficacy and safety in the randomized phase III trial ARIEL3

In ARIEL3 (NCT01968213), the poly(adenosine diphosphate-ribose) polymerase inhibitor rucaparib significantly improved progression-free survival versus placebo regardless of biomarker status when used as maintenance treatment for recurrent ovarian cancer. The aim of the current analyses was to evaluate the efficacy and safety of rucaparib in subgroups based on progression-free interval following penultimate platinum, number of prior chemotherapies, and prior use of bevacizumab. Patients were randomized 2:1 to rucaparib 600 mg twice daily or placebo. Within subgroups, progression-free survival was assessed in prespecified, nested cohorts: In the intent-to-treat population, median investigator-assessed progression-free survival was 8.2 months with rucaparib versus 4.1 months with placebo (n=151 vs n=76; HR 0.33, 95% CI 0.24 to 0.46, p12 months. Median progression-free survival was 10.4 versus 5.4 months (n=231 vs n=124; HR 0.42, 95% CI 0.32 to 0.54, p<0.0001) for patients who had received two prior chemotherapies, and 11.1 versus 5.3 months (n=144 vs n=65; HR 0.28, 95% CI 0.19 to 0.41, p<0.0001) for those who had received ≥3 prior chemotherapies. Median progression-free survival was 10.3 versus 5.4 months (n=83 vs n=43; HR 0.42, 95% CI 0.26 to 0.68, p=0.0004) for patients who had received prior bevacizumab, and 10.9 versus 5.4 months (n=292 vs n=146; HR 0.35, 95% CI 0.28 to 0.45, p<0.0001) for those who had not. Across subgroups, median progression-free survival was also significantly longer with rucaparib versus placebo in the Rucaparib maintenance treatment significantly improved progression-free survival versus placebo irrespective of progression-free interval following penultimate platinum, number of lines of prior chemotherapy, and previous use of bevacizumab.

EPIK-O/ENGOT-OV61: Alpelisib Plus Olaparib vs Cytotoxic Chemotherapy in High-Grade Serous Ovarian Cancer (Phase III Study)

Patients with platinum-resistant or -refractory high-grade serous ovarian cancer (HGSOC) have a poor prognosis, and their management represents a substantial unmet medical need. Preclinical data and results from a phase Ib trial demonstrated the efficacy and tolerability of the combination of the α-specific phosphatidylinositol-3-kinase (PI3K) inhibitor alpelisib plus the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib in platinum-resistant, non-

Comprehensive management of vulvovaginal cancers

AbstractVulvar and vaginal cancers represent rare malignancies, with an incidence of 2.7 per 100,000 women for vulvar cancer, predominantly affecting women older than 60 years, although rising rates are observed in younger demographics. Approximately 90% of vulvar cancers are squamous cell carcinoma and frequently are associated with human papillomavirus (HPV) infection. Vaginal cancer, constituting less than 1% of all female cancers, similarly exhibit HPV‐related trends. This review delineates the etiology, histopathology, and treatment strategies for carcinomas and vulvovaginal melanomas and sarcomas. Surgical intervention remains the primary treatment modality for vulvar cancer, involving tumor resection and inguinofemoral lymph node staging. For locally advanced vulvar carcinoma, chemoradiation is advised when exenterative surgery would be indicated. Recurrence rates within 2 years after diagnosis range from 12% to 37%. Unfortunately, systemic treatments for recurrent or metastatic disease are limited, with 5‐year survival rates at approximately 20%. Current evidence primarily derives from retrospective studies or small phase 2 trials or otherwise is extrapolated from the treatment of cervical cancer. Enrollment in clinical trials is strongly advocated, along with prompt access to best supportive care to mitigate the effect of locoregional progression on quality of life. Moreover, the psychosocial implications of treatment on body image and sexuality necessitate careful consideration. Future HPV vaccination initiatives may reduce cancer incidence, although significant effects of such vaccination will manifest over decades, underscoring the urgent need to enhance treatment efficacy and minimize morbidity in vulvar and vaginal cancers.

Advances in the Management of Recurrent Cervical Cancer: State of the Art and Future Perspectives

Abstract Purpose of Review This review aims to give an insight into the currently available options for recurrent/metastatic (R/M) cervical cancer (CC), along with the main future, potentially practice-changing perspectives in this field. Recent Findings Improvements in terms of tumor responses were observed with the use of immune checkpoints inhibitors (ICIs) in the previously treated CC population, followed by emerging striking data in terms of both antitumor activity and survival rates with the addition of the ICIs to platinum-based chemotherapy with or without bevacizumab in the first-line setting. Furthermore, the CC treatment landscape took another step forward in 2021 with the introduction of antibody–drug conjugates (ADCs) in the second-line setting, a highly targeted therapeutic strategy, which demonstrated to be a valid alternative option in the recurrent setting. Summary R/M CC is a hard-to-treat disease. However, after several years of limited systemic therapeutic options for the recurrent setting, the year 2018 marked a turning point for R/M CC patients, with the introduction of immunotherapy in the treatment paradigm, which completely reshaped the therapeutic armamentarium of the disease. Besides, another valuable treatment option represented by ADCs demonstrated its efficacy in the recurrent setting, thus further widening the treatment landscape for those patients. Yet, the introduction of immunotherapy in the upfront setting brought along new issues to be addressed such as the emerging ICIs resistance and the following need for alternative options in the post-ICIs setting. Several innovative therapeutic strategies are under investigation in ongoing clinical trials, with the aim of overcoming ICIs resistance with the addition of immunomodulatory agents or bypassing the ICIs resistance with novel alternative drugs.

Tisotumab Vedotin in Combination With Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer: Results From the innovaTV 205/GOG-3024/ENGOT-cx8 Study

PURPOSE Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081 ) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E). CONCLUSION TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.

Rucaparib for maintenance treatment of platinum-sensitive, recurrent ovarian carcinoma: Final results of the phase 3, randomized, placebo-controlled ARIEL3 trial.

In ARIEL3, rucaparib maintenance significantly improved progression-free survival (PFS; primary endpoint) and long-term follow-up (LTFU) outcomes (including PFS2: time to disease progression on subsequent therapy or death) versus placebo in patients with recurrent, platinum-sensitive ovarian cancer. Here we report the final analysis of overall survival (OS; key secondary endpoint), LTFU outcomes, and safety. OS and updated LTFU efficacy outcomes were analyzed (data cutoff date: April 4, 2022) across three nested populations (BRCA-mutated, homologous recombination deficient [HRD], and intention to treat [ITT]). Patients were randomized 2:1 to rucaparib (600 mg BID; n = 375) or placebo (n = 189). Median follow-up was 77.0 months. 168 patients in the placebo arm received subsequent treatment; of these, 77 (46 %) received a poly(ADP-ribose) polymerase inhibitor-containing treatment. Median OS from randomization post chemotherapy for rucaparib vs placebo was 45.9 vs 47.8 months (HR 0.83, 95 % CI 0.58-1.19) for the BRCA-mutated population; no OS benefit was found with rucaparib in the HRD and ITT populations. Median PFS2 for rucaparib vs placebo was 26.1 vs 18.4 months (HR 0.67, 95 % CI 0.48-0.94) for the BRCA-mutated population. Rucaparib numerically improved PFS2 and other LTFU outcomes versus placebo in the HRD and ITT populations. Safety was consistent with prior reports; myelodysplastic syndrome and/or acute myeloid leukemia occurred in 4 % and 3 % of patients in the rucaparib and placebo arms, respectively. OS was similar between treatment arms. PFS benefit with rucaparib was maintained through the subsequent therapy line. These data support rucaparib as maintenance treatment for recurrent ovarian carcinoma.

Multimodal tumor-agnostic ctDNA analysis for minimal residual disease detection and risk stratification in ovarian cancer: results from the MITO16a/MaNGO-OV2 trial

Advanced-stage epithelial ovarian cancer (EOC) remains a therapeutic challenge due to high relapse rates and limited survival, while standard post-surgical parameters such as residual tumor (RT) incompletely capture minimal residual disease (MRD) and offer limited insight into tumor evolution. To address this gap, we investigated whether a multimodal, tumor-agnostic analysis of circulating tumor DNA (ctDNA)-integrating tumor fraction (TF) and genome-wide fragmentomic profiles (PF)-could refine early risk stratification after cytoreductive surgery and enable longitudinal monitoring during therapy. A total of 393 plasma samples from 173 patients in the phase IV MITO16a/MaNGO-OV2a trial were analyzed by shallow whole-genome sequencing at three time points: post-surgery/pre-chemotherapy (B1), post-chemotherapy (B2), and at the end of maintenance therapy or upon disease progression during maintenance (B3). Associations with progression-free survival (PFS) and overall survival (OS) were assessed using multivariable Cox models adjusted for clinical covariates. TF was detectable in 97% of patients at B1, including those classified as optimally debulked, and outperformed established clinical covariates in predicting survival [PFS: hazard ratio (HR) 1.02, P = 0.008; OS: HR 1.04, P = 0.005]. PF provided independent prognostic values (PFS: HR 1.06, P = 0.010; OS: HR 1.10, P = 0.005), and combined TF/PF modeling identified subgroups with distinct survival trajectories beyond clinical predictors (PFS: HR 1.76, P = 0.015; OS: HR 2.06, P = 0.029). Longitudinal copy number profiling revealed dynamic remodeling under treatment pressure, with recurrent 19q13.42 amplification emerging at B2 and B3. Together, these findings establish multimodal ctDNA profiling as a sensitive, non-invasive strategy for MRD detection and longitudinal surveillance in advanced EOC, refining prognostic assessment beyond clinical and surgical factors while paving the way for precision-guided therapeutic management.

Particle Beam Re-irradiation in Oligo Recurrent Gynecological Malignancies

This study aimed to evaluate the efficacy and safety of proton beam radiotherapy (PBRT) and carbon ion radiotherapy (CIRT) as salvage treatments for oligorecurrent gynecological cancers. A retrospective analysis was performed on consecutive patients treated with PBRT or CIRT for recurrent gynecological tumors. The primary endpoints included the objective response rate (ORR) as well as 1- and 2-year local control (LC) survival rates. Toxicity was assessed as a secondary endpoint and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 scale. Actuarial outcomes were evaluated using the Kaplan-Meier method, and predictors were identified with the Log-rank test. A total of 27 patients (median age: 64.5 years; IQR = 56.0, 69.0) with 28 recurrent lesions were treated with either PBRT (N = 12) or CIRT (N = 16), without concurrent systemic therapies. The majority of patients were treated for recurrences of cervical cancer (N = 8, 29%), endometrial cancer (N = 7, 25%), and ovarian cancer (N = 6, 21%). The most frequent site of recurrence was lymph nodes (N = 14, 50%). Lesions treated with CIRT had a larger volume (median volume 118 [IQR = 66, 233.5] vs. 99 [IQR = 54, 152.3]) and lower alpha/beta ratios (median = 3.8 [IQR = 3.5, 4.5] vs. 7.3 [IQR = 3.5, 10.0]). The overall ORR was 68% within 6 months and did not significantly vary between the groups (p = 0.687). The 1- and 2-year LC rates were 100% and 100% for PBRT, compared to 83% and 62% for CIRT (p = 0.075). Larger lesion volumes (p = 0.035) and failure to achieve an ORR (p = 0.009) were associated with worse LC outcomes, while lymph node recurrences (p = 0.052) and lower alpha/beta ratios (p = 0.078) were potentially linked to better LC. Both treatments were well tolerated, with no grade ≥3 toxicities observed. PBRT and/or CIRT appeared as an effective and safe option for recurrent gynecological cancers in a real-world setting. Larger cohorts and longer follow-up are needed for further validation and refining patient selection.

Homologous recombination repair status in advanced endometrial cancer: an exploratory biomarker analysis from the randomized, phase II MITOEND 3 trial

Poly (ADP-ribose) polymerase (PARP) inhibitor use in endometrial cancer (EC) requires predictive biomarkers, currently lacking in clinical practice. This study assessed the incidence of homologous recombination deficiency (HRD) using genomic loss of heterozygosity (gLOH) and a machine learning-based HRD scar signature (HRDsig). MITO END 3 was a multicenter, phase II trial of advanced EC patients randomly assigned to receive platinum-based chemotherapy ± avelumab. Of 125 patients, 102 had tumor samples available for sequencing with FoundationOne®CDx. HRD was evaluated using gLOH (cut-off ≥16%, based on ARIEL3) and HRDsig (cut-off ≥0.7, validated pan-cancer). Among 102 evaluable samples, 5 were HRDsig-positive, 90 HRDsig-negative, and 7 HRDsig unknown. gLOH was high in 10 cases, low in 53, and not assessable in 39. Most HRDsig-positive (4/5) and gLOH-high (8/10) tumors were of endometrioid histology and carried TP53 mutations. None were microsatellite instability-high. A small subgroup of advanced EC patients shows HRD positivity by gLOH or HRDsig, potentially identifying those most likely to benefit from PARP inhibitors. These tumors are typically endometrioid with TP53 mutations.

Neoadjuvant chemotherapy followed by interval surgery versus primary debulking surgery in FIGO stage III-IV epithelial ovarian cancer: A systematic review and meta-analysis.

To compare survival and perioperative outcomes of Primary debulking surgery (PDS) versus neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) in newly diagnosed FIGO stage III-IV ovarian cancer. Primary outcomes were overall survival (OS) and progression-free survival (PFS). MEDLINE, Embase, CENTRAL, Web of Science, Scopus, Cochrane Library, major conference proceedings (inception to July 13, 2025) STUDY SELECTION: Phase-III randomized trials comparing survival outcomes between PDS and NACT-IDS, enrolling adults with newly diagnosed stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer. Following PRISMA, two reviewers independently screened, extracted and assessed risk-of-bias (RoB 1). Random-effects meta-analysis estimated pooled hazard ratios (HRs) for OS/PFS and risk ratios (RRs) for binary endpoints. Heterogeneity was quantified with the I² statistic. PROSPERO (CRD420251056445). Five RCTs (n = 2380 women), including one conference-only report, met criteria. NACT-IDS yielded no difference in OS (HR 1.00; 95 % CI 0.90-1.12; I² = 16 %) and PFS (HR 1.03; 95 % CI 0.92-1.16; I² = 39 %) versus PDS. Grade ≥ 3 perioperative complications were significantly less frequent with NACT-IDS (RR 0.43; 95 % CI 0.25-0.74; I² = 75 %) while CC-0 rates were higher (RR 2.02; 95 % CI 1.26-3.24; I² = 94 %). In FIGO stage III-IV, NACT-IDS achieves survival endpoints similar to PDS, while increasing the likelihood of complete macroscopic resection and reducing severe perioperative morbidity. Upfront surgery in advanced ovarian cancer management should likely be reserved for patients with feasible complete resection and presumed low morbidity.

Primary Analysis of EPIK-O/ENGOT-ov61: Alpelisib Plus Olaparib Versus Chemotherapy in Platinum-Resistant or Platinum-Refractory High-Grade Serous Ovarian Cancer Without BRCA Mutation

PURPOSE Patients with platinum-resistant/platinum-refractory high-grade serous ovarian cancer (HGSOC) without a BRCA mutation have poor prognosis and limited treatment options. We report efficacy and biomarker data from EPIK-O, which investigated alpelisib + olaparib versus single-agent chemotherapy in these patients. PATIENTS AND METHODS EPIK-O was an open-label, phase III trial that randomly assigned patients with platinum-resistant/platinum-refractory HGSOC with no germline or known somatic BRCA mutation 1:1 to alpelisib 200 mg once daily + olaparib 200 mg twice daily or treatment of physician's choice (TPC; paclitaxel 80 mg/m 2 once weekly or pegylated liposomal doxorubicin 40-50 mg/m 2 once every 28 days). Patients had 1-3 previous systemic therapies. Previous bevacizumab was required (unless contraindicated); previous poly(adenosine diphosphate-ribose) polymerase inhibitors were allowed. Primary end point was progression-free survival (PFS) per RECIST 1.1 (blinded independent review committee [BIRC]). Secondary efficacy end points included overall response rate (ORR; per BIRC), duration of response (per BIRC), and overall survival (OS; key secondary end point). RESULTS A total of 358 patients (alpelisib + olaparib [n = 180], TPC [n = 178]) were included. The median follow-up time was 9.3 months. At data cutoff (April 21, 2023), 33 (18.3%) and 30 (16.9%) patients remained on treatment with alpelisib + olaparib and TPC, respectively. The median PFS (BIRC) was 3.6 versus 3.9 months (hazard ratio [HR], 1.14 [95% CI, 0.88 to 1.48]; one-sided P = .84) for alpelisib + olaparib versus TPC. The ORR was 15.6% (95% CI, 10.6% to 21.7%) versus 13.5% (95% CI, 8.8% to 19.4%). The median OS was 10.0 versus 10.6 months (HR, 1.22; 95% CI, 0.87 to 1.71). The safety profile of alpelisib + olaparib was consistent with that observed for the individual agents. CONCLUSION The primary objective, PFS improvement, was not met in EPIK-O. No new or unexpected adverse events were observed. Biomarker analyses provided new insights for responders to alpelisib + olaparib.

Pembrolizumab plus chemotherapy with or without bevacizumab in East Asian participants with persistent, recurrent, or metastatic cervical cancer: results from KEYNOTE-826 final analysis

In the phase 3 KEYNOTE-826 study (NCT03635567), pembrolizumab plus chemotherapy with or without bevacizumab significantly improved progression-free survival (PFS) and overall survival (OS) in participants with persistent, recurrent, or metastatic cervical cancer. We report an exploratory analysis of outcomes for participants enrolled in East Asia based on the final analysis of KEYNOTE-826. Participants were randomized 1:1 to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles. All participants received chemotherapy with paclitaxel and cisplatin or carboplatin for up to 6 cycles, and optionally received bevacizumab at the investigator's discretion. PFS and OS were dual primary endpoints. Ninety-seven participants from East Asia were enrolled in the intention-to-treat population. At data cutoff (October 3, 2022), in the intention-to-treat population, median PFS in the pembrolizumab plus chemotherapy and placebo plus chemotherapy groups was 18.0 and 10.4 months, respectively (hazard ratio [HR]=0.42; 95% confidence interval [CI]=0.23-0.77); median OS was not reached and 20.4 months, respectively (HR=0.53; 95% CI=0.28-0.99). In the programmed cell death ligand 1 combined positive score (CPS) ≥1 population, median PFS was 29.3 and 10.9 months, respectively (HR=0.36; 95% CI=0.19-0.68); median OS was not reached and 17.4 months, respectively (HR=0.43; 95% CI=0.22-0.86). The most common adverse events with pembrolizumab plus chemotherapy versus placebo plus chemotherapy were alopecia (75% vs. 68%) and anemia (67% vs. 65%). These data support the use of pembrolizumab plus chemotherapy with or without bevacizumab for the treatment of persistent, recurrent, or metastatic cervical cancer in East Asian patients. ClinicalTrials.gov Identifier: NCT03635567.

Randomized study evaluating optimal dose, efficacy, and safety of E7386 plus lenvatinib versus treatment of physician’s choice in advanced/recurrent endometrial carcinoma previously treated with platinum-based chemotherapy and immune checkpoint inhibitors

Randomized controlled trial data for patients with endometrial cancer who experience disease progression after anti-programmed cell death [ligand] 1 (PD-[L]1) therapy are lacking. E7386, a novel small-molecule inhibitor, has been shown to enhance anti-angiogenesis when combined with lenvatinib. The escalation and expansion parts of Study 102 showed preliminary anti-tumor activity and manageable safety of E7386 plus lenvatinib in patients with advanced, un-resectable, or recurrent endometrial cancer previously treated with anti-PD-(L)1. This study aimed to determine the optimal dose of E7386 in combination with lenvatinib. E7386 plus lenvatinib will show a manageable safety profile and clinically meaningful anti-tumor activity in patients with advanced, un-resectable, or recurrent endometrial carcinoma previously treated with chemotherapy and anti-PD-(L)1 therapy. Study 102 is an open-label, global, phase 1b/2 trial. Patients with endometrial carcinoma will be randomized 1:1:1:1 to E7386 120 mg twice daily plus lenvatinib 14 mg once daily, E7386 60 mg twice daily plus lenvatinib 14 mg once daily, lenvatinib 24 mg once daily monotherapy, or treatment of physician's choice (doxorubicin 60 mg/m Eligible patients are aged ≥18 years with Eastern Cooperative Oncology Group performance status of 0 to 1 and must have advanced, un-resectable, or recurrent endometrial carcinoma that has progressed on/after prior platinum-based chemotherapy and PD-(L)1-directed therapy. Up to 3 previous lines of therapy are permitted. Individuals with prior treatment with lenvatinib or E7386 or known intolerance and/or known hypersensitivity to E7386, lenvatinib, doxorubicin, or paclitaxel, or any of their excipients, are not eligible to participate. The primary end points are safety and the objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator assessment at week 24. The study aims to include 120 patients across approximately 80 investigational sites in North America, Europe, and Asia-Pacific regions. Estimated Dates for Completing Accrual and Presenting Results: Enrollment is expected to take approximately 9 months, with presentation of results in 2026. The trial is registered at ClinicalTrials.gov, NCT04008797.

Efficacy of subsequent therapies in patients with advanced ovarian cancer who relapse after first-line olaparib maintenance: results of the PAOLA-1/ENGOT-ov25 trial.

The use of first-line poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is increasing in advanced ovarian cancer. Understanding the efficacy of first subsequent therapy (FST) in patients experiencing disease progression in the first-line setting is important to optimize postprogression treatments. We evaluated the efficacy of FST in patients from PAOLA-1/ENGOT-ov25 (NCT02477644) who received first-line olaparib maintenance. This post hoc analysis evaluated the efficacy of subsequent chemotherapy following disease progression by assessing time from FST to second subsequent therapy (SST) according to whether progression occurred during versus after first-line olaparib maintenance and FST type. A multivariate Cox model was used in the olaparib plus bevacizumab arm to identify prognostic factors influencing the efficacy of subsequent chemotherapy. Of 806 randomized patients, 544 (67.5%) progressed and received subsequent chemotherapy. The median time from FST to SST was shorter in patients in the olaparib plus bevacizumab arm who progressed during first-line olaparib maintenance (6.1 months) than in those who progressed after first-line olaparib maintenance (11.4 months). Multivariate analysis indicated that progression after (versus during) first-line olaparib maintenance influenced time from FST to SST (hazard ratio 0.65, 95% confidence interval 0.50-0.84; P = 0.0011) independently of platinum-free interval or clinical risk. Among patients who progressed and received platinum-based chemotherapy with a PARP inhibitor as FST, the efficacy of subsequent therapies was also dependent on whether progression occurred during versus after first-line olaparib maintenance. These results suggest that the timing of disease progression relative to first-line olaparib maintenance may impact the efficacy of subsequent platinum-based chemotherapy. Although results should be interpreted with caution, across all subgroups, including patients who received platinum-based chemotherapy with PARP inhibitor rechallenge as FST, the median time from FST to SST was longer if progression occurred after versus during first-line olaparib maintenance.

Pembrolizumab or Placebo Plus Adjuvant Chemotherapy With or Without Radiotherapy for Newly Diagnosed, High-Risk Endometrial Cancer: Results in Mismatch Repair-Deficient Tumors

Mismatch repair-deficient (dMMR) endometrial cancer (EC) is an inflamed phenotype with poor outcomes when meeting high-risk criteria and limited treatment options in the adjuvant setting. We report protocol-prespecified subgroup analysis of patients with dMMR tumors from the phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study (ClinicalTrials.gov identifier: NCT04634877 ) in newly diagnosed, high-risk EC after surgery with curative intent. Patients were randomly assigned to pembrolizumab 200 mg or placebo (six cycles) plus carboplatin-paclitaxel (four to six cycles) once every 3 weeks, then pembrolizumab 400 mg or placebo once every 6 weeks (six cycles), respectively. MMR status was a stratification factor. Patients received radiotherapy at investigator discretion. Investigator-assessed disease-free survival (DFS) was a primary end point. No formal hypothesis testing was performed for subgroup analysis. In the intention-to-treat population, 141 patients in the pembrolizumab arm and 140 in the placebo arm had dMMR tumors. At this interim analysis, hazard ratio for DFS favored pembrolizumab (0.31 [95% CI, 0.14 to 0.69]); median DFS was not reached in either group. Two-year DFS rates were 92.4% (95% CI, 84.4 to 96.4) and 80.2% (95% CI, 70.8 to 86.9), respectively. No new safety signals occurred. Longer-term follow-up of outcomes will be evaluated at final analysis. Preplanned subgroup analysis on the basis of the study's stratification factors suggests that pembrolizumab plus chemotherapy improves DFS and is clinically relevant for patients with dMMR tumors in the curative-intent setting.

The clinical landscape of antibody-drug conjugates in endometrial cancer

Clinical outcomes remain challenging in advanced or recurrent endometrial cancer due to tumor heterogeneity and therapy resistance. Antibody-drug conjugates are a novel class of cancer therapeutics, representing a promising treatment option for endometrial cancer. Antibody-drug conjugates consist of a high-affinity antibody linked to a cytotoxic payload through a stable linker. After binding to specific antigens on tumor cells, the drug is internalized, and the payload is released. In addition, the free intracellular drug may be released outside the target cell through a 'bystander effect' and kill neighboring cells, which is crucial in treating malignancies characterized by heterogeneous biomarker expression like endometrial cancer.This article aims to provide a comprehensive overview of the current clinical landscape of antibody-drug conjugates in the treatment of endometrial cancer. We conducted a thorough analysis of recent clinical trials focusing on efficacy, safety profiles, and the mechanisms by which antibody-drug conjugates target endometrial cancer. We focused particularly on the most promising antibody-drug conjugate targets in endometrial cancer under clinical investigation, such as human epidermal growth factor receptor 2 (HER2), folate receptor alpha (FRα), trophoblast cell-surface antigen-2 (TROP2), and B7-H4. We also briefly comment on the challenges, including the emergence of resistance mechanisms, and future development directions (especially agents targeting multiple antigens, combinatorial strategies, and sequential use of agents targeting the same antigen but using different payloads) in antibody-drug conjugate therapy for endometrial cancer.

Clinical Trial Protocol for ROSELLA: a phase 3 study of relacorilant in combination with nab-paclitaxel versus nab-paclitaxel monotherapy in advanced platinum-resistant ovarian cancer

Ovarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. Improving outcomes in women with platinum-resistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoid receptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol's antiapoptotic effects, enhancing chemotherapy's efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population. ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nab-paclitaxel or nab-paclitaxel monotherapy. The study's primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes. ClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18.

Single-Agent Trabectedin Versus Physician's Choice Chemotherapy in Patients With Recurrent Ovarian Cancer With BRCA-Mutated and/or BRCAness Phenotype: A Randomized Phase III Trial

PURPOSE Literature evidence suggests that trabectedin monotherapy is effective in patients with recurrent ovarian cancer (OC) presenting BRCA mutation and/or BRCAness phenotype. METHODS A prospective, open-label, randomized phase III MITO-23 trial evaluated the activity and safety of trabectedin 1.3 mg/m2 given once every 3 weeks (arm A) in BRCA 1/2 mutation carriers or patients with BRCAness phenotype (ie, patients who responded to ≥two previous platinum-based treatments) with recurrent OC, primary peritoneal carcinoma, or fallopian tube cancer in comparison with physician's choice chemotherapy in the control arm (arm B; pegylated liposomal doxorubicin, topotecan, gemcitabine, once-weekly paclitaxel, or carboplatin). The primary end point was overall survival (OS) evaluated in the intention-to-treat population. RESULTS Overall, 244 patients from 21 MITO centers were randomly assigned (arm A = 122/arm B = 122). More than 70% of patients received ≥three previous chemotherapy lines and 35.7% had received a poly (ADP-ribose) polymerase inhibitor (PARPi) before enrollment. Median OS was not significantly different between the arms: arm A: 15.8 versus arm B: 17.9 months ( P = .304). Median progression-free survival was 4.9 months in arm A versus 4.4 months in arm B ( P = .897). Among 208 patients evaluable for efficacy, the objective response rate was 17.1% in arm A and 21.4% in arm B, with comparable median duration of response (5.62 v 5.66 months, respectively). No superior effect was observed for trabectedin in the prespecified subgroup analyses according to BRCA mutational status, chemotherapy type, and pretreatment with a PARPi and/or platinum-free interval. Trabectedin showed a higher frequency of grade ≥3 adverse events (AEs), serious AEs, and serious adverse drug reactions compared with control chemotherapy. CONCLUSION Trabectedin did not improve median OS and showed a worse safety profile in comparison with physician's choice control chemotherapy.

First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The phase III, double-blind KEYNOTE-826 trial of pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with or without bevacizumab, showed statistically significant survival benefits with the addition of pembrolizumab for patients with persistent, recurrent, or metastatic cervical cancer (primary data cutoff: May 3, 2021). This article reports the protocol-specified final overall survival (OS) results tested in the PD-L1 combined positive score (CPS) ≥1, all-comer, and CPS ≥10 populations. At the final data cutoff (October 3, 2022), the median study follow-up duration was 39.1 months (range, 32.1-46.5 months). In the PD-L1 CPS ≥1 (N = 548), all-comer (N = 617), and CPS ≥10 (N = 317) populations, median OS with pembrolizumab–chemotherapy versus placebo–chemotherapy was 28.6 months versus 16.5 months (hazard ratio [HR] for death, 0.60 [95% CI, 0.49 to 0.74]), 26.4 months versus 16.8 months (HR, 0.63 [95% CI, 0.52 to 0.77]), and 29.6 months versus 17.4 months (HR, 0.58 [95% CI, 0.44 to 0.78]), respectively. The incidence of grade ≥3 adverse events was 82.4% with pembrolizumab–chemotherapy and 75.4% with placebo–chemotherapy. These results show that pembrolizumab plus chemotherapy, with or without bevacizumab, continued to provide clinically meaningful improvements in OS for patients with persistent, recurrent, or metastatic cervical cancer.

Telmisartan in Combination With Cytotoxic Regimens in Platinum-Resistant Ovarian Cancer

The primary study objective is to assess progression-free survival in patients with ovarian cancer receiving telmisartan plus selected standard of care chemotherapy regimens versus historical controls.

Exploratory Study on the Correlation Between HRD Score and PARPi Efficacy Based on Chinese Ovarian Cancer Patients

This study plans to retrospectively include 470 initial surgical specimens from 470 patients with epithelial ovarian, fallopian tube or primary peritoneal cancers who were treated with PARPi maintenance therapy in the hospital from 2018.01 to 2024.01. All patients included would be scored by the proprietary HRD ADx-GSS® algorithm with the detecting results of the three genomic statuses including heterozygous omission (LOH), telomere allelic imbalance (TAI), and large-segment translocation (LST). Finally, the correlation between the HRD scores and the prognosis of Chinese ovarian cancer patients and the efficacy of using PARPi as maintenance treatment would be explored.

Relacorilant in Combination With Nab-Paclitaxel in Advanced, Platinum-Resistant, High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian-Tube Cancer

The primary objectives of this study are to evaluate progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS) (evaluated independently, as dual primary endpoints) in patients treated with intermittent regimen of Relacorilant in combination with nab-paclitaxel compared with patients treated with nab-paclitaxel monotherapy.

Alpelisib Plus Olaparib in Platinum-resistant/Refractory, High-grade Serous Ovarian Cancer, With no Germline BRCA Mutation Detected

The objective of this study is to assess the efficacy and safety of the combination of alpelisib and olaparib compared with single agent cytotoxic chemotherapy in patients with platinum resistant or refractory high-grade serous ovarian cancer, with no germline BRCA mutation detected.

Carboplatin-Paclitaxel-Bevacizumab vs Carbo-Pacli-Beva-Rucaparib vs Carbo-Pacli-Ruca, Selected According to HRD Status, in Patients With Advanced Ovarian, Primary Peritoneal and Fallopian Tube Cancer, Preceded by a Phase I Dose Escalation Study on Ruca-Beva Combination

This trial is a randomized, open-label Phase I-2 multi-center study designed to evaluate the effect of Carboplatin-Paclitaxel-Bevacizumab (in combination and maintenance) vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib (Rucaparib only in maintenance) vs Carboplatin-Paclitaxel-Rucaparib (Rucaparib only in maintenance) on progression-free survival in patients with advanced high grade ovarian cancer treated according to HRD status . The trial will test the hypothesis that Carboplatin-Paclitaxel-Bevacizumab-Rucaparib and the Carboplatin-Paclitaxel-Rucaparib arms will improve the progression-free survival in comparison to standard Carboplatin-Paclitaxel-Bevacizumab in HRD negative (HR proficient) patients and that Carboplatin-Paclitaxel-Bevacizumab-Rucaparib will improve PFS with respect to Carboplatin-Paclitaxel-Rucaparib in HRD positive patients. The randomized phase of the study will be preceded by a single arm Phase I study which will be conducted only in the National Cancer Institute of Milan, aiming at evaluating the MTD of the combination Rucaparib-Bevacizumab. Once the MTD has been reached, the randomized study will start.

A Study of Mirvetuximab Soravtansine in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression

This study is designed to evaluate the efficacy and safety of mirvetuximab soravtansine (MIRV) in participants with platinum-resistant high-grade serous epithelial ovarian cancer, primary peritoneal, or fallopian tube cancer, whose tumors express a high-level of Folate Receptor-Alpha (FRα). Participants will be, in the opinion of the Investigator, appropriate for single-agent therapy for their next line of therapy. All participants will receive single-agent MIRV at 6 mg/kg adjusted ideal body weight administered on Day 1 of every 3-week cycle.

Study of Relacorilant in Combination With Nab-Paclitaxel for Patients With Recurrent Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

This is a Phase 2, open-label, randomized, 3-arm study to evaluate progression-free survival (PFS) in patients with recurrent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer treated with intermittent or continuous regimens of relacorilant in combination with nab-paclitaxel compared with patients treated with nab-paclitaxel alone.

Safety and Efficacy of Tisotumab Vedotin Monotherapy & in Combination With Other Cancer Agents in Subjects With Cervical Cancer

This is an open label, multi-center trial of tisotumab vedotin monotherapy and in combination with bevacizumab, pembrolizumab, or carboplatin in subjects with recurrent or stage IVB cervical cancer. The trial consists of two-parts a dose escalation part and an expansion part. The expansion part of the trial will be initiated once the Recommended Phase 2 Dose (RP2D) of the combinations have been determined in the dose escalation part.

A Study of Niraparib (GSK3985771) Maintenance Treatment in Participants With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy

This study aims to assess efficacy of Niraparib (GSK3985771) as maintenance treatment in participants with Stage III or IV ovarian cancer. Participants must have completed front-line platinum based regimen with complete response (CR) or partial response (PR). Data collection for Secondary Outcome measures is ongoing and the approximate duration of the study will be 7 years.

Platine, Avastin and OLAparib in 1st Line

Randomized, Double-Blind, Phase III Trial of Olaparib vs. Placebo in Patients with Advanced FIGO Stage IIIB - IV High Grade Serous or Endometrioid Ovarian, Fallopian Tube, or Peritoneal Cancer treated with standard First-Line Treatment, Combining Platinum-Taxane Chemotherapy and Bevacizumab Concurrent with Chemotherapy and in Maintenance.