Endometrial cancer—news from ASCO 2024

Long-term survival outcomes for hormonal therapy in premenopausal patients with clinical stage I endometrial cancer were investigated [1]. The cohort comprised patients with clinical stage I endometrial cancer included in the National Cancer Database. Patients were excluded from analysis in the case of discrepancies in AJCC clinical TNM stage, if diagnosis was not confirmed pathologically, if patients underwent radiation or chemotherapy prior to hysterectomy or hormonal therapy, or if they had unclassified endometrioid cancer. All patients were diagnosed between 2004 and 2020, had grade 1 or 2 endometrioid cancer, and were between 18 and 49 years of age. They either received primary hysterectomy or primary hormonal therapy. The latter cohort comprised around 5% of patients overall. In the group of patients less than 40 years, no difference in survival was found between those who had received primary hysterectomy or primary hormonal therapy (10-year survival of 97% versus 96%, respectively; hazard ratio [HR] 1.0), while patients between 40 and 49 years of age who received primary hormonal therapy showed a significantly inferior survival compared to the hysterectomy group (10-year survival of 97% versus 79%, respectively; HR 4.94). Thus, patients who wish to preserve fertility may be offered primary hormonal therapy instead of undergoing primary surgery. However, in this study the number of patients who received primary hormonal therapy was as low as 5%. Further analysis of the dataset is necessary to confirm that primary hormonal therapy can be considered safe in young patients who desire fertility preservation despite the diagnosis of endometrial cancer.

The long-term follow-up of selinexor maintenance in patients with TP53 wild-type (wt) advanced or recurrent endometrial cancer was reported and a prespecified subgroup analysis from the phase 3 ENGOT-EN5/GOG-3055/SIENDO study was presented [2]. Selinexor inhibits XPO1 which is a multiclient nuclear exporter. TP53 is a well-recognized prognostic marker for endometrial cancer; 50% of advanced or recurrent endometrial cancers are TP53 wt, and about 40–55% are both TP53wt and mismatch-repair proficient (pMMR). A total of 263 patients with stage IV or first relapse of endometrial cancer were enrolled in this study. All had previously received ≥ 12 weeks of taxane–carboplatin therapy which had had resulted in partial or complete remission according to RECIST criteria. After remission, patients received either selinexor 80 mg PO weekly or placebo. Patients with a BMI < 20 kg/m² received a dose of 60 mg PO weekly instead. In this phase III study, detailed molecular subclassification assessed by DNA and immunohistochemistry was performed. The subgroup of patients with TP53wt tumors was analyzed. The median age was 64 versus 62 years in the selinexor group (n = 77) and the placebo group (n = 36), respectively. ECOG performance status was 0–1 in 98% and 100%, respectively. The majority of patients (84% versus 81%) had endometrioid tumors. Four versus 8% of patients had serous cancers and 53% versus 50% had recurrent disease, respectively. Complete remission before the start of selinexor therapy was achieved in 40% versus 47%, respectively, while partial remission was reported in 60% and 53% of women, respectively. MMR deficiency was reported in 26% versus 25%, respectively. At a median follow-up period of 36.8 months, the median progression-free survival (PFS) in the selinexor and the placebo group was 28 months versus 5 months, respectively (HR 0.44; p = 0.0005). A significantly more favorable median PFS was also found for selinexor in the subgroup of patients with TP53wt/pMMR (40 months versus 5 months, respectively; HR 0.36; p = 0.0011). Preliminary overall survival analysis showed a trend towards improved survival in the subgroup of patients with selinexor in both the TP53wt and the TP53wt/pMMR subgroup. Compared to placebo, selinexor resulted in more grade ≥ 3 toxicities: 13% nausea, 3% vomiting, 4% diarrhea, 5% asthenia, 8% fatigue, 10% thrombocytopenia, 20% neutropenia, and 7% anemia. Although the data from this SIENDO substudy are quite convincing, further prospective data in the p53wt population are urgently needed. The current ENGOT-EN20 study prospectively investigates selinexor maintenance therapy after chemotherapy with carboplatin and paclitaxel for participants with p53wt, advanced or recurrent endometrial cancer.

A phase II study of fulvestrant plus abemaciclib in hormone-receptor positive advanced or recurrent endometrial cancer was carried out [4]. Of the 27 patients, 89% had endometroid cancer, the majority of them being graded 1 or 2 (84%). In all, 96% of tumors were estrogen receptor-positive. All patients had received 1 (48%) or 2 prior lines of systemic therapy. 41% of patients had prior hormone treatment. No complete response was found, while partial response occurred in 44% and stable disease in 20%, respectively. The median duration of response was 16 months.

Clinically valuable study data were presented at ASCO 2024. Particularly data from selinexor maintenance in p53wt endometrial cancer were encouraging. In addition, there now exists some evidence that primary hormonal therapy with a CDK4/6-inhibitor may be a valuable option for patients with clinical stage I endometrial cancer who are less than 40 years of age and who desire fertility preservation.