OBJECTIVE:To characterize the occurrence, duration, and outcomes of the most common non-hematological (nausea, vomiting, fatigue/asthenia) and hematological (anemia, neutropenia) adverse events experienced by patients receiving olaparib in the phase III SOLO2 trial. METHODS:SOLO2 (NCT01874353) is a randomized, double-blind, placebo-controlled trial. Eligible patients had histologically confirmed relapsed high-grade serous ovarian cancer or high-grade endometrioid cancer with a BRCA mutation and were in response after platinum-based chemotherapy. Patients were randomized 2:1 to olaparib tablets 300 mg twice daily (N = 196) or placebo (N = 99). Safety outcomes were analyzed in all randomized patients who received ≥1 dose of study drug (olaparib, n = 195; placebo, n = 99). RESULTS:The most common adverse events of interest (nausea, vomiting, fatigue/asthenia, anemia, and neutropenia) were generally reported early, within the first 1 to 3 months of olaparib treatment, and were mostly grade 1/2. For all adverse events of interest, the risk of experiencing an event was statistically significantly higher with olaparib than with placebo (nausea hazard ratio [HR] 3.38, p <.001; vomiting HR 1.86, p =.016; fatigue/asthenia HR 2.11, p <.001; anemia HR 5.80, p <.001; and neutropenia HR 2.66, p =.027). Of these adverse events, only nausea had a statistically significantly higher risk of experiencing a second event with olaparib than with placebo (HR 3.62, p <.001). The prevalence of nausea, fatigue/asthenia, and anemia was higher with olaparib than with placebo across all time points. The median time to resolution of the first adverse event for olaparib versus placebo was 1.7 versus 0.4 months (nausea), 2 versus 2 days (vomiting), 6.4 versus 2.3 months (fatigue/asthenia), 3.2 versus 2.9 months (anemia), and 29 versus 14 days (neutropenia). Fatigue/asthenia was the slowest adverse event to resolve. CONCLUSION:These data confirm that the use of olaparib as long-term maintenance therapy for patients with platinum-sensitive relapsed ovarian cancer is tolerable. Adverse events occurred early, were manageable, and few occurred with late onset.

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

BACKGROUND:Relacorilant is a selective glucocorticoid receptor antagonist that increases the sensitivity of many cancer cell types to chemotherapy. The efficacy and safety of relacorilant plus nab-paclitaxel were assessed in the phase 3 ROSELLA (GOG-3073, ENGOT-ov72, APGOT-Ov10, and LACOG-0223) trial; the combination showed significant improvement in progression-free survival among patients with platinum-resistant ovarian cancer compared with nab-paclitaxel monotherapy. Results of the final overall survival analysis are reported here. METHODS:In this open-label phase 3 trial, patients were randomly assigned 1:1 to receive relacorilant (150 mg orally the day before, day of, and day after nab-paclitaxel infusion) plus nab-paclitaxel (80 mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle) or nab-paclitaxel monotherapy (100 mg/m2 intravenously on the aforementioned schedule). Patients, aged 18 years or older, with one to three lines of previous anticancer therapy and platinum-resistant disease (progression <6 months from their last dose of platinum) were eligible. The trial was conducted at 117 hospitals and community oncology centres in 14 countries across Australia, Europe, Latin America, North America, and South Korea. Progression-free survival, assessed by blinded independent central review, and overall survival (time from randomisation to death from any cause) were dual primary endpoints. Additional prespecified endpoints included safety, second progression-free survival (time from randomisation to disease progression on subsequent anticancer therapy or death due to any cause, whichever occurred first), and patient-reported outcomes. This trial is registered at ClinicalTrials.gov, NCT05257408, and is ongoing. FINDINGS:Between Jan 5, 2023, and April 8, 2024, 381 patients were randomly assigned to the relacorilant combination group (n=188) or the nab-paclitaxel monotherapy group (n=193). All patients had received bevacizumab; 167 (44%) had received three previous lines of therapy, and 234 (61%) had received a poly(ADP-ribose) polymerase inhibitor. At a median follow-up of 24·8 months (95% CI 23·6-25·7), the addition of relacorilant to nab-paclitaxel resulted in a statistically and clinically significant improvement in overall survival compared with nab-paclitaxel monotherapy (hazard ratio for death 0·65 [95% CI 0·51-0·83]; p=0·0004); 18-month overall survival was 46% and 27%, respectively. The median overall survival in the relacorilant combination group was extended by 4·1 months compared with the nab-paclitaxel monotherapy group (16·0 [95% CI 13·0-18·3] vs 11·9 months [10·0-13·8]). Subsequent anticancer treatments were similar across study groups. Adverse events were similar in both groups when adjusted for duration of study treatment. Neutropenia (121 [64%]), anaemia (115 [61%]), fatigue (101 [54%]), and nausea (82 [44%]) were the most common adverse events in the relacorilant combination group. No new safety signals were observed with additional follow-up since the primary analysis. INTERPRETATION:The addition of relacorilant to nab-paclitaxel led to significantly longer overall survival in patients with platinum-resistant ovarian cancer, without the need for biomarker selection. The findings support relacorilant plus nab-paclitaxel as a potential new standard treatment option for patients with platinum-resistant ovarian cancer. FUNDING:Corcept Therapeutics.

5515 Background: Cyclin E1 gene amplification and protein over-expression is a marker of platinum resistance in high grade serous ovarian, fallopian tube or primary peritoneal cancer (HGSC), and may predict response to WEE1 inhibition. Adavosertib, a WEE1 inhibitor, has demonstrated activity in unselected women with recurrent ovarian and serous endometrial cancer. We aimed to evaluate the efficacy of adavosertib in women with recurrent platinum resistant HGSC with cyclin E1 over-expression, with and without gene amplification. Methods: IGNITE is a multicentre, phase 2 trial with 2 cohorts of women with recurrent platinum resistant HGSC. Tumors were assessed for cyclin E1 protein expression by IHC and CCNE1 copy number by FISH. Patients were assigned to Cohort 1 if tumors were cyclin E1 over-expressed (H-score>50) and amplified (≥8 copies), and Cohort 2 if tumors were overexpressed and nonamplified. Patients with evaluable disease by RECIST v1.1 or GCIG CA-125 criteria were included. Adavosertib 300mg PO was given daily on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was investigator assessed clinical benefit (CB) defined as absence of progression for ≥ 18 weeks. Here we present the 18-week response data for the first 32 patients treated from Cohort 2, with a data cut-off of August 2021. Results: Between Jan-2020 and May-2021, 32 patients were accrued to Cohort 2. Median age was 62 years (range 42-77) and 84% had received ≥2 prior lines of chemotherapy. Median cyclin E1 IHC H-score was 120 and 28 patients (88%) had measurable disease by RECIST. Median number of cycles commenced was 8 (range 1-19). Overall response rate (ORR) was 53% and CB rate was 61% for all evaluable patients. Seventeen patients (53%) required a dose reduction, most commonly for neutropenia or fatigue. Seventeen patients experienced ≥Grade 3 treatment related adverse event, and 4 patients (15%) discontinued due to toxicity. Conclusions: The efficacy results in a biomarker-selected cohort of patients are promising with a higher response rate than reported in previous studies of adavosertib in unselected women with recurrent HGSC. Duration of response and progression free survival data will be presented as data matures. Clinical trial information: ACTRN12619001185156P. [Table: see text]

CUPISCO (ClinicalTrials.gov identifier: NCT03498521) demonstrated longer progression-free survival (PFS) with comprehensive genomic profiling (CGP) and subsequent molecularly guided therapies (MGTs), versus standard platinum-based chemotherapy, in patients with previously untreated, unfavorable cancer of unknown primary (CUP) who reached disease control after induction chemotherapy (three cycles). We report efficacy and safety after >1 year of additional follow-up. Eligible patients were randomly assigned (3:1) to MGT (investigator-chosen after discussion in a molecular tumor board) or three further cycles of chemotherapy. The primary end point was PFS. Secondary end points included overall survival (OS) and safety. At data cutoff (December 6, 2024), 436 patients were randomly assigned (326 to MGT; 110 to chemotherapy). Median follow-up was 37.0 months (range, 0.0-67.8). Updated median PFS was 6.1 months (95% CI, 4.7 to 6.5) with MGT and 4.4 months (95% CI, 4.2 to 6.4) with chemotherapy (hazard ratio [HR], 0.75 [95% CI, 0.59 to 0.95]; P = .017); median OS was 15.2 months (95% CI, 13.9 to 18.4) and 12.8 months (95% CI, 9.8 to 15.4), respectively (HR, 0.79 [95% CI, 0.61 to 1.02]; P = .0689). No new safety signals were identified. These updated results aligned with the primary analysis, demonstrating the benefit of CGP with subsequent MGT and highlighting the importance of incorporating CGP at initial diagnosis to guide treatment decisions for patients with unfavorable CUP.

(Abstracted from Lancet Oncol 2025;26(10):1370-1381) Fifteen percent to 20% of endometrial cancer patients have a high-risk form of the disease; this classification indicates a higher risk of cancer recurrence and cancer-related death. The standard therapy for high-risk endometrial cancer is pelvic radiotherapy.

BACKGROUND:Relacorilant, a first-in-class selective glucocorticoid receptor antagonist, increases a tumour's sensitivity to chemotherapy by reducing cortisol signalling. This study aimed to show whether the addition of relacorilant to nab-paclitaxel improves progression-free and overall survival in females with platinum-resistant ovarian cancer. METHODS:This randomised, controlled, open-label phase 3 trial (ROSELLA [GOG-3073/ENGOT-ov72]) was done at 117 hospitals and community oncology treatment centres in 14 countries across Australia, Europe, Latin America, North America, and South Korea. Patients had to be aged 18 years or older and had to have a confirmed diagnosis of platinum-resistant, epithelial (ie, high-grade serous, endometrioid, or carcinosarcoma with a ≥30% epithelial component) ovarian, primary peritoneal, or fallopian tube cancer; up to three previous lines of anticancer therapy and previous bevacizumab and disease progression or intolerance to the most recent therapy; measurable disease according to the Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1); an Eastern Cooperative Oncology Group performance status of 0 or 1; and adequate organ function. Patients were assigned (1:1) to relacorilant (150 mg orally the day before, of, and after nab-paclitaxel infusion) plus nab-paclitaxel (80 mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle) or nab-paclitaxel monotherapy (100 mg/m2 intravenously on the aforementioned schedule). The dual primary endpoints were progression-free survival assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumours (version 1.1) and overall survival, and were assessed in all randomly assigned patients by intention to treat. The safety population included all randomly assigned patients who received at least one dose of the assigned treatment. This trial was registered at ClinicalTrials.gov, NCT05257408, and is ongoing. FINDINGS:Between Jan 5, 2023, and April 8, 2024, 381 patients were randomly assigned to the combination group (n=188) or to the nab-paclitaxel monotherapy group (n=193). Patients receiving relacorilant plus nab-paclitaxel had a statistically significant improvement in progression-free survival assessed by blinded independent central review compared with those receiving nab-paclitaxel monotherapy (hazard ratio 0·70 [95% CI 0·54-0·91]; median 6·54 months [95% CI 5·55-7·43] vs 5·52 months [3·94-5·88]; stratified log-rank p=0·0076). At the planned interim analysis, there was a clinically meaningful difference in overall survival with the addition of relacorilant to nab-paclitaxel (0·69 [95% CI 0·52-0·92]; 15·97 months [95% CI 13·47-not reached] vs 11·50 months [10·02-13·57]; log-rank p=0·0121). Adverse events were similar across study groups when adjusted for nab-paclitaxel exposure; no new safety signals were observed. INTERPRETATION:The addition of relacorilant to nab-paclitaxel prolonged progression-free survival and interim results also showed an improvement in overall survival. Together, the results position the combination of relacorilant and nab-paclitaxel as a potential new standard treatment for patients with platinum-resistant ovarian cancer. FUNDING:Corcept Therapeutics.

12099 Background: The MOST-S26 is a patient-reported outcome measure that complements follow-up after first-line treatment for ovarian cancer (OC). MOST-S26 enables assessment of physical and psychological symptoms, and well-being. A randomized trial was conducted to evaluate nurse-led follow-up for OC via telehealth using the MOST-S26 to structure consultations vs routine hospital follow-up (ACTRN12620000332921). A qualitative sub-study assessed acceptability of the intervention from patient and nurse perspectives. Methods: Semi-structured interviews via video or telephone explored experiences of receiving or delivering nurse-led follow-up. Patients that participated in at least two nurse-led follow-up appointments were eligible. Study nurses delivering the intervention were interviewed at the end of the trial. Interviews were recorded, transcribed and coded using a Framework Approach following five stages: familiarisation, developing a thematic framework, indexing, charting, mapping and interpretation. Results: From June 2021, 38 patients were enrolled at 6 Australian sites. The trial closed to acrual in April 2024. Twenty-one participants were interviewed (15 women with OC and 6 study nurses). Analysis identified 3 overarching themes: (1) key patient-centred benefits (convenience and flexibility; providing a sense of connection and feeling cared for; enabling personalised, holistic care and prompt management of symptoms; providing dedicated space for patients’ to freely express experiences and emotions); (2) challenges to delivery from nurses’ perspectives (emotional impact of patients' cancers recurring; lack of referral pathways; inability to observe physical cues; difficulties establishing rapport; and, lack of suitability for all patients e.g. non-English speaking or patients with low literacy); and, (3) Nurse views on usefulness of MOST-S26 to support consultations (provides a useful tool to guide consultations/referrals, detect recurrence, track symptoms over time, flag symptoms for discussion, and, helps patients’ reflect on their symptoms). Conclusions: Results confirmed acceptability of this type of follow-up for both OC patients and nurses. Both reported several benefits compared with standard hospital-based follow-up. Challenges that should be considered prior to routine implementation of this follow-up model included: the need to provide support to nurses to cope with the emotional impact of patients’ cancers recurring; developing clear referral pathways for symptom management; and considering the characteristics of patients most and least suitable for this type of follow-up. Clinical trial information: ACTRN12620000332921 .

INTRODUCTION:The number of phase 1 clinical trials has been increasing globally over the past decade. However, patient recruitment remains skewed towards younger populations with older adults remaining underrepresented, limiting generalizability. Few studies have systematically examined the role of comorbidities as a determinant of safety outcomes in phase 1 trials. Thus, we aimed to investigate the impact of age and comorbidity on safety outcomes of phase 1 trial participants. MATERIALS AND METHODS:This retrospective analysis examined electronic health records of patients aged ≥18 years enrolled in phase 1 trials for metastatic solid malignancies between January 2020 and May 2023. Patients were stratified into two age groups (<70 years vs. ≥70 years). Patients were classified as comorbid if they had Charlson Comorbidity Index (CCI) ≥3, Elixhauser Comorbidity Index (ECI) ≥4, or modified Elixhauser Comorbidity Index (mECI) >12. Eastern Cooperative Oncology Group (ECOG) performance status was also evaluated. Logistic regression models assessed associations between age, comorbidity, and safety outcomes: serious adverse events (SAE), dose-limiting toxicities (DLT), dose reductions/interruptions (DR/DI), cessation of treatment due to toxicity (COTT), and grade 3-5 toxicities. RESULTS:We included 229 patients, of whom 51 (22%) were aged ≥70 years. Among them, 79 (34%) experienced an SAE, 109 (48%) had DR/DI, 34 (15%) had COTT, 17 (7%) had DLT, and 99 (43%) developed grade 3-5 adverse events. Age was not significantly associated with a higher likelihood of adverse safety outcomes. However, patients with ECI ≥4 had significantly higher likelihood of SAE than those with ECI <4 (50% vs. 31%, p = 0.04, OR: 2.18, 95% CI: 1.08-4.44). Patients with ECOG ≥1 had higher likelihood of SAE than those with ECOG 0 (42% vs. 29%, p = 0.06, OR: 1.75, 95% CI: 1.01-3.05, p = 0.05). Patients with ECOG ≥1 had significantly higher likelihood of grade 3-5 adverse events than those with ECOG 0 (52% vs. 36%, p = 0.03, OR: 1.89, 95% CI: 1.11-3.23, p = 0.02). Other comorbidity indices were not significantly associated with safety outcomes. DISCUSSION:Age alone was not associated with safety outcomes in phase 1 clinical trials for metastatic solid malignancies. Instead, comorbidity burden and ECOG performance status were predictors of adverse events in our cohort of patients.

LBA5507 Background: Relacorilant is an investigational, oral, selective glucocorticoid receptor antagonist (SGRA) that increases tumor sensitivity to chemotherapy-induced apoptosis. In a phase 2 study, the addition of relacorilant to nab-paclitaxel improved progression-free survival (PFS) and showed a trend towards improved overall survival (OS), with a comparable safety profile to nab-paclitaxel monotherapy, in patients with platinum-resistant ovarian cancer (PROC). The aim of this phase 3 study is to confirm the efficacy and safety of relacorilant + nab-paclitaxel in a larger population. Methods: ROSELLA (NCT05257408) is a randomized, controlled, open-label, global study of relacorilant + nab-paclitaxel compared to nab-paclitaxel monotherapy in patients with PROC. Patients were randomized 1:1 to either relacorilant (150 mg the day before, day of, and day after nab-paclitaxel) + nab-paclitaxel (80 mg/m 2 on days 1, 8, and 15 of each 28-day cycle) or nab-paclitaxel alone (100 mg/m 2 on the aforementioned schedule). Randomization was stratified by prior lines of therapy and region. Key eligibility criteria included 1–3 prior lines of anticancer therapy and prior bevacizumab. The dual primary endpoints are PFS by blinded independent central review (BICR) and OS. Secondary endpoints include PFS by investigator, objective response rate, best overall response, duration of response, and safety. PFS and OS endpoints were analyzed using Kaplan-Meier methods. A 2-sided stratified log-rank test was used to compare treatment groups. Hazard ratios (HR) were estimated with a Cox regression model. Results: A total of 381 women were randomized, all baseline characteristics were well balanced and 39% had received prior therapy in the PROC setting. ROSELLA met its primary endpoint: Patients receiving relacorilant + nab-paclitaxel had a statistically significant improvement in PFS by BICR compared to nab-paclitaxel monotherapy (HR 0.70, 95% CI 0.54-0.91, median 6.5 v 5.5 months, P=0.008); PFS by investigator showed a consistent benefit (HR 0.71, P=0.003). At an interim analysis, there was a clinically significant improvement in OS with the addition of relacorilant to nab-paclitaxel (HR 0.69, 95% CI 0.52-0.92, median 16.0 v 11.5 months, P=0.01). Adverse events (AEs) were comparable across study arms, relacorilant + nab-paclitaxel was well tolerated with no new safety signals. The most frequently reported AEs were known toxicities of nab-paclitaxel: anemia (58%), neutropenia (56%), and nausea (39%). Conclusion: Relacorilant + nab-paclitaxel is the first treatment regimen to demonstrate a PFS and OS benefit in patients with PROC compared to a weekly taxane, the most efficacious comparator. These positive efficacy data and a favorable safety profile position relacorilant + nab-paclitaxel as a new standard for patients with PROC, without the need for biomarker selection. Clinical trial information: NCT05257408 .

Endometrial cancer comprises a heterogeneous group of neoplasms. Its incidence is increasing, as is mortality from endometrial cancer. This article updates many aspects surrounding endometrial cancer, covering histopathology, staging, surgical and non-surgical management, follow-up, and management of recurrent disease.