Anne-Claire Hardy-Bessard

Improving real-world evaluation of patient- and physician-reported tolerability: niraparib for recurrent ovarian cancer (NiQoLe)

Abstract Background Maintenance niraparib at an individualized starting dose (ISD) is established in platinum-sensitive recurrent ovarian cancer (PSROC). However, patients’ perspectives on the burden of prolonged maintenance therapy have not been reported in prospective trials or routine practice. Methods In the real-life multicenter NiQoLe study, patients with PSROC received ISD maintenance niraparib. The primary objective was to describe physician-reported adverse events (AEs) leading to treatment modification during the first 3 months. Secondary endpoints included patient-reported outcomes (symptomatic AEs using PRO-CTCAE, self-reported fatigue, and impact on daily activities/function using FACT-F) collected remotely weekly using a specifically designed electronic device. Results Most (80%) of 139 treated patients (median age = 70 years) began niraparib at 200 mg/day. Median treatment duration was 5.7 (range = 0.2-21.4) months. During the first 3 months, 86 patients (62%) required treatment modification (median = 27 days to modification). Physician-reported grade ≥3 niraparib-related AEs occurred in 34 patients (24%); 68 patients (49%) had treatment modification for AEs, predominantly thrombocytopenia. The most frequent patient-reported AEs (PRO-CTCAE) were fatigue, insomnia, constipation, and dry mouth. Self-reported AEs were severe in 66% of patients. At baseline, 33% of patients reported severe fatigue (FACT-F), which generally persisted during niraparib. Physicians systematically underestimated major patient-reported symptoms. Conclusions In routine practice, niraparib dose modification was often required during the first 3 months despite individualized dosing. Physicians underestimated the burden of fatigue and symptomatic AEs. Digital self-reporting of AEs is feasible, provides patient-centered information complementing physician-reported AEs, and allows fuller appreciation of toxicity in real-world studies. Clinical trial information NCT03752216

ESR1 Mutation in Endocrine Treatment-Naïve Endometrial Cancer: Prevalence, Characteristics, and Prognostic Implications, Results from the UTOLA Phase II GINECO Trial

Abstract Purpose: Aromatase inhibitors (AI) are used to treat estrogen receptor (ER)–positive low-grade endometrioid endometrial cancer. In breast cancer, ESR1 mutations are rare at diagnosis (<5%) but are frequently acquired in AI-resistant cases and are considered one of the major resistance mechanisms to endocrine therapy. This study aimed to assess the prevalence of ESR1 mutations in hormonotherapy-naïve endometrial cancer samples and correlate them with molecular profiles, ER expression, and clinical outcomes. Experimental Design: A total of 147 patients with advanced endometrial cancer who had responded to first-line chemotherapy were recruited into the UTOLA trial. Archival endometrial cancer tumor tissues underwent sequencing of 127 genes, including ESR1. Only hotspot mutations in the ligand-binding domain were evaluated. ESR1 mutation prevalence was validated in the Genomics England dataset. In UTOLA, tumors were classified as POLE, MMR deficient, TP53abn, or no specific molecular profiles (NSMP) based on the Proactive Molecular Risk Classifier for Endometrial Cancer (PROMISE) classification. Results: Of 147 patients, 137 had sufficient tumor material for sequencing. ESR1 mutations were identified in eight tumors (6%), including Y537S/C/N (n = 4), L536H/P (n = 2), and E380Q (n = 2). A similar prevalence (3.5%) was found among 1,311 tumors in the Genomics England dataset. All ESR1 mutation cases were low-grade endometrioid endometrial cancer, ER-positive, and PR-positive, and classified as NSMP. Among patients with metastatic NSMP low-grade endometrioid endometrial cancer, 22% (8/37) harbored ESR1 mutations. Survival outcomes after platinum chemotherapy were similar between patients with ESR1 mutation endometrial cancer and ESR1 wild type (median, not reached vs. 25.3 months; P = 0.114). Conclusions: ESR1 mutations, while rare overall in treatment-naïve endometrial cancer, are more prevalent in patients with NSMP low-grade endometrioid endometrial cancer, potentially affecting AI efficacy. ESR1 status should be considered in selecting hormonotherapy and as a stratification factor in AI trials.

ctDNA for Prognostication and Monitoring in Patients with Metastatic Endometrial Carcinoma Treated with Olaparib: Validation in the GINECO-UTOLA Trial

Abstract Purpose: ctDNA may offer a noninvasive means to evaluate tumor response and anticipate disease dynamics before radiologic changes in advanced endometrial carcinoma. Experimental Design: This ancillary analysis included patients from the multicenter, randomized, phase II GINECO-UTerin OLAparib (UTOLA) trial (NCT03745950) evaluating olaparib/placebo as maintenance after first-line platinum-based chemotherapy. Plasma samples were collected at screening after chemotherapy (baseline), 3 months (M3), and progression. ctDNA detection was assessed by a validated methylation-based Droplet Digital PCR (MethddPCR) assay targeting DNA positions universally methylated in endometrial carcinoma. Results: Among 130 evaluable patients, ctDNA was detected in 25 of 129 (19%, 1 technical fail) at baseline, 15 of 80 (19%) at M3, and 33 of 52 (63%) at progression. Baseline ctDNA positivity was independently associated with poorer progression-free survival (PFS) [median 1.81 vs. 7.39 months; adjusted HR = 5.33 (3.17–8.97)] and overall survival (OS) [10.3 vs. 24.7 months; adjusted HR = 3.98 (2.28–6.91); adjusted for age, stage IV at diagnosis, p53abn subgroup, and residual measurable lesions after chemotherapy]. Patients with baseline ctDNA had median OS of 9.36 months under olaparib versus 19.6 months under placebo (log-rank P = 0.05). Patients with increasing ctDNA at M3 had median PFS of 1.67 months, versus 9.64 months without, and median OS of 18.8 versus 25.8 months. ctDNA rising was predictive of poor postprogression OS under olaparib but not under placebo (interaction test, P < 0.001). Conclusions: MethddPCR-ctDNA is an independent prognostic biomarker for OS in advanced/metastatic endometrial carcinoma. MethddPCR-ctDNA may identify patients unlikely to benefit from PARP inhibition, guide therapeutic decisions, and should be further evaluated as a new stratification parameter in future endometrial carcinoma trials.

NIraparib and Quality of LifE is a Longitudinal Study Evaluating in Real Life the Tolerability of Niraparib.

This is a longitudinal, national, open, multi-centre phase IV study which will recruit up to 141 patients with ovarian cancer in late relapse treated with niraparib according to the labelling In France.