S. Cecere

PARPi and myeloid neoplasms; the Italian MITO-MaNGO experience based on a multicentric survey

The introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer has raised increasing concerns about PARPi-related myeloid neoplasms (PrMN). Therapy-related neoplasms, including myelodysplastic syndromes and acute myeloid leukemia, account for 10%-20% of cases. Expanding PARPi indications, longer survival, and aging populations may contribute to rising PrMN incidence. Randomized clinical trials and real-world analyses show a significant risk increase, but data on individual PARPi, treatment lines, and prior therapies are limited. We evaluated PrMN incidence across 17 Italian centers using a 71-item survey distributed to MITO (Multicenter Italian Trials on Ovarian cancer) and MaNGO (Mario Negri Gynecologic Oncology) centers, focusing on patients treated with PARPi outside clinical trials. Of 2320 patients (1254 BRCA-mutated), 56 (2.55%) developed MN: 35 myelodysplastic syndromes and 21 acute myeloid leukemia (2 patients had both, counted once). Among them, 31 had BRCA mutations (2.5%). Incidence by drug was: olaparib 2.5%, niraparib 2%, and rucaparib 3.4%. An unclear correlation emerged between treatment duration and PrMN risk, with a median onset of 18.9 months. Risk increased with additional therapy lines: 0.52% (first), 4.2% (second), 1.8% (third), 10.8% (fourth), and 12.2% (>fourth lines). Among PrMN cases, 4 achieved remission, 4 had partial responses, 8 progressed, and 37 died. While this survey is meant as hypotheses-generating, PrMN represent a rare but clinically relevant complication, particularly uncommon when PARPi are administered as first-line therapy. Their occurrence does not appear to be associated with the specific PARPi used or with BRCA mutation status. Early detection, monitoring, and identification of predictive factors are crucial as ovarian cancer outcomes improve and treatment exposure increases.

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.

The impact of body mass index on survival and surgical outcomes in ovarian cancer: insights from the MITO trials

Epithelial ovarian cancer accounts for approximately 80% of ovarian cancer cases. Although obesity is not a primary risk factor for its onset, a high body mass index may worsen prognosis and survival. This may result from chronic inflammation, metabolic and hormonal changes, and increased treatment toxicity and surgical complications associated with obesity. This study is a post-hoc analysis of data from 3 MITO (Multicenter Italian Trials in Ovarian Cancer) clinical trials (MITO-2, MITO-7, and MITO16/MaNGO), involving 2040 patients with epithelial ovarian cancer. The effects of body mass index on progression-free survival, overall survival, and surgical outcomes were evaluated. Statistical analyses included Cox regression models to assess the risk of progression and mortality in relation to body mass index, while also accounting for baseline clinical variables. Additionally, regression analysis was conducted to examine the association between body mass index and surgical outcomes, with mixed cumulative-link models used to analyze categories of post-operative residual tumor. Higher body mass index was significantly associated with poorer progression-free survival (p = .02) and overall survival (p = .001). Extreme obesity, in particular, increased the risk of disease progression and mortality, with adjusted hazard ratios of 1.47 (95% confidence interval [CI] 1.13 to 1.92) for progression-free survival and 1.69 (95% CI 1.20 to 2.38) for overall survival. Additionally, higher body mass index correlated with worse surgical outcomes, including a greater likelihood of residual tumor. This effect was significant across body mass index categories: overweight (odds ratio [OR] 1.29, 95% CI 1.07 to 1.56), obese (OR 1.43, 95% CI 1.09 to 1.93), and extremely obese (OR 1.73, 95% CI 1.15 to 2.60). The evidence supports the hypothesis that elevated body mass index negatively affects prognosis in patients with advanced ovarian cancer. Weight management represents a crucial component for improving clinical outcomes and quality of life in these patients. Future therapeutic strategies should ideally incorporate multi-disciplinary approaches, such as pre-habilitation, to optimize treatment tolerance and promote better post-operative recovery.