PolyADP-ribose polymerase (PARP) inhibitors (PARPis) represent the first clinically approved drugs able to provoke “synthetic lethality” in patients with homologous recombination-deficient (HRD) tumors. Four PARPis have just received approval for the treatment of several types of cancer. Besides, another three additional PARPis underlying the same mechanism of action are currently under investigation. Despite the success of these targeted agents, the increasing use of PARPis in clinical practice for the treatment of different tumors raised the issue of PARPis resistance, and the consequent disease relapse and dismal prognosis for patients. Several mechanisms of resistance have been investigated, and ongoing studies are currently focusing on strategies to address this challenge and overcome PARPis resistance. This review aims to analyze the mechanisms underlying PARPis resistance known today and discuss potential therapeutic strategies to overcome these processes of resistance in the future.

Endometrial carcinoma is the most frequent cancer of the reproductive female organs. Most endometrial cancers are diagnosed at early stage (75%). Treatment options depend on pathogenetic, histopathologic and clinical characteristic at the diagnosis. To improve patient management in the near future, recent research has focused on new molecular features; evidence has shown that these give a better definition of patient prognosis and can help in tailoring adjuvant treatments by identifying specific subgroups of patients whose tumors may benefit from specific therapeutic approaches. In this review, we will focus on current knowledge of adjuvant treatment of endometrial carcinoma, using a prognostic-risk group stratification based on pathogenetic, clinical and molecular features, and will take a look at the ongoing trials that will further change the therapeutic approach in coming years.

Objective: To evaluate the clinical benefit of platinum rechallenge in patients with platinum-resistant ovarian cancer (PROC) and to explore the predictive role of BRCA mutation status. Methods: We retrospectively evaluated platinum rechallenge in PROC at Vall d’Hebron University Hospital between 2010 and 2023. Eligibility required ≥1 prior non-platinum regimen and ≥12 months since the last platinum dose. Objective response rate (ORR) per RECIST 1.1 and survival outcomes were analyzed by BRCA status and prior treatment lines. Results: ORR was 57% (95%CI, 42.1–73.0%) in the overall cohort (n = 63), 77% in BRCA-mutated patients (n = 13), and 50% in BRCA wild-type patients (n = 46). Median progression-free survival (PFS) was 7.3 months overall, which was longer in BRCA-mutated versus BRCA wild-type patients (8.4 vs. 7.4 months; HR 0.47, 95%CI 0.23–0.94; p = 0.033). An exploratory subgroup analysis suggested longer PFS among BRCA-mutated patients with ≤4 prior lines; however, this small subgroup finding should be considered hypothesis-generating. A platinum-free interval >6 months after rechallenging was observed in 38.5% of BRCA-mutated versus 13% of BRCA wild-type patients. Conclusions: Platinum rechallenge showed clinically meaningful activity in selected patients with PROC after an extended interval of intervening non-platinum therapy. These findings support the concept that platinum sensitivity may be dynamic and suggest that BRCA status and clinical selection factors may help inform individualized treatment sequencing in the post-PARP inhibitor era. Prospective validation with broader molecular characterization is warranted.