Antonella Pietragalla

Oregovomab: an investigational agent for the treatment of advanced ovarian cancer

Ovarian cancer predisposition beyond BRCA1 and BRCA2 genes

Several genes associated with hereditary ovarian cancer have been discovered as a result of the work done with next generation sequencing. It is estimated that approximately 23% of ovarian carcinomas have a hereditary predisposition. The most common hereditary condition is represented by germline mutations in BRCA1 or BRCA2 genes that account for 20-25% of high grade serous ovarian cancer. A number of other hereditary ovarian cancers are associated with different genes, with a crucial role in the DNA damage response pathway, such as the mismatch repair genes in Lynch syndrome, TP53 in Li-Fraumeni syndrome, STK11 in Peutz-Jeghers syndrome, CHEK2, RAD51, BRIP1, and PALB2. The goal of this manuscript is to summarize the published data regarding the molecular pathways involved in the pathogenesis of non-BRCA related hereditary ovarian cancer and to provide a tool that might be useful in discussing risk assessment, genetic testing, prevention strategies, as well as clinical and therapeutic implications for patients with ovarian cancer.

BRCA status assessment in epithelial ovarian cancer and the challenge of tumor testing

Neoadjuvant chemoteraphy in unresectable ovarian cancer with olaparib and weekly carboplatin plus paclitaxel: a phase II, open label multicenter study (NUVOLA trial)

Neoadjuvant chemotherapy with interval debulking surgery represents an alternative treatment for advanced ovarian cancer. Currently, there are few data about the use of poly adenosine diphosphate-ribose polymerase inhibitors in the neoadjuvant setting. To evaluate whether the administration of olaparib in combination with standard chemotherapy in the neoadjuvant setting can improve tumor response. The addition of a poly adenosine diphosphate-ribose polymerase inhibitor to standard chemotherapy will achieve a higher response rate in BRCA mutated patients compared with standard chemotherapy TRIAL DESIGN: This is a multicenter, phase II, single arm, open label trial. Eligible patients will receive three cycles of weekly carboplatin plus paclitaxel, and intermittent olaparib administration. Responding patients will undergo an interval debulking surgery with pathological evaluation of response to chemotherapy. Patients must have histologically confirmed International Federation of Gynecology and Obstetrics stages III-IV primary ovarian, peritoneal, or fallopian tube cancers, high grade serous or endometrioid histology, not suitable for primary cytoreductive surgery with a documented BRCA1 or BRCA2 germline and/or somatic mutation. Rate of complete pathological response after three cycles of the experimental chemotherapy regimen. A total of 35 patients will be enrolled in the study. Expected complete 42 accrual in January 2022, with presentation of results by June 2022. NCT04261465.

NUVOLA TRIAL Open-label Multicentre Study

Around 15-25% of ovarian cancer (OC) patients carry germ-line mutation in BRCA1 or BRCA2 genes. Recent evidences showed that OC women with germline BRCA1/2 mutations (gBRCAmut) have an improved survival and higher platinum-sensitivity compared to BRCA1/2 naive (BRCAwt). Interestingly, disease appearance in BRCAmut women is more diffuse than in BRCAwt cases, with significantly higher peritoneal tumour load. Nonetheless, BRCAmut women additionally show a higher benefit of platinum-based neoadjuvant chemotherapy (NACT) plus interval debulking surgery compared with BRCAwt women in terms of clinical and pathological responses, suggesting that BRCA mutational status might be used as a molecular tool to personalize treatment in high-grade serous ovarian cancer (HGSOC) patients. OLAPARIB in BRCA mutation carriers Olaparib is a potent oral poly (ADP-ribose) polymerase (PARP) inhibitor that causes synthetic lethality in BRCA1/2-deficient tumour cells. In patients with platinum-sensitive relapsed serous ovarian cancer, olaparib maintenance treatment significantly improved the duration of progression-free survival compared with placebo (hazard ratio \[HR\] 0.35 \[95% CI (confidence interval) 0.25-0.49\]; p\<0.0001), with the greatest clinical benefit in patients with BRCA mutations (HR 0.18 \[95% CI 0.10-0.31\]; p\<0.0001). Preclinical data suggest that olaparib might also potentiate the efficacy of DNA-damaging chemotherapies, including platinum-containing drugs such as carboplatin. In a recent phase Ib/II study, olaparib plus weekly carboplatin and paclitaxel in relapsed ovarian cancer patients was shown to be safe, well tolerated and effective, especially in germline BRCA mutated (gBRCAmut) patients. Possibly, the addition of a PARP inhibitor (olaparib) to NACT in HGSOC patient with germline or somatic BRCA1/2 mutation is able to increase the pathological complete response rate to conventional chemotherapy. Combination of intermittent olaparib with weekly carboplatin and paclitaxel might achieve a higher pathological response rate, with an acceptable toxicity profile.