vx-970 and Ovarian-Neoplasms

The panel of therapeutic options available for medical treatment of relapsed ovarian cancer increased over the last years. In late, platinum-sensitive relapse, standard treatment remains platinum-based polychemotherapy. The choice between bevacizumab added to chemotherapy followed by maintenance and inhibitors of poly-(ADP-riboses) polymerases (PARPi) after response to platinum-based therapy should be discussed, taking into account prior treatment, contraindications, and disease characteristics (biology, symptoms…). The addition of bevacizumab at first platinum-sensitive relapse can be considered if it has not been administered in first line, and it is optional (rechallenge) if previously administered (but without Marketing Authorization in this setting). PARPi are indicated for maintenance therapy after response to platinum-based chemotherapy (whatever the treatment line), regardless of BRCA mutational status, in case of no prior administration. Early relapses are associated with poor prognosis and therapeutic options are more limited. They are treated by monochemotherapy without platinum agents, associated with bevacizumab if not administered previously. Beyond first early relapse, there is no standard and inclusion in a clinical trial should be proposed if possible. Several clinical studies assessing associations of immunotherapy and chemotherapy and/or antiangiogenic drugs and/or targeted therapies (such as PARPi) are ongoing in early or late relapse.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Azepines; Bevacizumab; Carcinoma, Ovarian Epithelial; Female; Genes, BRCA1; Genes, BRCA2; Humans; Immunoconjugates; Immunotherapy; Isoxazoles; Maintenance Chemotherapy; Maytansine; Neoplasm Recurrence, Local; Ovarian Neoplasms; Platinum Compounds; Poly(ADP-ribose) Polymerase Inhibitors; Pteridines; Pyrazines; Pyrimidines

In a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90% CI, 0.17-0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90% CI, 0.13-0.86) and not patients with RS-high tumors (HR 1.11, 90% CI, 0.47-2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required.

Topics: Antineoplastic Combined Chemotherapy Protocols; Ataxia Telangiectasia Mutated Proteins; Biomarkers, Tumor; Deoxycytidine; DNA Replication; Female; Gemcitabine; Humans; Isoxazoles; Mutation; Oncogenes; Ovarian Neoplasms; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazines; Recombinational DNA Repair; Retinoblastoma Binding Proteins