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Ovarian cancer is the second most common gynecologic malignancy in the United States (US) and the most common cause of gynecologic cancer-related death. The majority of ovarian cancers ultimately recur despite excellent response rates to upfront platinum and taxane-based chemotherapy. Maintenance therapy after frontline treatment has emerged in recent years as an effective tool for extending the platinum-free interval of these patients. Maintenance therapy with poly (ADP-ribose) polymerase inhibitors (PARPi) in particular has become part of standard of care in the upfront setting and in patients with platinum-sensitive disease. HR deficient (HRD) tumors have a nonfunctioning homologous recombination repair (HRR) pathway and respond well to PARPi, which takes advantage of synthetic lethality by concomitantly impairing DNA repair mechanisms. Conversely, patients with a functioning HRR pathway, i.e. HR proficient (HRP) tumors, can still elicit benefit from PARPi, but the efficacy is not as remarkable as what is seen in HRD tumors. PARPi are ineffective in some patients due to HR proficiency, which is either inherent to the tumor or potentially acquired as a method of therapeutic resistance. This review seeks to outline current strategies employed by clinicians and scientists to overcome PARPi resistanceeither acquired or inherent to the tumor.

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Purpose: Our study used transcriptomic and metabolomic strategies to determine the molecular profiles of HGSOC patient samples derived from primary tumor and ascites cells. These data identified clinically relevant heterogeneity among and within patients and highlighted global and patient-specific cellular responses to neoadjuvant chemotherapy (NACT). Experimental Design: Tissue from 61 treatment-naïve patients with HGSOC were collected. In addition, 11 benign, 32 ascites, and 18 post-NACT samples (matched to the individual patient's pre-NACT sample) were collected. RNA sequencing (RNA-seq) was performed on all samples collected. Two-dimensional spatial proteomic data was collected for two pairs of pre- and post-NACT. Untargeted metabolomics data using GCxGC-MS was generated for 30 treatment-naive tissues. Consensus clustering, analysis of differential expression, pathway enrichment, and survival analyses were performed. Results: Treatment-naïve HGSOC tissues had distinct transcriptomic and metabolomic profiles. The mesenchymal subtype harbored a metabolomic profile distinct from the other subtypes. Compared with primary tumor tissue, ascites showed significant changes in immune response and signaling pathways. NACT caused significant alterations in gene expression and WNT activity, and this corresponded to altered immune response. Overall, WNT signaling levels were inversely correlated with immune cell infiltration in HGSOC tissues and WNT signaling post-NACT was inversely correlated with progression-free survival. Conclusions: Our study concluded that HGSOC is a heterogenous disease at baseline and growing molecular differences can be observed between primary tumor and ascites cells or within tumors in response to treatment. Our data reveal potential exploratory biomarkers relevant for treatment selection and predicting patient outcomes that warrant further research.