PURPOSE Homologous DNA repair–deficient (HRD) ovarian cancers (OCs), including those with BRCA1/2 mutations, have higher levels of genetic instability, potentially resulting in higher immunogenicity, and have been suggested to respond better to immune checkpoint inhibitors (ICIs) than homologous DNA repair–proficient OCs. However, clinical evidence is lacking. The study aimed to evaluate the associations between BRCA1/2 mutations, HRD, and other genomic parameters and response to ICIs and survival in OC. METHODS This is a single-institution retrospective analysis of women with recurrent OC treated with ICIs. BRCA1/2 mutation status and clinicopathologic variables were abstracted from the medical records. Targeted and whole-exome sequencing data available for a subset of patients were used to assess tumor mutational burden (TMB), HRD, and fraction of genome altered (FGA). ICI response was defined as lack of disease progression for ≥ 24 weeks. Associations of BRCA1/2 status and genomic alterations with progression-free survival (PFS) and overall survival (OS) were determined using Cox proportional hazards models. RESULTS Of the 143 women treated with ICIs, 134 had known BRCA1/2 mutation status. Deleterious germline or somatic BRCA1/2 mutations were present in 31 women (24%). There was no association between presence of BRCA1/2 mutations and response ( P = .796) or survival. Genomic analysis in 73 women found no association between TMB ( P = .344) or HRD ( P = .222) and response, PFS, or OS. There were also no significant differences in somatic genetic alterations between responders and nonresponders. High FGA was associated with an improvement in PFS ( P = .014) and OS ( P = .01). CONCLUSION TMB, BRCA1/2 mutations, and HRD are not associated with response or survival, cautioning against their use as selection criteria for ICI in recurrent OC. FGA should be investigated further as a biomarker of response to immunotherapy in OC.

In ovarian cancer patients treated with immune checkpoint blockade, early discontinuation of therapy is common. • Symptomatic disease progression was common and accounted for early treatment discontinuation in the majority of patients. • Ovarian cancer patients with heavily pretreated, recurrent disease may not be suitable candidates for immunotherapy. • Pre-treatment clinical parameters can identify the patients at risk for early discontinuation and symptomatic progression.

Hypoxia-inducible factor (HIF), an important mediator of hypoxia response, is implicated in tumorigenesis in the setting of pseudohypoxia, such as in the inactivation of von Hippel–Lindau tumor suppressor protein (pVHL), leading to development and progression of clear cell renal cell carcinoma (ccRCC). Targeting downstream molecules in HIF pathway, such as vascular endothelial growth factor (VEGF), has led to improvement in clinical outcome for patients with advanced ccRCC, but such therapy thus far has been limited by eventual resistance and treat-ment failure. Following the discovery of HIF-2 alpha playing a key role in ccRCC carcinogenesis, inhibitors targeting HIF-2 alpha have been developed and have demonstrated encouraging efficacy and safety profile in clinical trials. This review discusses HIF-2 alpha as a promising therapeutic target for ccRCC.

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