Abstract
<div>AbstractPurpose:<p>To explore whether patients with <i>BRCA1/2</i>-mutated or homologous recombination deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial.</p>Patients and Methods:<p>Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. Programmed death-ligand 1 (PD-L1) status of tumor-infiltrating immune cells (IC) was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious <i>BRCA1/2</i> alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥ 16%, regardless of <i>BRCA1/2</i> mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan–Meier estimates.</p>Results:<p>Among biomarker-evaluable samples, 22% (234/1,050) harbored <i>BRCA1/2</i> mutations and 46% (446/980) were HRD. Median TMB was low irrespective of <i>BRCA1/2</i> or HRD. Only 3% (29/1,024) had TMB ≥10 mut/Mb, and 0.3% (3/1,022) were MSI-high. PFS was better in <i>BRCA2</i>-mutated versus <i>BRCA2</i>–non-mutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on ICs) was associated with HRD but not <i>BRCA1/2</i> mutations. PFS was not improved by adding atezolizumab in <i>BRCA2-</i>mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab in <i>BRCA1</i>-mutated tumors.</p>Conclusions:<p>Most ovarian tumors have low TMB despite <i>BRCA1/2</i> mutations or HRD. Neither <i>BRCA1/2</i> mutation nor HRD predicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by <i>BRCA1/2</i> mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-0048" target="_blank">See related commentary by Al-Rawi et al., p. 1645</a></i></p></div>
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