Blood Immune Signature Predicts Who Benefits Most From PARP Inhibitor Therapy in Ovarian Cancer

Epithelial ovarian cancer remains the deadliest gynecological malignancy globally, with most patients experiencing relapse despite initial response to platinum-taxane chemotherapy. PARP inhibitors (PARPi) like olaparib offer meaningful benefit, especially in patients with BRCA mutations or homologous recombination deficiency (HRD), but those with HRP tumors benefit far less. Improving outcomes for this subgroup is an urgent clinical need, and combining PARPi with immunotherapy represents a promising but largely unvalidated strategy.

SOLACE2 enrolled 114 women with platinum-sensitive recurrent ovarian cancer across Australian sites, randomizing them 1:1:1 to: (A) 12 weeks olaparib priming then durvalumab-olaparib, (B) 12 weeks olaparib plus low-dose cyclophosphamide priming then durvalumab-olaparib, or (C) continuous olaparib monotherapy. The primary endpoint was the proportion of patients progression-free at 36 weeks (PFS36). Crucially, the trial also prospectively evaluated the CUP-CC assay — a blood-based immune signature incorporating CCR4 upregulation, chemokines, and cytokines — as a prognostic and potentially predictive biomarker.

Neither priming arm met the pre-specified PFS36 threshold. PFS36 rates were 47.4% for olaparib priming, 48.7% for cyclophosphamide-olaparib priming, and 35.1% for olaparib monotherapy. However, both combination sequences numerically outperformed monotherapy. As expected, HRD patients (n=71) had significantly longer PFS than HRP patients (n=29), with a hazard ratio of 0.55. The most striking finding was the CUP-CC biomarker: CUP-CC-positive patients (n=58) had a hazard ratio of 0.31 compared to CUP-CC-negative patients (n=46), representing a highly significant survival advantage that was independent of HRD status and BRCA mutation.

The CUP-CC assay appears to identify patients with an immune microenvironment predisposed to respond to PARPi-based therapy, potentially through immune-mediated mechanisms beyond direct DNA repair exploitation. This is especially clinically meaningful for BRCA wild-type and HRP patients, who currently lack reliable predictive biomarkers. Low-dose cyclophosphamide, known to deplete regulatory T cells, was hypothesized to enhance immunogenic cell death and improve the efficacy of subsequent durvalumab, but this mechanistic benefit was not clearly demonstrated in the overall trial results.

The trial was limited by its sample size, which reduced statistical power to detect modest treatment differences. The CUP-CC findings are exploratory and require prospective validation in larger cohorts. Nonetheless, SOLACE2 positions the CUP-CC assay as a promising tool for patient selection in future PARPi and immunotherapy combination trials, particularly for the underserved HRP population.