68Gallium-labelled FAP-inhibitors outperforms 18F-fluorodeoxyglucose PET/CT for recurrent ovarian cancer in the poly adenosine diphosphate-ribose polymerase inhibitor era.

Precise evaluation is pivotal in managing relapsed ovarian cancer, particularly as poly adenosine diphosphate-ribose polymerase inhibitor (PARPi) maintenance therapy can render some recurrent lesions difficult to detect. We aimed to investigate the clinical applications and underlying mechanisms of 68Gallium-labelled FAP-inhibitors (68Ga-FAPI) compared with 18F-fluorodeoxyglucose positron emission tomography/computerized tomography (18F-FDG PET/CT) in recurrent ovarian cancer. Between January 2022 and July 2023, patients with suspected recurrent ovarian cancer at Fudan University Shanghai Cancer Center underwent both PET/CT imaging modalities. To minimize heterogeneity, the final analysis included only patients with platinum-sensitive high-grade serous ovarian cancer. Clinical characteristics, treatment strategies, and pathological findings were collected. Additional analyses included immunohistochemistry, single-nucleus RNA sequencing (snRNA-seq), and patient-derived organoid (PDO) models experiments. Eighty-nine eligible patients were prospectively enrolled. Concordant imaging findings were observed in only 37 (41.6%) patients. Thirty-three patients underwent surgery, and 28 (84.8%) achieved complete resection. The overall diagnostic accuracy was 96.3% for FAPI compared with 86.9% for FDG. Patients receiving PARPi maintenance therapy were more likely to have additional FAPI-positive (FAPI+) lesions, while bevacizumab appeared to influence FAPI uptake. Patients with additional FAPI-detected lesions experienced shorter progression-free survival, particularly those with prior PARPi maintenance therapy. In PDO models, FAPI-positive/FDG-negative (FAPI+/FDG-) tumors after PARPi maintenance therapy were resistant to PARPi re-challenge. Immunohistochemistry staining and snRNA-seq analyses revealed hypoglycolytic tumor features and activation of cancer-associated fibroblasts (CAFs) in these lesions. 68Ga-FAPI demonstrated superior lesion detection and diagnostic accuracy compared with 18F-FDG PET/CT for recurrent ovarian cancer, especially in the PARPi era. Hypoglycolysis and CAF activation may underlie PARPi resistance in FAPI+/FDG- lesions.