PSMA PET Tumor-to-Salivary Gland Ratio to Predict Response to [¹⁷⁷Lu]PSMA Radioligand Therapy: An International Multicenter Retrospective Study

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy can improve the outcome of patients with advanced metastatic castration-resistant prostate cancer, but patients do not respond uniformly. We hypothesized that using the salivary glands as a reference organ can enable selective patient stratification. We aimed to establish a PSMA PET tumor-to-salivary gland ratio (PSG score) to predict outcomes after [¹⁷⁷Lu]PSMA. Methods: In total, 237 men with metastatic castration-resistant prostate cancer treated with [¹⁷⁷Lu]PSMA were included. A quantitative PSG (qPSG) score (SUV_mean ratio of whole-body tumor to parotid glands) was semiautomatically calculated on baseline [⁶⁸Ga]PSMA-11 PET images. Patients were divided into 3 groups: high (qPSG. 1.5), intermediate (qPSG 5 0.5-1.5), and low (qPSG, 0.5) scores. Ten readers interpreted the 3-dimensional maximum-intensity-projection baseline [⁶⁸Ga]PSMA-11 PET images and classified patients into 3 groups based on visual PSG (vPSG) score: high (most of the lesions showed higher uptake than the parotid glands) intermediate (neither low nor high), and low (most of the lesions showed lower uptake than the parotid glands). Outcome data included a more than 50% prostate-specific antigen decline, prostate-specific antigen (PSA) progression-free survival, and overall survival (OS). Results: Of the 237 patients, the numbers in the high, intermediate, and low groups were 56 (23.6%), 163 (68.8%), and 18 (7.6%), respectively, for qPSG score and 106 (44.7%), 96 (40.5%), and 35 (14.8%), respectively, for vPSG score. The interreader reproducibility of the vPSG score was substantial (Fleiss weighted k, 0.68). The more than 50% prostate-specific antigen decline was better in patients with a higher PSG score (high vs. intermediate vs. low, 69.6% vs. 38.7% vs. 16.7%, respectively, for qPSG [P, 0.001] and 63.2% vs 33.3% vs 16.1%, respectively, for vPSG [P, 0.001]). The median PSA progression-free survival of the high, intermediate, and low groups by qPSG score was 7.2, 4.0, and 1.9 mo (P, 0.001), respectively, by qPSG score and 6.7, 3.8, and 1.9 mo (P, 0.001), respectively, by vPSG score. The median OS of the high, intermediate, and low groups was 15.0, 11.2, and 13.9 mo (P 5 0.017), respectively, by qPSG score and 14.3, 9.6, and 12.9 mo (P 5 0.018), respectively, by vPSG score. Conclusion: The PSG score was prognostic for PSA response and OS after [¹⁷⁷Lu]PSMA. The visual PSG score assessed on 3-dimensional maximum-intensity-projection PET images yielded substantial reproducibility and comparable prognostic value to the quantitative score.