Homologous recombination repair gene alteration is strongly associated with more prostate-specific membrane antigen-positive metastases in newly diagnosed hormone-sensitive prostate cancer with ≤5 conventional imaging defined distant metastases.

[BACKGROUND] The differences in imaging between prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and conventional imaging (CI) significantly impact disease staging, subsequently influencing the scope and clinical efficacy of stereotactic body radiotherapy (SBRT). In this multicenter retrospective study, we aimed to explore the effect of homologous recombination repair (HRR) gene status on the imaging differences between PSMA PET/CT and CI, which may have important implications for treatment selection.

[PATIENTS AND METHODS] A total of 1214 newly diagnosed hormone-sensitive prostate cancer (HSPC) patients with ≤ 5 CI-defined distant metastatic lesions were included. All patients underwent PSMA PET/CT, CI, and circulating tumor DNA testing for 19 HRR genes. The PSA response was defined as achieving a PSA level of < 0.1 ng/ml after 6 months.

[RESULTS] The median PSA level was 22.7 ng/ml. In the comparison of bone metastasis detection rates, the proportion of patients with higher detection rates on PSMA PET/CT than on CI was similar between BRCA mutation carriers and those with other HRR gene mutations (43.6% vs. 39.3%, p = 0.554), yet significantly higher in both groups compared to non-mutation carriers (20.5%, p = 0.00001). Similar results were observed in the analysis of metastasis detection rates for distant lymph nodes and regional lymph nodes. In non-metastatic HSPC patients without PSMA-positive distant disease who accepted radical prostatectomy (RP), patients without HRR gene mutations exhibited a significantly higher PSA response rate compared to HRR gene mutated patients (96.9% vs. 90.2%, p = 0.003).

[CONCLUSIONS] HRR gene alterations were significantly associated with a higher number of PSMA-positive metastases in newly diagnosed HSPC with ≤ 5 CI-defined distant metastases and worse outcomes in non-metastatic HSPC accepting RP. This finding suggests that HRR gene status should be considered as a potential indicator for recommending PSMA PET/CT in the design of clinical trials involving SBRT and in shaping imaging strategies.