Assessing Interlesional Tumor Response and Patient Outcomes with Sequential PSMA PET/CT in Metastatic Castration-Resistant Prostate Cancer

The impact of heterogeneous interlesional tumor response on outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) remains unclear. We aimed to evaluate the role of prostate-specific membrane antigen (PSMA) PET/CT in assessing patient outcomes on the basis of global tumor response and interlesional tumor response. Methods: We retrospectively analyzed data for 24 patients with mCRPC treated with androgen receptor pathway inhibitors who underwent [⁶⁸Ga]Ga-PSMA-11 PET/CT at baseline and at weeks 4 and 12 of therapy as well as conventional imaging at baseline and week 12 of therapy. Global PET/CT response was evaluated in accordance with the European Association of Urology/European Association of Nuclear Medicine criteria, classifying patients as having progressive disease (PD) or nonprogressive disease (non-PD) (i.e., complete response, partial response, or stable disease) and was correlated with overall survival (OS), prostate-specific antigen-progression-free survival (PSA-PFS) (i.e., time from diagnosis to PSA progression or death from any cause), radiologic progression-free survival, and time to no longer clinically benefiting from treatment. For interlesional assessment, a subset of PSMA-positive lesions was extracted from each patient and compared longitudinally. Patients classified as having either interlesional progression or interlesional homogeneous response were included in the OS and PSA-PFS analyses. Results: The median OS was 22 mo for patients with PD (n = 8) and 51 mo for those with non-PD (n = 16) (hazard ratio [HR], 28.2; P < 0.0001). PSMA PET/CT-based response was significantly associated with median PSA-PFS (6.5 mo vs. not reached [NR]; HR, 20.5; P = 0.0001), radiologic progression-free survival (9 mo vs. NR; HR, 12.2; P = 0.002), and time to no longer clinically benefiting from treatment (12 mo vs. NR; HR, 18.6; P = 0.0002) for patients with PD versus non-PD, respectively. The results were similar at week 12 and remained statistically significant. Interlesional assessment was performed for 125 PSMA-positive lesions in 20 (83%) patients. At week 12, 9 (45%) of 20 patients had interlesional progression, which was significantly associated with worse outcomes compared with patients who had an interlesional homogeneous response (median PSA-PFS, 7 mo vs. NR; HR, 19.2; P < 0.0001; median OS, 16 mo vs. 52 mo; HR, 31.2; P < 0.0001, respectively). Conclusion: Assessment of interlesional tumor response at week 12 by sequential PSMA PET/CT enabled the identification of patients with mCRPC who had worse outcomes after treatment with an androgen receptor pathway inhibitor.