Prostate-Specific Membrane Antigen Radioligand Therapy in Patients with Aggressive-Variant Prostate Cancer

Aggressive-variant prostate cancer (AVPC) is characterized by several high-risk features and is typically treated with chemotherapy. In this study, we evaluated the outcomes of patients with AVPC who received prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT). <b>Methods</b>: This retrospective study included patients with AVPC with metastatic castration-resistant prostate cancer who received PSMA RLT at 3 academic centers. Patients with AVPC were further stratified into 2 subcategories: AVPC-C (clinicopathologic), referring to patients who met AVPC on the basis of clinical or pathologic features, and AVPC-MS (molecular signature), referring to patients who met AVPC criteria on the basis of genomic alterations. Prostate-specific antigen (PSA) response was calculated in the overall cohort, and PSA progression-free survival and overall survival (OS) were calculated in the paired cohort. In the segmentation cohort, SUV_mean and total tumor volume were quantified using MIM software. <b>Results</b>: In total, 82 patients were classified as having AVPC, of whom 47 (57%) had AVPC-C and 35 (43%) had AVPC-MS. In the overall cohort, the percentage of patients who had a reduction in PSA of at least 50% or more from baseline was similar between the AVPC and non-AVPC groups (62.1% vs. 60.7%, respectively). In the paired cohort, the median PSA progression-free survival in the AVPC group was 3.2 mo (95% CI, 2.5-5.7 mo), compared with 4.2 mo (95% CI, 3.5-5.1 mo) in the non-AVPC group (<i>P</i> = 0.10). The median OS was shorter in the AVPC group (11.8 mo; 95% CI, 9.7-14.9 mo) compared with the non-AVPC group (13.3 mo; 95% CI, 12.1-15.0 mo; <i>P</i> = 0.04). There was no difference in median OS between AVPC-MS and AVPC-C subgroups (11.9 mo vs. 10.9 mo, respectively; <i>P</i> = 0.8). In the segmentation cohort, there was a trend toward lower SUV_mean in patients with AVPC (5.9 vs. 6.6 in patients without AVPC, <i>P</i> = 0.07); however, there was no difference in median total tumor volume between the groups (253.4 mL vs. 298.6 mL, respectively; <i>P</i> = 0.6). <b>Conclusion:</b> Although patients with AVPC exhibited significantly worse OS after PSMA RLT, the percentage of patients treated with PSMA RLT who had a reduction in PSA of at least 50% or more from baseline was similar between the AVPC and non-AVPC groups. These findings support the consideration of PSMA RLT as a treatment option in patients with AVPC who have adequate PSMA expression.