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). Methods: 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, SUVmean and total tumor volume were quantified using MIM software. Results: 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 (P = 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; P = 0.04). There was no difference in median OS between AVPC-MS and AVPC-C subgroups (11.9 mo vs. 10.9 mo, respectively; P = 0.8). In the segmentation cohort, there was a trend toward lower SUVmean in patients with AVPC (5.9 vs. 6.6 in patients without AVPC, P = 0.07); however, there was no difference in median total tumor volume between the groups (253.4 mL vs. 298.6 mL, respectively; P = 0.6). Conclusion: 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.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2026 Mar 05 [Epub ahead of print]
Moein Moradpour, Abuzar Moradi Tuchayi, Surekha Yadav, Fei Jiang, Irene A Burger, Sabin George Pop, Devaki Shilpa Surasi, Akram Hussein, Ishan Arora, Ana Aparicio, Ivan de Kouchkovsky, Robert R Flavell, Thomas A Hope
Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California., Department of Epidemiology and Biostatistics, University of California, San Francisco, California., Department of Nuclear Medicine, Kantonsspital Baden, Affiliated Hospital for Research and Teaching of the Faculty of Medicine of the University of Zurich, Baden, Switzerland., Department of Nuclear Medicine, MD Anderson Cancer Center, University of Texas, Houston, Texas., Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas., Department of Medicine, Hematology and Oncology Division, University of California, San Francisco, San Francisco, California., Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California; .