Abstract 6511: Androgen receptor (AR) genomic alterations and clinical outcome with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy
Authors: Sun Michael , Niaz Muhammad , Thomas Charlene , Schaap Ariel , Lacuna Kristine , Vlachostergios Panagiotis , Christos Paul , Molina Ana M. , Nanus David M. , Sternberg Cora N. , Osborne Joseph , Bander Neil H. , Tagawa Scott T. 
Published: September 2020

Abstract
Background: Prostate-specific membrane antigen is a cell-surface glycoprotein commonly expressed on prostatic adenocarcinomas (PC). PSMA expression is related to AR signaling, generally with increased PSMA expression with dysregulation of the AR pathway. Targeted radionuclide therapies (TRT) involving radionuclides (177Lu, 225Ac, 90Y) conjugated to PSMA-specific antibodies (e.g. J591) or small molecule ligands (e.g. PSMA-617) are being developed and utilized in clinical trials. Genetic profiling of PC may predict responsiveness to PSMA-based therapies. Because of the relationship of AR and PSMA expression, we sought to assess the association between AR genomic aberrations and outcome following PSMA-TRT.
Methods: Eligible subjects with progressive metastatic castration-resistant PC were enrolled in prospective PSMA-TRT clinical trials. Those who underwent targeted or whole-exome sequencing of their tumors were analyzed. Pre-treatment baseline clinical data were collected; outcome measures included PSA decline and overall survival (OS) post-therapy. Chi-square test was used to assess the association of AR alterations and PSA decline with multivariable logistic regression to control for known factors associated with response. The Kaplan-Meier method was used to assess OS with multivariable cox proportional hazards regression analysis to evaluate the independent effect of AR alterations on OS after controlling for prognostic variables.
Results: 66 men with median age 69.6 years were enrolled. 38 (57%) received 177Lu-PSMA-617, 16 (24%) 177Lu-J591, 7 (11%) 225Ac-J591, and 5 (8%) both 177Lu-PSMA-617 and 177Lu-J591. The majority (59%) were poor-risk CALGB (Halabi) prognostic group. 31 patients (47%) had AR amplifications or resistance mutations. Patients with AR alterations were less likely to experience ≥30% PSA decline (32.3% vs. 62.9%, p=0.025) compared to wild-type, though this association was less significant after controlling for radionuclide dose and PSMA imaging intensity. AR alterations were associated with shortened OS (12.43 vs. 21.07 months, p=0.043). After controlling for radionuclide dose, Halabi group, PSMA imaging intensity, and receipt of subsequent FDA-approved life-prolonging therapies, AR alterations still were associated with shortened OS (HR 2.07 [1.02-4.2], p=0.04).
Conclusion: AR resistance mutations and amplifications appear to result in poorer outcome following PSMA-TRT both in terms of PSA decline and overall survival. Genetic sequencing may inform responses to PSMA-based therapies, and prospective genomic panel testing is ongoing.
Supported by: Weill Cornell Medicine, Prostate Cancer Foundation, Department of Defense, NIH
Citation Format: Michael Sun, Muhammad Niaz, Charlene Thomas, Ariel Schaap, Kristine Lacuna, Panagiotis Vlachostergios, Paul Christos, Ana M. Molina, David M. Nanus, Cora N. Sternberg, Joseph Osborne, Neil H. Bander, Scott T. Tagawa. Androgen receptor (AR) genomic alterations and clinical outcome with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6511.