Dynamic androgen receptor alterations (ARa) ctDNA profiles and clinical outcomes in metastatic prostate cancer (mPC).

5069 Background: The AR plays a pivotal role in PC pathogenesis and ARa, including ligand binding domain mutations and amplifications, can evolve under the selective pressure of androgen deprivation therapy and androgen receptor signaling inhibitors (ARSi). Next-generation sequencing of circulating tumor DNA (ctDNA) enables non-invasive, longitudinal monitoring of AR dynamics in patients (pts) undergoing systemic therapies. This study aims to explore the dynamic changes in ctDNA profiles, particularly focusing on the AR gene and its association with clinical outcomes. Methods: We utilized GuardantINFORM, a clinical-genomics database containing de-identified ctDNA test results and commercial payer-claims data. Eligible pts had a diagnosis of mPC and underwent ctDNA testing pre (within 3 months prior to initiation) and post (within 3 months of discontinuation prior to initiating subsequent treatment) ARSi, poly ADP‐ribose polymerase inhibitors (PARPi), and taxane chemotherapy. The primary endpoint was to characterize changes in molecular alterations pre- and post-therapy. Secondary endpoints included overall survival (OS), time to treatment discontinuation (TTD), and time to next treatment (TTNT) for pts receiving with ctDNA testing within 3 months prior to 1L ARSI for mCRPC. Results: From a database of 21,682 pts with PC, 145 had ctDNA collected pre/post ARSI, 54 pre/post PARPi, and 115 pre/post taxane chemotherapy. We observed increased ARa across the three treatment groups (%pre/%post): ARSi (17/35), PARPi (39/43), and taxanes (44/58) (Table). In the ARSi group, most common (%pre/%post) ARa included AR amplifications (11/23), AR T878A (5/9), AR L702H (2/6) and AR H875Y (0.7/1.4). In the PARPi group, the most prevalent (%pre/%post) ARa comprised AR amplifications (24/32), AR L720H (15/15), AR T878A (11/9) and AR F877L (2/6). In the taxane group, notable (%pre/%post) ARa consisted of AR amplifications (33/44), AR L702H (4/10), AR H875Y (3/9) and AR T878A (7/8). 1294 pts had ctDNA testing prior to 1L ARSi for mCRPC and were included in the outcomes analysis. Pts with ARa showed worse TTD (2.8 vs 4.3, p<0.0001), TTNT (6.9 vs 4.8, p<0.0001) and (OS (15.3 vs 49.3, p<0.0001). Conclusions: Our study elucidates evolving changes in AR in mPC using ctDNA profiling. We observed an increase in ARa following ARSi, PARPi, and taxane treatment in mPC. Furthermore, our findings highlight associations between ARa and clinical outcomes, emphasizing the potential for personalized treatment strategies in mPC pts based on molecular profiling. Table: see text