Background: AR alterations evolve under the selective pressure of testosterone suppression and AR targeted agents. In metastatic, castration-resistant prostate cancer (mCRPC) AR’s mutational landscape and therapeutics targeting is still an unexplored area. Here we evaluate AR mutations in the circulating tumor DNA (ctDNA) of patients treated with AR targeted agents such as abiraterone (abi), enzalutamide (enza) and in combination (abi + enza) setting in a large Tempus real-world mCRPC cohort. Methods: De-identified records of patients with mPC who underwent Tempus xF next-generation sequencing (NGS) ≥ 6 months after treatment initiation of abi, enza, or abi + enza were selected for analysis. If patients had multiple NGS samples, the most recent sample was used. The assay is a targeted liquid biopsy panel that detects single-nucleotide variants and insertions and/or deletions in 105 genes, copy number variants in six genes, and chromosomal rearrangements in seven genes. Results: The cohort included 1,122 patients treated with abi only (n=483), enza only (n=374), or prior exposure to abi + enza (n=265). Pathogenic/likely pathogenic mutations were detected in 15% (n=71) of patients treated with abi,15% (n=56) treated with enza, and 27% (n=71; P<0.001) treated with both.The most frequent AR alterations were L702H (18%, 32%, and 25%) and T878A (34%, 3.6%, and 21%) and H875Y (7%, 12%, and 8.5%) in abi, enza, and abi + enza, respectively (Table). L702H and T878A alterations were found in an additional 8.5%, 3.6% and 9.9% of patients treated with abi, enza, or abi + enza, respectively. Alterations in L702A and H875T were found in 2.8%, 8.9% and 9.9% of patients treated with abi, enza, and abi + enza respectively. Approximately 4.2%, 1.8% and 1.4% (abi, enza, abi +enza) of treated patients had alterations in T878A and H875Y. Other single-hit alterations included 6 patients with W742C and 4 patients with F877L. Conclusions: AR mutations have implications for clinical decision making and drug development in patients treated with abiraterone and/or enzalutamide.

¹n (%).