Abstract LB089: Exploring androgen receptor alterations (ARa) and their potential association with efficacy of first-line (1L) talazoparib (TALA) + enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC): A post hoc analysis of

Abstract Background: In TALAPRO-2 (NCT03395197), patients (pts) unselected for homologous recombination repair gene alterations (HRRm) received TALA + ENZA or PBO + ENZA as 1L treatment for mCRPC. TALA + ENZA significantly improved radiographic progression-free survival (rPFS) and overall survival vs PBO + ENZA. We explored ARa prevalence and potential associations with efficacy. Methods: This is a post hoc exploratory agnostic analysis of a TALAPRO-2 dataset of prospectively collected/retrospectively analyzed plasma ctDNA (clinical trial assay based on FoundationOne®Liquid CDx; N = 681 informative records for safety population). Alterations were defined as known/likely pathogenic variants. rPFS was assessed per blinded independent central review. Data cutoff Aug 16, 2022. Results: Overall, 227/681 (33%) pts in the safety population had ARa (TALA + ENZA: 121/336 [36%]; PBO + ENZA: 106/345 [31%]). ARa were numerically modestly-enriched in pts bearing HRRm compared with pts lacking HRRm (80/206 [39%] vs 147/475 [31%], p = 0.05, Fisher’s exact test). TALA + ENZA improved rPFS vs PBO + ENZA in pts bearing or lacking ARa (Table) with similar trends in AR short variants or amplifications. Within treatment arms, ARa and ARa subtypes (short variants, amplifications) were associated with shorter rPFS (Table); this difference was significant (p < 0.01) in all cases except for short variants in the PBO + ENZA arm (p = 0.110). Limitations included not characterizing AR splice variant transcripts and low ctDNA in some pts. Conclusion: AR short variants and amplifications have been implicated in resistance to androgen deprivation therapy and novel hormonal therapies such as ENZA. In TALAPRO-2, TALA + ENZA improved rPFS vs PBO + ENZA in pts with or without ARa, consistent with therapeutic exploitation of cross-talk between AR and DNA repair pathways. Citation Format: Glenn Liu, A. Douglas Laird, Neeraj Agarwal, Stefanie Zschäbitz, Karim Fizazi, Nobuaki Matsubara, Jae Young Joung, Lawrence I. Karsh, Joan Carles, André P. Fay, Michelle Saul, Xinmeng Jasmine Mu, Steven M. Yip, Merrida Childress, Jijumon Chelliserry, Cynthia G. Healy, Fong Wang, Matko Kalac, Josep M. Piulats, Arun A. Azad. Exploring androgen receptor alterations (ARa) and their potential association with efficacy of first-line (1L) talazoparib (TALA) + enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC): A post hoc analysis of TALAPRO-2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB089.