TPS241 Background: Current therapeutic strategies for metastatic castration-resistant prostate cancer (mCRPC) include treatment with next-generation androgen receptor signaling inhibitors (ARSIs), such as enzalutamide, darolutamide, and apalutamide, which all target the ligand-binding domain (LBD) of the AR, and abiraterone, an androgen biosynthesis inhibitor. Approximately 5% to 10% of patients will have primary resistance to ARSIs and most initial responders will develop resistance within 1 to 3 years. Eventually, nearly all men with prostate cancer treated with ARSIs develop resistance via several mechanisms including activation of AR genomic alterations, epigenetic alterations, and expression of truncated constitutively active AR splice variants. Hence, there is substantial unmet need for treatment of men with mCRPC resistant to at least one next-generation ARSI. ONCT-534 is a DAARI with a novel mechanism of action that combines inhibition of AR function with degradation of the AR protein. Importantly, this activity includes interaction with the N-terminal domain (NTD), rendering it effective against splice variants and LBD mutants, unlike existing ARSIs. ONCT-534 has demonstrated preclinical activity in prostate cancer models against unmutated AR and multiple forms of AR alteration, including amplification, mutations in the LBD, and splice variants with loss of LBD. Methods: ONCT-534-101 is a phase 1/2, multi-center study to evaluate the safety, tolerability, antitumor activity, and pharmacokinetics of ONCT-534 in subjects with mCRPC without neuroendocrine differentiation or small cell features who have relapsed or are refractory (R/R) to at least one next-generation ARSI. The study will be separated into a Phase 1 Dose Escalation and a Phase 2 Dose Expansion. The Phase 1 portion will evaluate approximately 27 subjects in 5 dose levels using an adaptive Bayesian Optimal Interval (BOIN) design to assess safety, tolerability and DLT at escalating doses and to determine the MTD and inform the 2 dose levels or schedules to be tested in Phase 2. DLTs will be assessed during the first 28 days of treatment. The AR phenotype and AR levels of each subject’s disease will be evaluated pre- and post-treatment. The Phase 2 portion will evaluate approximately 32 subjects in 2 randomized cohorts to assess safety and tolerability of ONCT-534, compare the 2 different dose levels or schedules to select the optimal dose for further study, and assess the preliminary antitumor activity of ONCT-534. In both phases, after a screening period, eligible subjects with mCRPC will receive their assigned dose regimen of ONCT-534, which will be administered orally daily for 2 years or until disease progression and no longer clinically benefiting from treatment or development of unacceptable toxicity. The study was opened for enrollment September 2023. Clinical trial information: NCT05917470 .