Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these agents are not curative. cBTKi share pharmacologic liabilities such as low oral bioavailability and a short half-life that may lead to suboptimal BTK target coverage, especially in rapidly proliferating tumors with high BTK protein turnover, such as accelerating CLL/SLL, which can manifest as acquired resistance to cBTKi. Novel therapeutic agents addressing both intolerance and resistance while also improving efficacy are needed. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates (ORR) and was well tolerated in patients with CLL/SLL irrespective of prior therapy (including cBTKi), number of prior lines of therapy, BTK C481 mutation status, or reason for prior cBTKi discontinuation. The objective of this study is to compare efficacy and tolerability of pirtobrutinib versus ibrutinib in patients with CLL/SLL. Methods: BRUIN CLL-314 (NCT05254743) is a global, phase 3, open-label, randomized study comparing pirtobrutinib with ibrutinib. Approximately 650 BTKi-naïve patients, either treatment-naïve (up to 30%) or previously treated with other non-BTKi agents, will be randomized 1:1 to receive daily 200 mg pirtobrutinib once daily or 420 mg ibrutinib as continuous monotherapy. Randomization will be stratified by del(17p) status (yes/no) and number of prior lines of therapy (0 vs 1 vs ≥2). Enrollment for this study is ongoing. Adults with CLL/SLL who require therapy per iwCLL 2018 criteria are eligible. Key exclusion criteria include prior exposure to any BTKi, use of some concomitant therapies including anticoagulants, such as warfarin and other vitamin K antagonists, significant cardiovascular disease, active infections, and other clinically significant conditions. The primary objective is to establish non-inferiority of pirtobrutinib versus ibrutinib by comparing the ORR per iwCLL guidelines assessed by an independent review committee. Superiority of pirtobrutinib versus ibrutinib in progression-free survival is a key secondary outcome. Other endpoints include duration of response, overall survival, time-to-next treatment, tolerability, and patient-reported outcomes. Trial efficacy and safety will be monitored by an independent data monitoring committee. Clinical trial information: NCT05254743.