This is a study for participants with a type of blood cancer called mantle cell lymphoma (MCL). The main purpose is to compare pirtobrutinib (LOXO-305) to other drugs that work in a similar way that have already been approved by the United States Food and Drug Administration (US FDA). Participation could last up to two years, and possibly longer, if the disease does not progress.

This is a Phase 3 global, randomized, open-label study comparing pirtobrutinib (Arm A) to investigator's choice of ibrutinib, acalabrutinib or zanubrutinib (Arm B) in MCL patients who have received 1 or more lines of therapy and are BTK inhibitor naïve.

Inclusion Criteria:

• Confirmed MCL diagnosis
• Previously treated with at least one prior line of systemic therapy for MCL
• Measurable disease per Lugano criteria
• Eastern Cooperative Oncology Group (ECOG) 0-2
• Absolute neutrophil count ≥ 0.75 × 109/L without granulocyte-colony stimulating factor support within 7 days of screening
• Hemoglobin ≥ 8 g/dL not requiring transfusion support or growth factors within 7 days of screening
• Platelets ≥ 50 × 109/L not requiring transfusion support or growth factors within 7 days of screening.
• AST and ALT ≤ 3.0 x upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 x ULN.
• Creatinine clearance of ≥ 30 mL/min according to Cockcroft/Gault Formula

Exclusion Criteria:

• Prior treatment with an approved or investigational BTK inhibitor
• History of bleeding diathesis
• History of stroke or intracranial hemorrhage within 6 months of randomization
• History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor modified T-cell (CAR-T) therapy within 60 days of randomization
• Clinically significant cardiovascular disease
• Prolonged QT interval corrected using Fridericia's formula (QTcF) > 470 ms on 2/3 consecutive ECGs, and mean QTcF>470 ms on all 3 ECGs
• Known HIV infection or active HBV, HCV, or CMV infections. (Certain participants with controlled HBV infections may still be eligible)
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption
• Ongoing chronic treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers which cannot be stopped within 3-5 half lives of the CYP3A inhibitor therapy prior to start of study drug treatment.
• Patients requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist.
• Vaccination with live vaccine within 28 days prior to randomization