The purpose of this study is to compare the efficacy and safety of pirtobrutinib (LOXO-305; Arm A) compared to BR (Arm B) in patients with CLL/SLL who have not been treated. Participation could last up to five years.

Inclusion Criteria:

• Confirmed diagnosis of CLL/SLL requiring therapy, per iwCLL 2018 criteria
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
• Adequate organ function
• Platelets greater than or equal to (≥)75 x 10⁹/liter (L) (≥50 × 10⁹/L for patients with evidence of bone marrow infiltrate), hemoglobin ≥8 grams/deciliter (g/dL), and absolute neutrophil count ≥0.75 x 10⁹/L
• Kidney function: Estimated creatinine clearance ≥40 milliliters per minute (mL/min)

Exclusion Criteria:

• Known or suspected Richter's transformation at any time preceding enrollment

• Prior systemic therapy for CLL/SLL

• Presence of 17p deletion

• Central nervous system (CNS) involvement

• Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP])

• Significant cardiovascular disease

• Active hepatitis B or hepatitis C

• Active cytomegalovirus (CMV) infection

• Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection

• Known human immunodeficiency virus (HIV) infection, regardless of cluster of differentiation 4 (CD4) count

• Concurrent use of investigational agent or anticancer therapy except hormonal therapy

• Patients requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist

• Vaccination with a live vaccine within 28 days prior to randomization

• Patients with the following hypersensitivity:

  • Known hypersensitivity, including anaphylaxis, to any component or excipient of pirtobrutinib or bendamustine
  • Prior significant hypersensitivity to rituximab