Background: First-line treatment with pembrolizumab + pemetrexed/platinum improved clinical outcomes in patients with advanced nonsquamous NSCLC in KEYNOTE-021 and KEYNOTE-189. Poly(ADP-ribose) polymerase inhibitors (PARPi), including olaparib, have been shown to upregulate PD-L1 expression in preclinical studies, and preliminary evidence suggests potential therapeutic benefit and acceptable safety with PARPi plus anti–PD-(L)1 therapy. KEYLYNK-006 (NCT03976323) evaluates first-line pembrolizumab + pemetrexed/platinum followed by pembrolizumab + olaparib vs pembrolizumab + pemetrexed in patients with metastatic nonsquamous NSCLC. Methods: This phase III, randomized, open-label trial enrolls patients aged ≥18 years with histologically/cytologically confirmed treatment-naive, metastatic, nonsquamous NSCLC. Patients (target n = 792) receive induction pembrolizumab 200 mg + pemetrexed 500 mg/m² + carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m² Q3W for 4 cycles. Patients with PR/CR or SD are randomized (target n = 618) 1:1 to pembrolizumab 200 mg Q3W (31 cycles) + maintenance olaparib 300 mg twice daily or pembrolizumab + pemetrexed 500 mg/m² Q3W stratified by ECOG PS (0 vs 1), PD-L1 tumor proportion score (<50% vs ≥50%), and response (CR/PR vs SD). Tumor imaging per RECIST version 1.1 (≤5 per organ; maximum 10 total lesions) by central review (BICR) is performed at baseline and Q6W until 60 weeks after randomization, then Q9W until disease progression, start of new cancer therapy, study withdrawal, or death. Primary endpoints are PFS (RECIST 1.1 by BICR) and OS estimated by the Kaplan-Meier method, stratified log-rank test, and Cox proportional hazard model with Efron’s method of tie handling. Secondary endpoints are safety and quality of life; ORR and duration of response are exploratory endpoints. AEs are monitored throughout the study until 30 days after the last dose of treatment (90 days for serious AEs) and graded using NCI CTCAE, version 4.0. The study began enrolling in June 2019. Clinical trial information: NCT03976323.