328 Phase 3 study of olaparib ± bevacizumab versus bevacizumab + fluorouracil in patients with unresectable or metastatic colorectal cancer not progressing on first-line FOLFOX + bevacizumab (LYNK-003)

Background Platinum-based regimens, such as FOLFOX (fluorouracil [5-FU], leucovorin, oxaliplatin), are recommended standard of care first-line options in metastatic colorectal cancer (CRC). Maintenance therapy with a less intensive treatment regimen in metastatic CRC patients who do not progress during intensive first-line platinum–based induction therapy can enhance clinical benefit and reduce toxicity associated with long-term exposure to oxaliplatin. The phase 3 CAIRO3 study demonstrated PFS benefit and a trend toward OS benefit in patients who discontinued oxaliplatin and switched to a maintenance regimen of fluoropyrimidine and bevacizumab. Olaparib is an oral PARP inhibitor that has shown efficacy in platinum-sensitive cancers. LYNK-003 is a randomized, open-label, phase 3 trial evaluating the efficacy and safety of olaparib, alone or in combination with bevacizumab, compared with bevacizumab plus 5-FU in patients with unresectable or metastatic CRC that has not progressed following first-line induction with FOLFOX plus bevacizumab. Methods Adult (≥18 years) patients with histologically confirmed unresectable or metastatic CRC that has not progressed following a first-line induction course of ≥6 cycles of FOLFOX plus bevacizumab and who can no longer tolerate oxaliplatin are eligible. Patients are required to have ECOG performance status score 0–1, adequate organ function, and provide tumor tissue for biomarker analysis. Patients will be randomly assigned 1:1:1 to olaparib 300 mg twice-daily (BID) plus bevacizumab 5 mg/kg every 2 weeks (Q2W), olaparib 300 mg BID, or 5-FU 2400 mg/m2 over 46–48 hours Q2W plus bevacizumab 5 mg/kg Q2W. Treatment will be stratified according to response to prior FOLFOX plus bevacizumab induction (stable disease [SD] vs partial response [PR]/complete response [CR]), mutation status (BRAFmut and/or Rasmut vs BRAFwt plus Raswt), and number of cycles of prior FOLFOX plus bevacizumab induction (6–8 vs >8 cycles). Responses will be assessed by computed tomography/contrast-enhanced magnetic resonance imaging per RECIST 1.1 by blinded independent central review (BICR) every 8 weeks during the first year and every 12 weeks thereafter. Study treatments will continue until documented progressive disease, unacceptable toxicity, intercurrent illness that prevents further administration of study intervention, investigator’s decision to discontinue the patient, consent withdrawal, pregnancy, or administrative reasons requiring cessation of study intervention. The primary endpoint is PFS per RECIST 1.1 by BICR and the key secondary endpoint is OS. Additional secondary endpoints are objective response rate and duration of response; safety and tolerability will also be reported. Approximately 525 patients will be enrolled. Results N/A Conclusions N/A Acknowledgements The authors thank the patients and their families for participating in these trials and all investigators and site personnel. Medical writing and/or editorial assistance was provided by Doyel Mitra, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Trial Registration ClinicalTrials. gov, ID number NCT04456699 Ethics Approval The study protocol and all amendments were approved by the relevant Institutional Review Board or ethics committee at each study site. All patients provided written informed consent to participate in the clinical trial.