LYNK-003 Trial of Olaparib in Metastatic Colorectal Cancer Halted Due to Futility
The LYNK-003 trial evaluating olaparib monotherapy or in combination with bevacizumab in patients with unresectable or metastatic colorectal cancer who have not progressed following first-line induction has ended due to futility.
The phase 3 LYNK-003 trial evaluating olaparib (Lynparza) with or without bevacizumab (Avastin) for the treatment of patients with unresectable or metastatic colorectal cancer who have not progressed following first-line induction has stopped for futility, according to Merck.1
This action is based on the recommendation of an independent Data Monitoring Committee (DMC) following reviewed data from a planned interim analysis which showed the efficacy of olaparib as both a monotherapy and in combination with bevacizumab to be relative to control, meeting the criteria for futility. As a result, both experimental arms will be discontinued.
Olaparib is a first-in-class PARP inhibitor that is being co-developed and co-commercialized with AstraZeneca. The inhibitor is being designed to potentially exploit DNA damage response (DDR) pathway deficiencies, including BRCA mutations, to preferentially kill cancer cells.
Olaparib is currently being tested in a range of tumor types with defects and dependencies in the DDR to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types.
In the randomized, open-label, phase 3 LYNK-003 trial (NCT04456699), experts sought to evaluate the use of olaparib as monotherapy or in combination with bevacizumab compared with bevacizumab in combination with fluoropyrimidine-based chemotherapy. A total of 309 patients with unresectable or metastatic colorectal cancer who had not progressed following first-line induction were enrolled.2
Enrollment was open to patients aged 18 years and older with histologically-confirmed metastatic or unresectable colorectal adenocarcinoma which had not progressed after a first-line induction course of at least 6 cycles of fluorouracil/leucovorin (FOLFOX)plus bevacizumab or 4 cycles of capecitabine/oxaliplatin (CAPOX) plus bevacizumab as first-line therapy. Patients must have experienced unacceptable toxicity to oxaliplatin, provided to the iCRO 1 set of baseline radiographic images taken before or during the CAPOX plus bevacizumab or oxaliplatin, FOLFOX plus bevacizumab induction period and at least 42 days prior to the imaging performed during screening, and had an ECOG status of 0-1 within 10 days prior to randomization.
In the olaparib plus bevacizumab arm, patients were administered oral olaparib at 300 mg twice a day in addition to intravenous bevacizumab 5 mg/kg once every 2 weeks while those who received olaparib alone were given oral olaparib 300 mg twice a day. These arms were compared with the active comparator arm where patients received bevacizumab plus investigators' choice of chemotherapy. Treatment continued until progressive disease or the end of study.
The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival, objective response rate, duration of response, and safety.
At the prespecified interim analysis for PFS, olaparib alone and combined with bevacizumab met the criteria for futility by the DMC. There were no new safety signals observed with olaparib within this trial, and the safety profiles of olaparib as a monotherapy and combined with bevacizumab were consistent with that observed in previously reported studies.
Study investigators on the trial will be informed of the recommendation from the DMC and advise patients to speak to their physician regarding what to do next for treatment. Data from this study is expected to be shared in a future scientific forum.
