The phase III ZEST clinical trial, designed to evaluate the PARP inhibitor niraparib for the prevention of breast cancer recurrence in patients with circulating tumor DNA (ctDNA), failed to accrue enough patients positive for ctDNA, according to results presented at the 2024 San Antonio Breast Cancer Symposium (SABCS; Abstract GS3-01). From the lessons learned from this trial, investigators suggest beginning ctDNA testing during treatment rather than waiting for treatment completion, as done in ZEST, and including patients with high-risk disease, which may lead to more patients with a positive ctDNA test who would be eligible for treatment.
Nicholas Turner, MD, PhD
Identifying patients with measurable residual disease (MRD) after treatment and intervening with appropriate therapies is critical to delaying or preventing disease recurrence, according to study presenter Nicholas Turner, MD, PhD, Director of Clinical Research and Development at The Royal Marsden Hospital and Institute of Cancer Research in London. “The aim was to develop a new treatment strategy for patients with stage 1 to 3 breast cancer who have detectable ctDNA and therefore are at higher risk of recurrence,” said Dr. Turner.
ZEST Trial Details
To be eligible for the trial, patients were required to have stage 1 to 3 triple-negative or BRCA-mutated, hormone receptor (HR)-positive breast cancer; to have completed their recommended treatment (patients with HR-positive breast cancer were permitted to continue a stable regimen of endocrine therapy); and to have detectable ctDNA, as measured by a personalized test that examined blood samples for 16 mutations specific to each patient’s tumor. Of the 1,901 patients who underwent ctDNA testing to determine their eligibility for the trial, 147 (7.7%) had detectable ctDNA and were therefore eligible. Of these patients, 55% had detectable ctDNA within 6 months of completing treatment. Of the 147 patients, 98 had detectable ctDNA on their first test, at which point 51 (55%) already had disease recurrence detectable by imaging. For the 48 patients who had detectable ctDNA on subsequent tests, 21 (44%) had recurrence that was detectable by imaging at the time of their first ctDNA-positive test.
Prior to trial termination, 40 patients were enrolled and randomly assigned to receive either niraparib or placebo. This was an insufficient number of patients to allow for meaningful assessment of niraparib efficacy; however, median recurrence-free interval was 11.4 months with niraparib and 5.4 months with placebo. Six patients in the niraparib arm and four patients in the placebo arm remained recurrence-free at the time of data cutoff.
“While the low enrollment and early termination of the study precludes any conclusions about the efficacy of niraparib, the challenges the study faced have implications for future clinical trial design,” said Dr. Turner.
“First, given our observation that half of patients with detectable ctDNA already had relapsed disease, future studies should begin ctDNA testing prior to the end of neoadjuvant therapy instead of waiting for completion of treatment,” he recommended, noting that periodic ctDNA testing throughout neoadjuvant therapy may help to identify patients who are still ctDNA-positive after neoadjuvant therapy. This is particularly relevant, he added, for triple-negative breast cancers, which can relapse rapidly if neoadjuvant treatment fails to clear the cancer.
“Further, future studies should also focus on patients at higher risk of relapse who are more likely to have ctDNA-positive disease, such as patients with stage 2B or 3 cancers that do not have a pathologic complete response after neoadjuvant therapy. We may also want to focus on different subtypes where ctDNA is potentially more impactful with longer lead times over relapse,” he said.
Disclosure: The study was supported by GSK. Dr. Turner has received advisory board honoraria from AstraZeneca, Lilly, Pfizer, Roche/Genentech, Novartis, GSK, Repare Therapeutics, Relay Therapeutics, Gilead Sciences, Inivata, Guardant Health,and Exact Sciences; and has received research funding from AstraZeneca, Pfizer, Roche/Genentech, MSD, Guardant Health, Invitae, Inivata, Personalis, and Natera.
