The ZEST clinical trial, designed to evaluate niraparib (Zejula) to prevent breast cancer recurrence in patients with circulating tumor DNA (ctDNA), failed to accrue enough ctDNA-positive patients, according to results presented at the Symposium for San Antonio Breast Cancer. SABCS), held 10-13 December 2024.
As some of the lessons learned from this trial, the researchers suggest starting ctDNA testing during treatment rather than waiting for completion of treatment as in ZEST, and including patients with high-risk disease, which may lead to more patients with a positive ctDNA test who will therefore be eligible for therapeutic intervention.
Identifying patients with minimal residual disease (MRD) after treatment and intervening with appropriate therapies is critical to delaying or preventing disease relapse, explained study presenter Nicholas Turner, MD, PhD, director of clinical research and development at The Royal Marsden Hospital and Institute of Cancer Research in London.
Turner and colleagues initiated the phase III ZEST clinical trial to evaluate the potential of the PARP inhibitor niraparib to prevent breast cancer recurrence in patients with MRD, defined in this study as the presence of ctDNA after completion of recommended therapy the marchers.
The goal was to develop a new treatment strategy for patients with stage 1 to 3 breast cancer who have detectable ctDNA and are therefore at higher risk of recurrence.”
Nicholas Turner, MD, PhD, director of clinical research and development, The Royal Marsden Hospital and Institute of Cancer Research
To be eligible for the trial, patients had to have stage 1 to 3 triple-negative or BRCA-mutated, hormone receptor (HR)-positive breast cancer. have completed recommended therapy (patients with HR-positive breast cancer were allowed to continue a stable endocrine therapy regimen); and have detectable ctDNA, as measured by a personalized test that screened 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 six months of completing treatment. Ninety-eight of the 147 patients had detectable ctDNA at their first examination, so 51 (55%) of them already had relapsed disease detectable by imaging. For the 48 patients who had detectable ctDNA on subsequent tests, 21 (44%) had a relapse that was detectable by imaging at the time of the first positive ctDNA test.
Compared with patients without detectable ctDNA, those who were ctDNA positive were more likely to have positive lymph nodes, larger tumors, stage 3 disease, residual disease after neoadjuvant therapy, and to have received both neoadjuvant and adjuvant therapy.
Before the trial was terminated, 40 patients were enrolled and randomized to receive either niraparib or placebo. This was an insufficient number of patients to allow a meaningful assessment of the efficacy of niraparib. however, the median recurrence-free interval was 11.4 months for patients in the niraparib arm and
5.4 for those participating in the placebo arm. Six patients in the niraparib arm and four patients in the placebo arm remained relapse-free at the time of data cut-off.
“While the low enrollment and early termination of the study precludes any conclusions about the efficacy of niraparib, the challenges faced by the study have implications for future clinical trial design,” said Turner.
“First, given our observation that half of the patients with detectable ctDNA already had recurrent disease, future studies should start ctDNA testing before the end of neoadjuvant therapy rather than waiting for completion of therapy,” he recommended, noting that the periodic ctDNA testing throughout neoadjuvant therapy would help identify patients who remain ctDNA positive after neoadjuvant therapy. He added that this is especially important for triple-negative breast cancers, which can relapse quickly if neoadjuvant therapy fails to clear the cancer.
“Furthermore, 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 who do not have a complete pathologic response after neoadjuvant therapy. He may also want to focus on different subtypes where ctDNA is potentially more impactful with longer lead times against relapse,” he said.
The study was supported by GSK. Turner has received advisory board honoraria from AstraZeneca, Lilly, Pfizer, Roche/Genentech, Novartis, GSK, Repair Therapeutics, Relay Therapeutics, Gilead, Inivata, Guardant Health, Exact Sciences. Turner has received research funding from AstraZeneca, Pfizer, Roche/Genentech, MSD, Guardant Health, Invitae, Inivata, Personalis, and Natera.
