Early Detection of Relapse in Early-Stage Breast Cancer: The ZEST Study

The ZEST study (NCT05329317) was a phase 3, randomized, double-blind trial designed to investigate whether niraparib, a PARP inhibitor, could improve disease-free survival in patients with early-stage breast cancer who had detectable circulating tumor DNA (ctDNA) after completing curative-intent treatment but had no radiographic evidence of recurrence.

The study included patients with stage I-III disease and either triple-negative breast cancer (TNBC) or BRCA-mutated HER2-negative breast cancer. A personalized ctDNA assay called Signatera, based on whole-exome sequencing of tumor tissue and matched normal blood, was used to detect ctDNA. Patients could begin ctDNA testing for minimally residual disease at any time after the end of definitive treatment (EODT). Patients with hormone receptor (HR)–positive disease were allowed to continue their stable endocrine therapy regimen. Upon ctDNA detection, patients underwent radiographic staging to rule out metastatic disease. If no metastasis was found, patients were randomized 1:1 to receive either niraparib (200 or 300 mg/day, adjusted for weight and platelet count) or a placebo. Imaging was conducted every 12 weeks. The primary endpoint of the study was the safety of niraparib. Disease-free survival, defined as the time from randomization to either recurrence or death from any cause, was also evaluated.

As of May 8, 2024, 2746 patients had been prescreened, and 1901 had at least 1 ctDNA test result. Only 147 patients (8%) tested positive for ctDNA, leading to early termination of the study because of the low rate of ctDNA detection. The median age of the 1901 patients was 52 years (range, 22-88 years). Most patients (89%) had TNBC (135 ctDNA+), and 11% had BRCA-mutated HR-positive disease (12 ctDNA+).

From the 147 ctDNA-positive patients, 66% tested positive on their first test, 91% on either their first or second test, and 59% were within 6 months of EODT. Patients who tested positive for ctDNA were more likely to have positive lymph nodes, larger tumor size (T3/T4), more advanced-stage (stage III), residual disease after neoadjuvant therapy, and to have received both neoadjuvant and adjuvant therapy, compared with patients without detectable ctDNA.

Importantly, 72 (49%) of the 147 ctDNA-positive patients had radiographic recurrence at initial staging before randomization, highlighting the aggressive nature of their disease. The rate of radiographic recurrence was 52% at the time of the first positive ctDNA test and 44% at the time of the second or later positive ctDNA test.

Of the 147 ctDNA-positive patients, only 40 were enrolled and randomized (18 niraparib, 22 placebo). Ninety percent of these patients had TNBC, and 10% had BRCA-mutated HR-positive disease. At the time of data cutoff, 6 patients in the niraparib arm and 4 in the placebo arm remained on study without radiographic recurrence. Median disease-free survival was 11.4 months for niraparib versus 5.4 months for placebo (hazard ratio, 0.64, 95% CI, 0.30-1.39). No new safety signals for niraparib were observed.

The ZEST study was terminated early because of the low rate of ctDNA detection and the high rate of metastatic disease at the time of ctDNA detection, making it challenging to complete enrollment. While ctDNA testing began any time after EODT, ctDNA positivity occurred most often on the first test and within 6 months of EODT. Patients, predominantly those with TNBC, had a high rate of radiographic recurrence at the time of ctDNA detection, consistent with the recurrence pattern of TNBC. These findings highlight the importance of early ctDNA testing and careful selection criteria for future trial designs.

Source

Turner N. Circulating tumor DNA surveillance in ZEST, a randomized, phase 3, double-blind study of niraparib or placebo in patients with triple-negative breast cancer or HER2+ BRCA-mutated breast cancer with molecular residual disease after definitive therapy. Presented at: San Antonio Breast Cancer Symposium. December 13, 2024; San Antonio, TX. Abstract SESS-2027.