The ZEST clinical trial aimed to test the effectiveness of niraparib (Zejula) in preventing the return of breast cancer in patients who have circulating tumor DNA (ctDNA). However, the trial did not manage to recruit enough patients who were positive for ctDNA, as stated in the findings shared at the San Antonio Breast Cancer Symposium (SABCS) from December 10-13, 2024.
From this trial, researchers learned several valuable lessons. They recommend starting ctDNA testing during treatment rather than waiting until after treatment, as was done in ZEST. Additionally, enrolling high-risk patients could result in a greater number of individuals testing positive for ctDNA, making them suitable for therapeutic interventions.
It is crucial to identify patients with minimal residual disease (MRD) post-treatment and provide appropriate therapies to help delay or prevent a recurrence of the disease. This was explained by Nicholas Turner, MD, PhD, who is the director of clinical research and development at The Royal Marsden Hospital and Institute of Cancer Research in London.
Turner and his team designed the ZEST phase III clinical trial to explore how the PARP inhibitor niraparib could prevent breast cancer recurrence in patients with MRD, specifically defined in this study as the presence of ctDNA after completing their recommended treatment.
The objective was to develop a new treatment method for patients with stage 1 to 3 breast cancer who have detectable ctDNA, indicating a higher risk of recurrence.
Nicholas Turner, MD, PhD, director of clinical research and development, The Royal Marsden Hospital and Institute of Cancer Research
For trial participation, patients had to be diagnosed with stage 1 to 3 triple-negative or BRCA-mutated, hormone receptor (HR)-positive breast cancer; they were required to have completed their recommended treatment (patients with HR-positive breast cancer could continue stable endocrine therapy); and they needed to show detectable ctDNA through a personalized test that identified 16 mutations unique to their tumor type in blood samples.
Out of 1,901 patients who underwent ctDNA testing for trial eligibility, only 147 (7.7%) showed detectable ctDNA and were qualified for inclusion. Among these patients, 55% had detectable ctDNA within six months of finishing treatment. Ninety-eight of the 147 had detectable ctDNA on their initial test, and of those, 51 (55%) were already showing signs of disease recurrence through imaging. Similarly, of the 48 patients who tested positive for ctDNA later on, 21 (44%) had observable recurrence at the time of their first positive ctDNA test.
Patients with detectable ctDNA were more likely to have positive lymph nodes, larger tumors, stage 3 disease, residual disease after neoadjuvant therapy, and had often received both neoadjuvant and adjuvant therapies when compared to those without detectable ctDNA.
Before the trial ended, 40 patients had been enrolled and randomly assigned to receive either niraparib or a placebo. However, this number was too low for a substantial evaluation of niraparib’s effectiveness; nonetheless, patients in the niraparib group had a median recurrence-free interval of 11.4 months compared to 5.4 months for the placebo group. At the data cutoff point, six patients in the niraparib group and four in the placebo group still had not experienced any recurrence.
“While the low patient count and premature end of the study prevent any conclusions regarding niraparib’s efficacy, the obstacles encountered carry lessons for future clinical trial designs,” stated Turner.
“Given our finding that half of the patients with detectable ctDNA already showed signs of relapse, future trials should start ctDNA testing prior to the conclusion of neoadjuvant therapy, rather than waiting until treatment is finished,” he suggested. He pointed out that regular ctDNA testing during neoadjuvant therapy could assist in identifying patients who remain ctDNA-positive after this stage, which is crucial for triple-negative breast cancers that can relapse quickly if neoadjuvant treatment isn’t successful.
“Additionally, future research should focus on patients more likely to have ctDNA-positive disease, especially those with stage 2B or 3 cancers that do not achieve a pathologic complete response following neoadjuvant therapy. We may also want to look into different subtypes where ctDNA might have a more significant impact and where relapse can be detected earlier,” he added.
This study received support from GSK. Turner has received advisory board fees from various pharmaceutical companies, including AstraZeneca, Lilly, Pfizer, Roche/Genentech, Novartis, GSK, Repare Therapeutics, Relay Therapeutics, Gilead, Inivata, Guardant Health, and Exact Sciences. He has also been funded for research by AstraZeneca, Pfizer, Roche/Genentech, MSD, Guardant Health, Invitae, Inivata, Personalis, and Natera.
Source:
American Association for Cancer Research