SAN ANTONIO — The randomized phase 3 ZEST trial, which was aimed at evaluating niraparib (Zejula) for prevention or delay of breast cancer recurrence in patients with minimal residual disease (MRD) following definitive therapy, was abandoned when the target randomization levels couldn’t be met.
The failure of the trial leaves open the question of whether therapy guided by MRD as measured by circulating tumor DNA (ctDNA) testing could delay or prevent recurrence. Also unanswered is the problem of what to recommend to patients when their ctDNA tests hint at residual breast cancer but you can’t find the tumor to prove it, reported Nicholas Turner, MD, PhD, director of clinical research and development at The Royal Marsden Hospital and Institute of Cancer Research in London, United Kingdom.
“ZEST was the first phase 3 trial of MRD-guided therapy in breast cancer. The trial was terminated, though, because of low randomization rate, and this largely reflected broad entry criteria that allowed a relatively large number of low-risk patients to enroll that resulted in a low rate of ctDNA detection,” he said in an oral abstract session at San Antonio Breast Cancer Symposium (SABCS) 2024.
Positivity Low
The trial design stipulated that patients with stages I-III breast cancers who had completed standard therapy with curative intent and had no clinical signs of recurrence would be monitored with serial ctDNA testing to monitor for MRD. Eligible patients included those with triple-negative breast cancer (TNBC) regardless of BRCA status, and hormone receptor-positive breast cancer with BRCA (mutated or wildtype) detected in tumors.
When ctDNA positivity was found, patients with radiographic evidence of recurrence would be taken off study, while those with no clinical evidence of recurrence would be randomized to receive the poly(ADP-ribose) polymerase (PARP) inhibitor niraparib or placebo.
However, as noted before, the trial was halted after 1901 patients had been enrolled, but only 40 were randomized, due to low ctDNA detection rates.
The entry criteria for the trial were broad, Turner acknowledged, and as a result 66.5% of patients enrolled had either stage I or stage II disease, and 34.7% had had pathologic complete responses after definitive therapy. This meant that a large proportion of patients had low-risk disease and were therefore unlikely to have disease progression for some time, if ever.
Another factor confounding the trial was that for patients with TNBC, who accounted for 88.5% of patients enrolled, ctDNA positivity was detected most frequently on the first test, usually within 6 months of the end of treatment. In addition, there was a high prevalence of metastatic disease at the time that ctDNA was detected. Of the 147 patients who were positive for ctDNA at the time of their first ctDNA test, 73 (50%) had developed metastases. These cases of early recurrence meant that the hypothesis — prevention or delay of recurrence with niraparib — could not be tested in these patients.
The findings suggest that ctDNA testing should be started early in the course of disease for patients with TNBC, perhaps before the end of neoadjuvant therapy, especially for patients with TNBC, which has a high likelihood of early relapse. In addition, further studies of ctDNA-directed therapy should focus on patients with a higher likelihood of ctDNA positivity, such as those with stage IIB or III cancers who do not have a pCR after neoadjuvant therapy, Turner said.
Value of ctDNA
Invited discussant Ian Krop, MD, PhD, from the Yale Cancer Center in New Haven, Connecticut, commented that decision-making in breast cancer has become increasingly challenging as new agents such as immune checkpoint inhibitors, CDK4/6 inhibitors, and PARP inhibitors become available.
Current risk stratification methods — based on anatomic, molecular, or genomic features of tumors, or functional markers such as pathologic completed response — can estimate a patient’s probability of recurrence, but don’t reflect an individual patient’s risk. That’s where ctDNA testing could make a difference, he said.
“In early breast cancer, multiple studies show a very strong association between detectable ctDNA presence and distant recurrence and offer the potential of finally moving away from probabilistic testing and being able to identify the actual person who will develop recurrence without intervention. But as of now, no study has shown prospectively that intervening on a positive test improves outcomes, and no study has shown that de-escalating therapy based on a negative test is safe,” he said.
“So, given this lack of evidence that ctDNA-guided therapy in early breast cancer improves outcomes, using these types of tests to guide therapy should only be done as part of a trial, and I can’t really stress that enough,” Krop added.
In a briefing for media prior to Turner’s presentation, moderator Carlos Arteaga, MD, FAACR, from the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center in San Antonio, asked Turner whether ctDNA is ready for clinical practice.
“These assays tell us, yes, there is tumor there, somewhere. It’s about to rear its ugly head, now or maybe several months down the road, but does it tell us what to treat with?,” he asked.
“We’ve shown here that ctDNA can pick up nearly all the people who are going to relapse, but we don’t really know yet how to use that information to guide therapy and whether identifying it early can improve outcomes,” Turner replied.
The ZEST study was supported by GSK. Turner received advisory board honoraria from AstraZeneca, Lilly, Pfizer, Roche/Genentech, Novartis, GSK, Repare Therapeutics, Relay Therapeutics, Gilead, Inivata, Guardant Health, Exact Sciences, and research funding from AstraZeneca, Pfizer, Roche/Genentech, MSD, Guardant Health, Invitae, Inivata, Personalis, and Natera. Krop disclosed consulting for Daiichi/Sankyo, Lilly, Novartis, Genetech/Roche, Merck, and AstraZeneca, data-monitoring board participation for Novartis and Seagen, and grant/research support from Genentech/Roche, Macrogenics, and Pfizer. Arteaga disclosed serving as a scientific advisor to Novartis, Eli Lilly, Merck, AstraZeneca, Daiichi Sankyo, OrigiMed, Immunomedics, Puma Biotechnology, Taiho Oncology, Sanofi, and Susan G. Komen Foundation and receiving grant support from Pfizer, Eli Lilly, and Takeda.
The study was independently supported. Smith and Jones report no relevant financial
Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape Medical News.