The ZEST medical trial, designed to guage niraparib (Zejula) for the prevention of breast most cancers recurrence in sufferers with circulating tumor DNA (ctDNA), did not accrue sufficient sufferers constructive for ctDNA, in line with outcomes introduced on the San Antonio Breast Most cancers Symposium (SABCS), held December 10-13, 2024.
As among the classes realized from this trial, investigators counsel starting ctDNA testing throughout remedy slightly than ready for remedy completion as completed in ZEST, and together with sufferers with high- threat illness, which can result in extra sufferers with a constructive ctDNA take a look at who would subsequently be eligible for intervention with a therapeutic.
Figuring out sufferers with minimal residual illness (MRD) after remedy and intervening with acceptable therapies is essential to delaying or stopping illness recurrence, defined research presenter Nicholas Turner, MD, PhD, the director of medical analysis and improvement at The Royal Marsden Hospital and Institute of Most cancers Analysis in London.
Turner and colleagues initiated the ZEST section III medical trial to guage the potential of the PARP inhibitor niraparib to stop breast most cancers recurrence in sufferers with MRD, outlined on this research because the presence of ctDNA after the completion of their really useful remedy course.
The intention was to develop a brand new remedy technique for sufferers with stage 1 to three breast most cancers who’ve detectable ctDNA and subsequently are at greater threat of recurrence.”
Nicholas Turner, MD, PhD, director of medical analysis and improvement, The Royal Marsden Hospital and Institute of Most cancers Analysis
To be eligible for the trial, sufferers had been required to have stage 1 to three triple-negative or BRCA-mutated, hormone receptor (HR)-positive breast most cancers; to have accomplished their really useful remedy (sufferers with HR-positive breast most cancers had been permitted to proceed a secure routine of endocrine remedy); and to have detectable ctDNA, as measured by a personalised take a look at that examined blood samples for 16 mutations particular to every affected person’s tumor.
Of the 1,901 sufferers who underwent ctDNA testing to find out their eligibility for the trial, 147 (7.7%) had detectable ctDNA and had been subsequently eligible. Of those sufferers, 55% had detectable ctDNA inside six months of finishing remedy. Ninety-eight of the 147 sufferers had detectable ctDNA on their first take a look at, at which level 51 (55%) of them already had illness recurrence that was detectable by imaging. For the 48 sufferers who had detectable ctDNA on subsequent checks, 21 (44%) had recurrence that was detectable by imaging on the time of their first ctDNA-positive take a look at.
In contrast with sufferers with out detectable ctDNA, those that had been ctDNA-positive had been extra more likely to have constructive lymph nodes, bigger tumors, stage 3 illness, residual illness after neoadjuvant remedy, and to have acquired each neoadjuvant and adjuvant remedy.
Previous to trial termination, 40 sufferers had been enrolled and randomly assigned to obtain both niraparib or placebo. This was an inadequate variety of sufferers to permit for significant evaluation of niraparib efficacy; nevertheless, median recurrence-free interval was 11.4 months for sufferers within the niraparib arm and
5.4 for these within the placebo arm. Six sufferers within the niraparib arm and 4 sufferers within the placebo arm remained recurrence-free on the time of information cutoff.
“Whereas the low enrollment and early termination of the research precludes any conclusions in regards to the efficacy of niraparib, the challenges the research confronted have implications for future medical trial design,” mentioned Turner.
“First, given our remark that half of sufferers with detectable ctDNA already had relapsed illness, future research ought to start ctDNA testing previous to the top of neoadjuvant remedy as a substitute of ready for completion of remedy,” he really useful, noting that periodic ctDNA testing all through neoadjuvant remedy would assist determine sufferers who’re nonetheless ctDNA-positive after neoadjuvant remedy. He added that that is significantly related for triple-negative breast cancers, which might relapse quickly if neoadjuvant remedy fails to clear the most cancers.
“Additional, future research also needs to give attention to sufferers at greater threat of relapse who usually tend to have ctDNA-positive illness, similar to sufferers with stage 2B or 3 cancers that do not need a pathologic full response after neoadjuvant remedy. We can also need to give attention to completely different subtypes the place ctDNA is probably extra impactful with longer lead instances over relapse,” he mentioned.
The research was supported by GSK. Turner has acquired advisory board honoraria from AstraZeneca, Lilly, Pfizer, Roche/Genentech, Novartis, GSK, Repare Therapeutics, Relay Therapeutics, Gilead, Inivata, Guardant Well being, Precise Sciences. Turner has acquired analysis funding from AstraZeneca, Pfizer, Roche/Genentech, MSD, Guardant Well being, Invitae, Inivata, Personalis, and Natera.
Supply:
American Affiliation for Most cancers Analysis
