The ZEST scientific trial, designed to guage niraparib (Zejula) for the prevention of breast most cancers recurrence in sufferers with circulating tumor DNA (ctDNA), didn’t accrue sufficient sufferers constructive for ctDNA, in line with outcomes offered on the San Antonio Breast Most cancers Symposium (SABCS), held December 10-13, 2024.
As among the classes discovered from this trial, investigators recommend starting ctDNA testing throughout therapy slightly than ready for therapy completion as completed in ZEST, and together with sufferers with high- danger illness, which can result in extra sufferers with a constructive ctDNA take a look at who would due to this fact be eligible for intervention with a therapeutic.
Figuring out sufferers with minimal residual illness (MRD) after therapy and intervening with acceptable therapies is vital to delaying or stopping illness recurrence, defined examine presenter Nicholas Turner, MD, PhD, the director of scientific analysis and improvement at The Royal Marsden Hospital and Institute of Most cancers Analysis in London.
Turner and colleagues initiated the ZEST part III scientific trial to guage the potential of the PARP inhibitor niraparib to forestall breast most cancers recurrence in sufferers with MRD, outlined on this examine because the presence of ctDNA after the completion of their beneficial therapy course.
The intention was to develop a brand new therapy technique for sufferers with stage 1 to three breast most cancers who’ve detectable ctDNA and due to this fact are at larger danger of recurrence.”
Nicholas Turner, MD, PhD, director of scientific analysis and improvement, The Royal Marsden Hospital and Institute of Most cancers Analysis
To be eligible for the trial, sufferers have been required to have stage 1 to three triple-negative or BRCA-mutated, hormone receptor (HR)-positive breast most cancers; to have accomplished their beneficial therapy (sufferers with HR-positive breast most cancers have been permitted to proceed a secure routine of endocrine remedy); and to have detectable ctDNA, as measured by a customized 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 have been due to this fact eligible. Of those sufferers, 55% had detectable ctDNA inside six months of finishing therapy. 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 have been ctDNA-positive have 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 have 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 knowledge cutoff.
“Whereas the low enrollment and early termination of the examine precludes any conclusions about the efficacy of niraparib, the challenges the examine confronted have implications for future scientific trial design,” mentioned Turner.
“First, given our statement that half of sufferers with detectable ctDNA already had relapsed illness, future research ought to start ctDNA testing previous to the tip of neoadjuvant remedy as a substitute of ready for completion of therapy,” he beneficial, 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 notably related for triple-negative breast cancers, which may relapse quickly if neoadjuvant therapy fails to clear the most cancers.
“Additional, future research must also give attention to sufferers at larger danger of relapse who usually tend to have ctDNA-positive illness, resembling sufferers with stage 2B or 3 cancers that should not have a pathologic full response after neoadjuvant remedy. We may need to give attention to totally different subtypes the place ctDNA is probably extra impactful with longer lead occasions over relapse,” he mentioned.
The examine 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, Actual Sciences. Turner has acquired analysis funding from AstraZeneca, Pfizer, Roche/Genentech, MSD, Guardant Well being, Invitae, Inivata, Personalis, and Natera.
