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 optimistic for ctDNA, in response to outcomes introduced on the San Antonio Breast Most cancers Symposium (SABCS), held December 10-13, 2024.
As a few of the classes discovered from this trial, investigators counsel starting ctDNA testing throughout therapy slightly than ready for therapy completion as executed in ZEST, and together with sufferers with high- danger illness, which can result in extra sufferers with a optimistic ctDNA check who would subsequently be eligible for intervention with a therapeutic.
Figuring out sufferers with minimal residual illness (MRD) after therapy and intervening with acceptable therapies is important to delaying or stopping illness recurrence, defined research presenter Nicholas Turner, MD, PhD, the director of medical analysis and growth 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 forestall breast most cancers recurrence in sufferers with MRD, outlined on this research because the presence of ctDNA after the completion of their beneficial therapy course.
The purpose was to develop a brand new therapy technique for sufferers with stage 1 to three breast most cancers who’ve detectable ctDNA and subsequently are at larger danger of recurrence.”
Nicholas Turner, MD, PhD, director of medical analysis and growth, 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 beneficial therapy (sufferers with HR-positive breast most cancers had been permitted to proceed a steady routine of endocrine remedy); and to have detectable ctDNA, as measured by a personalised check 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 therapy. Ninety-eight of the 147 sufferers had detectable ctDNA on their first check, 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 exams, 21 (44%) had recurrence that was detectable by imaging on the time of their first ctDNA-positive check.
In contrast with sufferers with out detectable ctDNA, those that had been ctDNA-positive had been extra more likely to have optimistic lymph nodes, bigger tumors, stage 3 illness, residual illness after neoadjuvant remedy, and to have obtained 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,” stated Turner.
“First, given our commentary 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 an alternative of ready for completion of therapy,” he beneficial, noting that periodic ctDNA testing all through neoadjuvant remedy would assist establish sufferers who’re nonetheless ctDNA-positive after neoadjuvant remedy. He added that that is significantly 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 wouldn’t have a pathologic full response after neoadjuvant remedy. We might also wish to give attention to completely different subtypes the place ctDNA is doubtlessly extra impactful with longer lead occasions over relapse,” he stated.
The research was supported by GSK. Turner has obtained advisory board honoraria from AstraZeneca, Lilly, Pfizer, Roche/Genentech, Novartis, GSK, Repare Therapeutics, Relay Therapeutics, Gilead, Inivata, Guardant Well being, Actual Sciences. Turner has obtained analysis funding from AstraZeneca, Pfizer, Roche/Genentech, MSD, Guardant Well being, Invitae, Inivata, Personalis, and Natera.
Supply:
American Affiliation for Most cancers Analysis
