The ZEST medical trial, designed to judge 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 line with outcomes introduced on the San Antonio Breast Most cancers Symposium (SABCS), held December 10-13, 2024.
As a number of the classes realized from this trial, investigators recommend starting ctDNA testing throughout therapy fairly than ready for therapy completion as achieved in ZEST, and together with sufferers with high- threat illness, which can result in extra sufferers with a optimistic ctDNA check 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 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 judge 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 beneficial therapy course.
The goal 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 increased 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 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 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 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 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 assessments, 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 have been ctDNA-positive have been extra prone to have optimistic 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; nonetheless, 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 about 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 tip 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 might relapse quickly if neoadjuvant therapy fails to clear the most cancers.
“Additional, future research also needs to concentrate on sufferers at increased threat of relapse who usually tend to have ctDNA-positive illness, comparable to sufferers with stage 2B or 3 cancers that should not have a pathologic full response after neoadjuvant remedy. We may wish to concentrate on totally different subtypes the place ctDNA is probably extra impactful with longer lead occasions over relapse,” he stated.
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, Actual Sciences. Turner has acquired analysis funding from AstraZeneca, Pfizer, Roche/Genentech, MSD, Guardant Well being, Invitae, Inivata, Personalis, and Natera.
