A combination of the PARP inhibitor olaparib (Lynparza) and the investigational ATR inhibitor ceralasertib showed clinical benefit in paediatric patients with solid tumours exhibiting DNA replication stress and/or DNA repair deficiencies, according to new data.
The results from the Phase I portion of the Phase I/II AcSé-ESMART trial were presented at the AACR Annual Meeting 2023.
“To our knowledge, the combination of PARP inhibitors and ATR inhibitors has not been widely investigated in adult tumour types,” said Susanne Gatz, an associate clinical professor in paediatric oncology at the Institute of Cancer and Genomic Sciences of the University of Birmingham in the United Kingdom, who presented the study. “This is the first proof of principle that the combination is well tolerated and can lead to clinically relevant responses in paediatric cancers.”
The AcSé-ESMART trial
AcSé-ESMART is an international European proof-of-concept platform trial intended to match paediatric, adolescent, and young adult patients with relapsed or treatment-refractory cancers with a treatment regimen targeted to their cancer’s mutational profile.
Gatz and colleagues, including Birgit Geoerger, head of the AcSé-ESMART trial, have so far evaluated 15 different treatments, mostly combination strategies, in more than 220 children following mandatory high-throughput genomic profiling of their tumours.
Arm N of AcSé-ESMART is tailored toward patients with malignancies that exhibit defects in DNA replication and damage repair. Impairments in homologous recombination (HR), a type of DNA repair, can sensitise cells to drugs called PARP inhibitors.
“Paediatric cancer cells proliferate rapidly and have some element of replication stress and a dependency on ATR,” Gatz said. “We think there might be a kind of primary resistance of paediatric cancers to PARP inhibitors and that combination with an ATR inhibitor could potentially overcome that.”
In the Phase I portion of AcSé-ESMART arm N, patients received a median of 3.5 cycles of treatment. Five patients experienced dose-limiting adverse events (thrombocytopenia and neutropenia), and two such events occurred at the recommended Phase II dose.
One patient with pineoblastoma experienced a confirmed partial response and received treatment for 11 cycles. Another patient with neuroblastoma experienced stable disease until cycle 9 of treatment, at which point their disease converted to a partial response. The response was confirmed after cycle 11, and the patient is still undergoing treatment in cycle 12.
Two patients in cycle 8 and one patient in cycle 15 also remain on treatment. None of the patients with clinical benefit had BRCA mutations.
Need to apply drugs more creatively
Gatz explained that paediatric cancers are often driven by complex mechanisms, making it difficult to identify an effective treatment regimen. Single-agent therapies targeting one mutated protein are often insufficient in paediatric patients, necessitating additional research into combination therapies and mechanisms of response.
Gatz and colleagues plan to evaluate biomarkers of response from the raw sequencing data of the enrolled patients, from the expression of key target proteins such as ATM, and from RNA sequencing data. Gatz noted that these analyses may identify ‘molecular constellations’ indicative of response to olaparib plus ceralasertib.
“There are enormously valuable drugs currently in development and, provided there is a good clinical or preclinical rationale, we need to apply them more creatively to diseases for which the drug is not currently indicated,” Gatz said.
