Researchers have found that a combination of the PARP inhibitor olaparib and the investigational ATR inhibitor ceralasertib showed clinical benefit in pediatric patients with solid tumors exhibiting DNA replication and/or damage repair deficiencies, according to new findings presented by Gatz et al at the American Association for Cancer Research (AACR) Annual Meeting 2023.
Background
“To our knowledge, the combination of PARP inhibitors and ATR inhibitors has not been widely investigated in adult tumor types,” explained lead study author Susanne Gatz, MD, PhD, Senior Clinical Lecturer of Pediatric Oncology at the Institute of Cancer and Genomic Sciences at the University of Birmingham. “This is the first proof of principle that the combination [may be] well tolerated and can lead to clinically relevant responses in pediatric cancers,” she added.
The new phase I/II AcSé-ESMART trial (ClinicalTrials.gov identifier NCT02813135) is an international European proof-of-concept platform trial designed to match pediatric, adolescent, and young adult patients who have relapsed or refractory tumors with treatment regimens targeted to their cancer’s mutational profile. Dr. Gatz and her colleagues have currently evaluated 15 different treatments—many of which have been combination strategies—in over 220 pediatric patients following mandatory high-throughput genomic profiling of their tumors.
Arm N of the AcSé-ESMART trial was tailored toward patients with malignancies exhibiting defects in DNA replication and damage repair. Impairment in homologous recombination has been known to sensitize cancer cells to PARP inhibitors, which have proven effective against specific adult cancer types that have homologous recombination deficiencies—most notably, mutations in BRCA1 or BRCA2 genes. How to best use PARP inhibitors in pediatric patients where BRCA1 or BRCA2 mutations are rarely found may be unclear.
“Pediatric cancer cells proliferate rapidly and have some element of replication stress and a dependency on ATR [ataxia telangiectasia and Rad3-related kinase],” Dr. Gatz explained. “We think there might be a kind of primary resistance of pediatric cancers to PARP inhibitors and that combination with an ATR inhibitor could potentially overcome that,” she said.
Pediatric 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 these patients, necessitating additional research into combination therapies and mechanisms of response.
Study Methods and Results
In the new phase I, arm N portion of the AcSé-ESMART trial, the researchers enrolled 18 pediatric and young adult patients with relapsed or refractory solid tumors that harbored mutations believed to cause homologous recombination deficiencies or replication stress. The researchers assigned the patients to receive three dose levels of oral olaparib twice daily and ceralasertib on days 1 through 14 of each 28-day cycle for a median of 3.5 treatment cycles. The researchers determined that the recommended phase II dose regimen was 150 mg of olaparib and 80 mg of ceralasertib in patients aged 12 to 18 years. However, the recommended dose regimen for pediatric patients younger than 12 years remained undetermined.
Among the patients participating in the trial, five of them experienced dose-limiting adverse events such as thrombocytopenia and neutropenia—two of which occurred at the recommended phase II doses. 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 researchers reported that the patient continues to undergo treatment in cycle 12. Two patients in cycle 8 and one patient in cycle 15 also continue to undergo treatment. None of the patients with clinical benefit had BRCA mutations.
Conclusions
“So far, it is unclear if the molecular alterations [that served as the basis through] which the patients were enrolled in this trial are the sole reasons for response,” Dr. Gatz emphasized. “Further, it may be difficult to identify patterns of response in specific tumor types [as a result of] the tumor-agnostic nature of the study. Nevertheless, this study design can give preliminary indications of signals in specific alterations and tumor types and can provide the basis for future clinical trials,” she suggested.
The researchers plan to evaluate biomarkers of response from the raw sequencing data of the patients who participated in the trial—including the expression of key target proteins such as ATM and from RNA-sequencing data. They hope that these analyses may identify molecular constellations indicative of response to the combination therapy.
“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,” Dr. Gatz concluded.
Disclosure: The research in this study was sponsored by the Gustave Roussy Cancer Campus. Additional funding was provided by the French Institut National de Cancer, Imagine for Margo, Fondation ARC, AstraZeneca France, AstraZeneca Global R&D, AstraZeneca UK, Cancer Research UK, Fondation Gustave Roussy, and Little Princess Trust/Children’s Cancer and Leukaemia Group.
