The combination of PARP and ATR inhibition with olaparib and ceralasertib was tolerable but showed limited efficacy in pediatric patients with advanced malignancies harboring DNA replication stress and DNA repair deficiencies, according to findings from arm N of the phase 1/2 AcSé-ESMART trial.
The combination of PARP and ATR inhibition with olaparib (Lynparza) and ceralasertib (AZD6738) was tolerable but showed limited efficacy in pediatric patients with advanced malignancies harboring DNA replication stress and DNA repair deficiencies, according to findings from arm N of the phase 1/2 AcSé-ESMART trial (NCT02813135) presented at the 2023 AACR Annual Meeting.1,2
Patients (n = 18) in the study received a median of 3.5 treatment cycles (range, 1-15+). Two confirmed partial responses were reported in 1 patient with pineoblastoma and 1 with neuroblastoma after the third and ninth cycle of therapy, respectively.
Best response was stable disease (SD) in 9 patients, of which 3 derived prolonged SD for more than 4 treatment cycles (neuroblastoma, n = 2; papillary spinal cord tumor, n = 1). The remaining patients had progressive disease as best response (n = 7).
“To our knowledge, the combination of PARP inhibitors and ATR inhibitors has not been widely investigated in adult tumor types,” lead study author, Susanne Gatz, MD, PhD, an associate clinical professor in pediatric oncology at the Institute of Cancer and Genomic Sciences of the University of Birmingham in the United Kingdom, said in a press release.2 “This is the first proof of principle that the combination is well tolerated and can lead to clinically relevant responses in pediatric cancers.”
To be eligible for enrollment, patients had to be under 18 years of age with a diagnosis of a relapsed or refractory malignancy. They needed to have undergone molecular profiling with whole-exome and whole-genome sequencing with or without RNA sequencing in order to be paired with the treatment regimen best matched to their mutational profile. Patients 18 years of age and older were allowed if they had been diagnosed with a pediatric malignancy.
The study was conducted across 15 to 20 centers in France, Italy, Spain, The Netherlands, and the United Kingdom.
The presentation focused on arm N of 3 arms that evaluated agents targeted toward the DNA repair pathway: WEE1 (arm C), PARP, (arm D) and PARP/ATR (arm N). Of the 18 patients that had been enrolled in phase 1 in arm N, 100% were enriched for response. Phase 2 is ongoing.
“Pediatric 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 pediatric cancers to PARP inhibitors, and combination with an ATR inhibitor could potentially overcome that.”
Arm N employed a dose-escalation, Bayesian Optimal interval design, followed by 2 dose-expansion cohorts: Cohort 1 included patients with homologous recombination deficiency with a focus on ATM, which included 11q loss. Cohort 2 included patients with replication stress, including MYC/MYCN amplification, CCNE1 amplification, and gene fusions including ESWR1::FLI1, SS18::SSX, and PAX3/7::FOXO1.
The primary objectives of phases 1 and 2 were to establish the recommended phase 2 dose (RP2D) of the combination in children and adolescents, and determine its antitumor activity in molecularly enriched patient cohorts, respectively. Secondary objectives included the characterization of the regimen’s toxicity profile, pharmacokinetic activity, and the association between tumor response and molecular alterations and circulating tumor DNA.
Patients were enrolled to the dose-escalation phase between February 2021 and September 2022, with data cutoff of January 2023.
A total of 18 patients with sarcoma (n = 8; 44.4%), central nervous system tumors (n = 5; 27.8%), neuroblastoma (n = 4), and hepatic fibrolamellar carcinoma (n = 1) were included, treated, and evaluable for dose-limiting toxicities (DLTs) and efficacy. The median age was 16.5 years (range, 4.0-24.0) and most patients were male (n = 10).
Most patients had a performance status of 90% (53%), followed by 100% (35%), 70% (6%), and 60% (6%). Additionally, most patients had metastatic disease at study entry (n = 16; 89%) and all had progressive disease and prior exposure to chemotherapy. The median number of prior lines of therapy was 3 (range, 2-7). Notably, 1 patient with Ewing sarcoma and 1 with neuroblastoma had received prior olaparib.
Patients aged 3 to 6 years received 30 mg of ceralasertib twice daily on days 1 to 14 plus 50 mg of olaparib twice daily on days 1 to 28. Patients aged 6 to 12 years received 40 mg of ceralasertib plus 100 mg of olaparib in the same administration schedule.
Only sufficient data for the RP2D was generated for the cohort of patients aged 12 to 18+, in which the optimal dose was defined as 80 mg of ceralasertib on days 1 to 14 plus 150 mg of olaparib on days 1 to 28. Both agents were administered twice daily.
Gatz noted that although PARP inhibitors are known to enrich for response in adult patients with BRCA mutations, none of the patients who experienced clinical benefit in the study had BRCA mutations.
Regarding safety, grade 3 or greater and thrombocytopenia and neutropenia were the most common DLTs in dose levels 1 and 2. “The main toxicities were hematologic and gastrointestinal,” Gatz said.
“So far, it is unclear if the molecular alterations based on which the patients were enrolled in this trial are the sole reasons for response,” Gatz said. “Further, it may be difficult to identify patterns of response in specific tumor types due to 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.”
Pharmacokinetic analysis and recruitment for the two HRD and replication-stress expansion cohorts at the RP2D is ongoing. Confirmation of RP2D and pharmacokinetic analysis in younger children is ongoing.
“Retrospective molecular in-depth correlative analysis will be key to identify new hypothesis for patient selection and potential biomarkers for response,” Gatz concluded.
Disclosures: Dr Gatz reported consultancy for EMB Serono and grant/contract with Bayer.