A combination of the PARP inhibitor olaparib (Lynparza®; AstraZeneca) and the investigational Ataxia telangiectasia mutated rad3 related (ATR) inhibitor ceralasertib (AZD6738), showed clinical benefit in pediatric patients with solid tumors exhibiting DNA replication stress and/or DNA repair deficiencies. This is the conclusion based on results from the phase I portion of the phase I/II AcSé-ESMART trial at the annual meeting of the American Association for Cancer Research (AACR), held April 14-19, 2023 at the Orange County Convention Center in Orlando, Florida.

Study rationale
The researchers noted that in pediatric cancer, the rationale for this combination is based on the observation that many cancers show evidence of a constitutively active ATR pathway due to endogenous replication/transcription stress (RS) which can be targeted by ATRi. In this setting, the PARP inhibitor serves as additional replication stressor/ATRi sensitizer.

They also explained that classical BRCA alterations are rare and alterations conferring homologous recombination deficiency (HRD) likely require a combination approach including PARP inhibitors.

“To our knowledge, the combination of PARP inhibitors and ATR inhibitors has not been widely investigated in adult tumor types,” noted Susanne A. Gatz, MD, Ph.D., an associate clinical professor in pediatric 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 pediatric cancers,” she added.

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Susanne A. 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

Proof-of-concept platform
AcSé-ESMART study, sponsored by Gustave Roussy Cancer Campus, the French Institut National de Cancer (INCa), Imagine for Margo, Fondation ARC, AstraZeneca, Cancer Research UK, Fondation, Gustave Roussy (parraignage medecin-chercheur), and Little Princess Trust/Children’s Cancer and Leukaemia Group (CCLG), is an international European proof-of-concept platform trial intended to match pediatric, 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, MD, PhD, 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 tumors.

Defects in DNA replication
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 sensitize cells to drugs called PARP inhibitors. PARP inhibitors have proven effective against specific adult cancers with HR deficiencies—most notably, mutations in BRCA1 or BRCA2. However, how to best use PARP inhibitors in pediatric patients where BRCA1/2 mutations are rarely found remains unclear.

“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 that combination with an ATR inhibitor could potentially overcome that,” she added.

Study design
In the phase I portion of AcSé-ESMART arm N, researchers enrolled 18 pediatric and young adult patients with relapsed or treatment-refractory solid tumors that harbored mutations believed to confer HR deficiencies or replication stress.

Three dose levels of twice-daily oral olaparib (given continuously) and ceralasertib (given on days 1 through 14 of each 28-day cycle) were evaluated.

The recommended phase II dose was determined to be 150 mg of olaparib and 80 mg of ceralasertib in patients aged 12 to 18. The recommended dose regimen for children younger than 12 remains to be determined.

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, a malignant tumor that grows in a part of the brain known as the pineal gland and primarily occurs in children, experienced a confirmed partial response and received treatment for 11 cycles.

Another patient with neuroblastoma, a tumor that develops from neuroblasts or nerve tissue of the adrenal gland, neck, chest, or spinal cord (usually before a child the age of 5 years), 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.

Gatz explained that 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 pediatric patients, necessitating additional research into combination therapies and mechanisms of response.

“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,” she noted.

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.

Study limitations
‘Limitations of this study include a small, non-randomized sample intended primarily as a proof of concept and to determine the optimal dose for study expansion.

Clinical trial
European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (ESMART) – NCT02813135
Ceralasertib (AZD6738) Alone and in Combination With Olaparib or Durvalumab in Patients With Solid Tumors – NCT03682289

Highlights of prescribing information
Olaparib (Lynparza®; AstraZeneca) [Prescribing Information]

Reference
[1] Gatz SA, Rubio San Simón A, Archambaud B,  Abbou S, Cleirec M, Leruste A, Defachelles AS, André N, Rubino J, Nebchi S, Rondof W, Smith SA, Mortimer PGS, Loembé B, et al. Phase I/II study of the PARP inhibitor olaparib and ATR inhibitor ceralasertib in children with advanced malignancies: Arm N of the AcSé-ESMART trial. In: Proceedings of the 114th Annual Meeting of the American Association for Cancer Research; 2023 April 14-19; Orlando, FL. Philadelphia (PA): AACR; 2023. Abstract/Poster nr CT019

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