by Leah Lawrence
Early-phase trials testing the safety and efficacy of PARP inhibition plus ataxia telangiectasia- and Rad3-related kinase (ATR) inhibition in biomarker-selected patients show intriguing results, researchers reported at the AACR Annual Meeting 2023.
“ATR inhibition prevents recovery from PARP inhibitor-induced DNA damage via rapid, irreversible replication catastrophe and unscheduled mitosis entry, eventually leading to cell death,” explained Timothy A. Yap, MBBS, PhD, of the University of Texas MD Anderson Cancer Center. “The combination of a PARP inhibitor and an ATR inhibitor provides a rational approach to improve PARP inhibitor efficacy.”
In fact, in preclinical studies in models harboring homologous recombination deficiency (HRD), the combination of PARP inhibition and ATR inhibition was shown to delay and overcome acquired PARP inhibitor resistance.
At the meeting, Dr. Yap presented pooled results of two phase-1 trials looking at three PARP inhibitors each combined with the ATR inhibitor camonsertib in patients with relapsed or refractory solid tumors with DNA damage repair (DDR) alterations (Abstract CT018).
The TRESR trial tested camonsertib plus talazoparib and the ATTACC trial tested camonsertib plus niraparib or olaparib. The low-dose intermittent regimens of camonsertib plus the PARP inhibitors appeared safe with transient hematologic adverse effects.
The clinical benefit rate for the 90 heavily pretreated patients evaluable for efficacy was 48%.
Responses were seen across multiple tumor types — including ovarian, breast, and pancreatic — across mutations (9 responders had BRCA 1/2 alterations), and with each of the PARP inhibitor combinations. Anticancer activity was also observed in patients with platinum-resistant and PARP-inhibitor resistant tumors with predefined genomic alterations.
Those patients with late-line ovarian cancer derived the most benefit from the combination with an overall response rate of 32%, a clinical benefit rate of 58%, and a median progression-free survival of 7 months.
“The concomitant low-dose intermittent dosing schedule of PARP inhibition and ATR inhibition is proof of principle that you can combine DDR inhibitors improving tolerability,” said study discussant Fiona Simpkins, MD, of the University of Pennsylvania. She added that these combinations warrant further investigation in biomarker-selected populations, especially in platinum-resistant ovarian cancer.
Later in the same session, which was devoted to novel biomarker-driven trials, Susanne A. Gatz, MD, of the Institute of Cancer and Genomic Sciences, University of Birmingham, United Kingdom, presented results from the first-in-child, phase 1/2 AcSé-ESMART trial combining the PARP inhibitor olaparib with the ATR inhibitor, ceralasertib, in children with advanced malignancies (Abstract CT019).
The rationale for this combination is that in the pediatric realm, many cancers have evidence of a constitutively active ATR pathway due to endogenous replication/transcription stress, which can be targeted by an ATR inhibitor. Although BRCA alterations are rare in pediatric malignancies – unlike in adult malignancies – alterations conferring HRD likely require a combination approach including PARP inhibition.
The trial enrolled 18 children or adolescents with relapsed or refractory cancer with available advanced molecular profiling at relapse. For inclusion, all patients had to have molecular alterations consistent with HRD or replication stress in their tumor.
Olaparib was given twice daily continuously in combination with ceralasertib twice daily on days 1-14 of a 28-day cycles. Dose level 1 varied by age group at olaparib 150/100/50 mg twice daily and ceralasertib 80/40/30 mg twice daily for ages 12-18 years, 6-11 years, and 3-5 years, respectively. Dose Level 1 was the recommended phase 2 dose.
“We indeed saw preliminary activity in this dose-escalation trial,” Dr. Gatz said.
The patients received a median of 3.5 cycles of therapy. There were two confirmed partial responses: one in a patient with pineoblastoma and one with neuroblastoma. Nine additional patients had stable disease as best response, and three of these patients had prolonged stable disease for more than four cycles. Seven patients had progressive disease as best response.
Dr. Gatz said that the combination was well tolerated overall with toxicity consisting mainly of thrombocytopenia, neutropenia, anemia, and gastrointestinal effects.
In discussing the results of the pediatric trial, Julia L. Glade Bender, MD, of Memorial Sloan Kettering Cancer Center, thanked Dr. Yap and colleagues for their work on the TRESR and ATTACC trials, without which, she said, she would have been concerned that there was not enough signal for this approach in pediatrics if there was no adult indication. However, she added that clearly the predictive biomarkers for targeted therapies in adult malignancy may not always translate to pediatric oncology.
“When you look, you see only one BRCA2 homozygous deletion and this patient had stable disease for only a short duration,” Dr. Glade Bender said. “Meanwhile, 11q loss and sarcoma driven translocation associated with replication stress goes across the spectrum of response. This begs the question, ‘What are the appropriate biomarkers in pediatric cancer for DNA damage response pathway?’”
With this in mind, “post hoc and iterative analyses of responders and non-responders will be absolutely critical to understanding the role of DDR inhibitors in treating patients with pediatric malignancy,” Dr. Glade Bender said.
The ATTACC trial was sponsored by Repare Therapeutics in collaboration with Roche Pharma AG. The AcSé-ESMART trial was sponsored by Gustave Roussy in collaboration with the National Cancer Institute of France.
Dr. Yap reported grant/research support (to Institution): Acrivon, Artios, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint, BMS, Boundless bio, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, Ideaya ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seagen, Tesaro, Vivace, and Zenith. He has done consulting work with AbbVie, AstraZeneca, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Athena, Atrin, Avoro, Axiom, Baptist Health Systems, Bayer, BeiGene, Blueprint Medicines, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Circle Pharma, Clovis, CUHK Committee, Cybrexa, Dark Blue Therapeutics, Diffusion, Ellipses.Life, EMD Serono, F-Star, Genentech, Genmab, Gerson and Lehrman Group, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Idience, Ignyta, I-Mab, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, LRG1, MEI pharma, Mereo, Merck, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Panangium, Pegascy, PER, Pfizer, Piper-Sandler, Pliant Therapeutics, Prolynx, Radiopharm Theranostics, Repare, resTORbio, Roche, Sanofi, Schrodinger, Seagen, Synthis Therapeutics, Terremoto Biosciences, Tessellate Bio, TD2 Theragnostics, Tome Biosciences, Varian, Versant, Vibliome, Xinthera, Zai Labs, Zentalis, and ZielBio.
Dr. Glade Bender reported relationships with Jazz Pharmaceuticals, Bristol Myers Squibb, Eisai, Springworks Therapeutics, Merck Sharp & Dohme, Pfizer, Eli Lilly, Loxo-Oncology, Cellectar, Bayer, and Amgen.
Dr. Gatz reported relationships with EMD Serono and Bayer.
Dr. Simpkins reported relationships with AstraZeneca.
This article was published by OBR Oncology.