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Ataxia Telangiectasia Mutated and Rad3-Related Kinase (ATR) Inhibitors: Some Promise for Patients with Ataxia-Telangiectasia Mutated (ATM) Genitourinary Cancers?

We now have FDA approval for the PARP inhibitor, olaparib, in prostate cancer, for men who harbor any one of many potential homologous recombination repair (HRR) gene mutations.1 However, we have not seen extreme efficacy beyond the BRCA2 population of patients. In the PROFOUND randomized phase 3 trial that showed the survival benefit of olaparib over standard novel hormonal therapy for men with HRR-deficient metastatic castration-resistant prostate cancer, patients with ATM alterations had notably less profound outcomes with olaparib.2

We have subsequently, seen multiple publications that support the concept that there are differential responses between patients with ATM and BRCA2 mutated prostate cancers, the two most commonly mutated DNA repair genes in prostate cancer.3,4 There are likely many reasons for this difference in outcomes. In many studies, zygosity status is often not reported, hence it is difficult to know whether a patient harbors a mono-allelic or bi-allelic mutation. ATM may have many mono-allelic alterations, and those tumors were likely bound to never respond to a PARP inhibitor. Additionally, Clonal Hematopoiesis of Indeterminate Potential (CHIP) can interfere with cell-free DNA testing from blood and lead to incorrect interpretation of results.5 ATM is a large gene that may be particularly prone to having somatic mutations found as age related clones in the cells of the blood and bone marrow. Finally, the result of a tumor even with a bi-allelic ATM mutation is likely different than that of one that harbors a BRCA2 mutation, as both ATM and ATR are positioned at the forefront of the DNA damage response.6

ATM and ATR are serine/threonine kinases that respond to DNA damage by phosphorylating the checkpoint kinases CHK1 and CHK2, respectively.7 This allows activation of specific cell cycle checkpoints and delays cell cycle progression while promoting DNA repair pathways.8 It is important to recognize that while ATM is recruited to double strand DNA breaks and activates DNA repair pathways, it also cooperates with CHK2 to modulate cells cycle control via MDM2 and subsequent stabilization, prevention of degradation,9 and causing phosphorylation of p53 to induce G1 cell cycle arrest. Therefore, it is not surprising that a PARP inhibitor, which can inhibit single strand break repair, may not be adequate on its own to abrogate the effects of a pathogenic ATM mutation.

ATR has broader functions and can also respond to single strand breaks and stalled replication forks.8 ATRs response to replication stress and DNA damage is through interaction with CHK1 to promote S-phase to prevent entry into mitosis until the damage/stress is resolved.10 ATR also can interact with CHK2 during the G2/M transition and work to prevent cell cycle progression in response to ionizing radiation.11 Interestingly, while ATM is frequently mutated in prostate cancer, ATR function is almost never lost, as both mutations and reduced expression situations are rare.12 Malignant cells are extremely dependent on ATR functions, and dysregulation of other DNA repair genes can induce replicative stress by promoting cell cycle progression, which further stimulates the ATR/CHK1 pathway.

It comes to reason that inhibition of ATR may have antineoplastic activity in men with prostate cancer, especially in patients whose tumors harbor ATM alteration. Functional ATR may also serve as a resistance mechanism to PARP inhibitors. The combination of olaparib with the ATR inhibitor, Elimusertib (BAY 1895344) showed enhanced tumor reduction in PARP inhibitor sensitive prostate and breast cancer xenograft models.13 The phase 1 trial with Elimusertib was tolerable for patients with heavily pre-treated advanced solid tumors, including prostate cancer, and responders had ATM protein loss and/or deleterious ATM mutations.14 This may be early hints of synergistic activity of ATR inhibitors in ATM-deficient cancers, supporting the concept of synthetic lethality.

Below, I list some ongoing trials exploring the use of novel ATR inhibitors. Most of these are early phase trials and allow the accrual of a broad variety of solid tumors, including patients with genitourinary cancers. This includes prostate, bladder, and even neuroendocrine differentiated cancers, as the biology of ATR spans across tumor types. Although most below do not require ATM mutation, that is likely because they are early phase trials, and many of the below trials are utilizing combination therapy. Hopefully, as more experience is attained, more precision focus will be taken to future trial inclusion criteria to accrue patients who have tumors where ATR inhibition has greater potential for synthetic lethality.

ATR inhibitors in clinical trials for patients with genitourinary cancers

  • DDRiver Solid Tumors 208 - Phase 1 trial of Berzosertib in combination with topotecan (NCT05246111)
  • Phase 1/2 study of Berzosertib plus Sacituzumab govitecan in small cell lung cancer, extra-pulmonary small cell neuroendocrine cancer and homologous recombination-deficient cancers resistant to PARP inhibitors (NCT04826341)
  • Phase 1/2 study of Berzosertib with Lubinectedin in small cell and high grade neuroendocrine cancers
  • Phase 1/2 study of Berzosertib with Avelumab for DNA damage repair deficient solid tumors (NCT04266912)
  • Phase 1 study of Elumusertib (BAY1895344) in patients with solid tumors with deleterious ATM mutation or low expression or DNA damage response deficient metastatic castration-resistant prostate cancer (NCT03188965)
  • Phase 1 study of Elimusertib (BAY1895344) in combination with irinotecan or topotecan in patients with poorly differentiated neuroendocrine cancers (NCT04514497)
  • Phase 1 study of Elimusertib with gemcitabine/cisplatin with a special focus on urothelial cancer (NCT04491942)
  • ATRiUM – Phase 1 study of Ceralasertib with gemcitabine for metastatic solid tumors progressed on or unwilling to receive standard therapy (NCT03669601)
  • PLANETTE - Phase 2a study of Ceralasertib in ATM altered metastatic castration resistant prostate cancer (NCT04564027)
  • Phase 2 trial of Ceralasertib alone and in combination with Olaparib or Durvalumab in patients with select solid tumors, including renal cell (ARID1A by immunohistochemistry), urothelial (ARID1A by immunohistochemistry) and metastatic castration-resistant prostate cancer (ATM loss by immunohistochemistry) (NCT03682289)
  • Phase 1/2 study of ART0380 as monotherapy or with gemcitabine or irinotecan for solid tumors that don’t express ATM by immunohistochemistry, including those who have received PARP inhibitors for those who are BRCA mutated (NCT04657068)

Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer.
  2. De Bono J, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2020; 382:2091-102.
  3. Su CT, et al. Differential responses to taxanes and PARP inhibitors in ATM- versus BRCA2-mutated metastatic castrate-resistant prostate cancer. Prostate 2023; 83:227-36.
  4. Sokolova AO, et al. Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations. Prostate 2021; 81:1382-9.
  5. Jensen K, et al. Association of Clonal Hematopoiesis in DNA Repair Genes With Prostate Cancer Plasma Cell-free DNA Testing Interference. JAMA Oncol 2021; 7:107-10.
  6. Gulliver C, Hoffman R, and Baillie GS. Ataxia-telangiectasia mutated and ataxia telangiectasia and Rad3-related kinases as therapeutic targets and stratification indicators for prostate cancer. In J Biochem Cell Biol 2022; 147:106230.
  7. Smith J, et al. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res 2010; 108:73-112.
  8. Matsuoka S, et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 2007; 316:1160-6.
  9. Cheng Q, et al. ATM activates p53 by regulating MDM2 oligomerization and E3 processivity. EMBO J 2009; 28:3857-67.
  10. Saldivar JC, et al. The essential kinase ATR: ensuring faithful duplication of a challenging genome. Nat Rev Mol Cell Biol 2017; 18:622-36.
  11. Simoneau A and Zou L. An extending ATR-CHK1 circuitry: the replication stress response and beyond. Curr Opi Genet Dev 2021; 71:92-8.
  12. Karnitz LM, and Zou L. Molecular Pathways: Targeting ATR in Cancer Therapy. Clin Cancer Res 2015; 21:4780-5.
  13. Wengner AM, Scholz A, Haendler B. Targeting DNA Damage Response in Prostate and Breast Cancer. Int J Mol Sci 2020; 21.
  14. Yap TA, et al. First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors. Cancer Discov 2021; 11:80-91.
Related Content:

ASTRO 2022: Transcriptomic Analysis of ATM Expression in Localized Prostate Cancer – Implications for Radiotherapy Treatment


IBCN 2022: ATM Loss and Therapeutic Vulnerabilities in Bladder Cancer