- Researchers have found two drugs to be safe and effective in treating individuals with advanced solid tumors.
- These medications, ATR inhibitor elimusertib and PARP inhibitor AZD5305, can block key mediators behind DNA damage response (DDR).
- In clinical studies, these drugs only induced “reversible and manageable” adverse side effects in some participants.
An estimated 1.9 million new cancer cases are expected to arise and over 609,000 cancer-related deaths will occur in the United States in 2022. This amounts to 5,250 new cases and 1,670 deaths every day.
Research now suggests that a class of novel drugs may offer promise for people with advanced forms of cancer.
These treatments work by binding to ATR, a key component of the DNA damage response (DDR) pathway. This halts the activation of DNA damage mechanisms and the growth of tumor cells.
Lead investigator Dr. Timothy Yap, associate professor of Investigational Cancer Therapeutics, presented the findings at the American Association for Cancer Research (AACR) Annual Meeting 2022 on April 10, 2022.
The human DNA is constantly susceptible to damage by normal cellular processes or exposure to external toxic agents.
Prof. Steve Jackson is the University of Cambridge Frederick James Quick and Cancer Research UK Professor of Biology and Head of Cancer Research UK Laboratories at the Wellcome Trust/Cancer Research UK Gurdon Institute. He was not involved in the current studies.
In a March 2022 podcast, Prof. Jackson explains: “[The DDR is] the system that repairs most double-strand breaks that arise in human cells after radiation after certain chemotherapeutics that are using cancer. It’s also needed to generate the immune system as well.”
When the DDR works properly, it helps maintain the genome’s integrity and staves off the development of cancer and other diseases.
Dr. Osita Onugha is a thoracic surgeon and assistant professor of thoracic surgery at Saint John’s Cancer Institute at Providence Saint John’s Health Center in Santa Monica, CA. He was not involved in this research.
In an interview with Medical News Today, Dr. Onugha shared that, as we age, “our DNA repair mechanisms don’t work as effectively.” This is why cancer typically affects older people.
As such, the DDR plays a significant role in cancer onset and treatment.
When DDR defects in this network happen, cancer cells start growing uncontrollably and evading cell death.
ATR (Ataxia telangiectasia mutated and Rad3-related) kinase is a protein that regulates DDR. ATR inhibitors can fight tumors on their own and in conjunction with chemotherapy, immunotherapy, and radiotherapy.
Poly ADP ribose polymerase (PARP) is another type of protein or enzyme that activates the DDR network. PARP inhibitors block PARP activity by trapping PARP1 and PARP2.
These medicines also selectively kill cancer cells.
In a Phase 1b expansion trial, Elimusertib showed significant anti-tumor potential against several types of solid tumors. This drug is a highly selective and potent ATR inhibitor.
During this study, 143 individuals with advanced solid tumors received at least one dose of elimusertib. The participants had multiple types of gynecologic, colorectal, breast, prostate, and other advanced cancers.
The most frequent adverse effects of this treatment were anemia and neutropenia, which are common with chemotherapy. Staggering or lowering doses helped manage and reverse these conditions.
In 35% of the participants across cancer types, elimusertib showed clinical benefit with disease control for at least 4 months. The drug continued to be effective for longer than 6 months in a sizable portion of the participants as well.
The elimusertib trial was funded by Bayer.
AZD5305 shows promise, too
Researchers also treated 61 patients with second-generation PARP inhibitor AZD5305 in a phase I/IIa PETRA trial. This was the first-in-class and first-in-human study to assess the drug’s safety and effectiveness.
Patients had advanced breast, pancreatic, prostate, or ovarian cancer.
Dr. Yap reports: “By selectively inhibiting and trapping PARP1, AZD5305 achieved greater antitumor efficacy across select tumor and molecular subtypes, more durable target inhibition, and superior tolerability compared to first-generation dual PARP1/2 inhibitors in preclinical models.”
The most common side effects were anemia, neutropenia, and thrombocytopenia, a low blood platelet count. Incidences of nausea and chemotherapy-related blood issues were low compared to first-generation PARP inhibitors.
The AZD5305 trial was funded by AstraZeneca.
Dr. Yap and his colleagues say that more research is necessary “to better identify molecular biomarkers to predict which patients are most likely to benefit from elimusertib monotherapy.”
Scientists are already running expansion trials to study how AZD5305 works in PARP inhibitor-naïve populations. They are also evaluating increased doses of combination therapies with anticancer drugs trastuzumab deruxtecan and datopotamab deruxtecan.
Dr. Onugha felt that the current studies are significant for cancer research because “they confirm things that we already know, but they confirm it scientifically.”
However, the small sample sizes make it difficult “to make sweeping conclusions.” Ideally, he said, these kinds of studies should include at least 5,000 participants.
The surgeon also said that, although major pharmaceutical companies underwrote this research, “they had no true benefit from that financially, at least directly.”
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