A low dose of alnodesertib added to standard chemotherapy significantly reduced the likelihood of disease progression among people with platinum-resistant high-grade serous ovarian carcinoma (HGSOC) in an early clinical trial.
Findings from the Phase 2a study (NCT04657068) were announced by Artios Pharma, which is developing alnodesertib and sponsored the trial.
“The encouraging clinical signals we observed in patients when low dose alnodesertib was added to gemcitabine suggest that this approach warrants further evaluation,” said Antonio Gonzalez-Martin, MD, PhD, the trial’s principal investigator at Clínica Universidad de Navarra in Spain, in an Artios press release.
Why platinum-resistant ovarian cancer is difficult to treat
HGSOC is a form of gynecological cancer marked by the uncontrolled growth of cells in or around the ovaries. First-line treatment usually involves platinum-based chemotherapies, but many patients eventually stop responding to these drugs.
“With approximately 70% of patients with ovarian cancer eventually relapsing following platinum-based chemotherapy, there is a high unmet need for promising new therapies like alnodesertib to improve clinical outcomes in platinum-resistant HGSOC and other tumors with high replication stress,” Gonzalez-Martin said.
For cells to divide, they must copy their DNA. When this process happens rapidly, as in fast-growing tumors like HGSOC, mistakes can occur, leading to DNA damage. This process, known as replication stress, can be deadly for cancer cells if they cannot repair the resulting DNA damage.
Many cancer cells rely on a DNA repair protein called ATR (ataxia telangiectasia and Rad3-related) to help fix DNA damage caused by replication stress. Alnodesertib, formerly known as ART0380, is an oral therapy designed to block ATR activity, leaving cancer cells more vulnerable to DNA damage. The experimental medication is designed to work alongside existing gynecologic cancer treatments such as gemcitabine, a chemotherapy that damages cancer-cell DNA.
The randomized Phase 2a ovarian cancer cohort included 64 people with platinum-resistant HGSOC. All participants received gemcitabine — half were treated with chemotherapy alone, while the other half also received a low dose of alnodesertib.
Trial results suggest alnodesertib may slow disease progression
After six months, 34% of patients treated with alnodesertib remained alive without disease progression, compared with 23% of those given chemotherapy alone. According to Artios, based on the study’s predefined statistical threshold, this corresponded to a statistically significant 29% reduction in the risk of disease progression or death.
Over the course of the trial, 41% of patients initially assigned to gemcitabine alone crossed over to receive alnodesertib after their disease progressed. Artios reported that “several patients experienced longer and clinically relevant disease control when low dose alnodesertib was added to the treatment regimen.”
The company said overall survival and treatment response rates were similar between the two groups. However, because many patients in the gemcitabine-only group later received alnodesertib after their disease progressed, the company said these results cannot be interpreted definitively.
Safety results were also similar in both groups. Grade 3 or higher treatment-emergent adverse events occurred in about two-thirds of patients, with comparable rates in those who did or did not receive alnodesertib. No treatment-related deaths were reported.
“This randomized Phase 2a study evaluating a low dose of alnodesertib and the labelled dose of gemcitabine in platinum-resistant ovarian cancer achieved the primary endpoint of progression-free survival, further establishing proof-of-concept in our differentiated approach of inhibiting ATR in tumors with high replication stress,” said Ian Smith, chief medical officer at Artios.
“These data support further investigation of alnodesertib plus DNA-damaging agents, which we are currently evaluating at higher doses of alnodesertib plus low dose irinotecan [another DNA-damaging chemotherapy] in patients with colorectal and pancreatic cancer.”
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