The DNA repair inhibitor prexasertib shrank the tumors of a third of the ovarian cancer patients treated with it in a Phase 2 clinical trial, preliminary results show.
Its developer, Eli Lilly, said the participants had recurring cancer that failed to respond to platinum-based chemotherapy. The specific form was high-grade serious ovarian carcinoma —or HGSOC — without BRCA gene mutations.
The cancer of those whose tumors shrank did not progress for a median of 7 1/2 months after the start of treatment, researchers said.
They said the therapy was particularly beneficial for women whose disease returned within six months of completing platinum-based chemo.
The study, published in The Lancet Oncology, is titled “Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept phase 2 study.”
“I’m glad this new, promising drug may contribute to our patients’ benefit,” Dr. Jung-Min Lee, a trial investigator at the National Cancer Institute’s Center for Cancer Research, said in a press release. He was the lead author of the study.
Prexasertib inhibits the checkpoint 1 and 2 proteins, CHK1 and CHK2. They pause the cell cycle — or process by which a cell divides into two cells — to repair DNA mutations that occur during the process. Because cancer cells divide at a faster pace, making them particularly susceptible to DNA errors, they have higher amounts of CHK1 and CHK2.
Prexasertib binds to these proteins, preventing them from pausing the cell cycle. The accumulation of DNA errors in cancer cells eventually leads to their death.
The Phase 2 trial (NCT02203513) was designed to test prexasertib’s ability to help HGSOC patients, with or without BRCA gene mutations. A normal gene produces functional BRCA protein that can repair DNA errors. Scientists believe the mutations generate faulty versions of the protein that make cells more susceptible to DNA-damaging agents, like prexasertib.
The first part of the trial involved 28 women without BRCA mutations whose median age was 64. They had received a median of five treatments. Seventy-eight percent had cancer that had failed to respond to platinum treatment or that recurred after treatment.
Patients received prexasertib in 28-day cycles of once a day for 14 days, then none for 14 days. Four patients withdrew from the study early due to travel inconvenience or illness.
After two months of treatment, the tumors of 33 percent of patients had shrunk, and their disease did not progress for a median of 7 1/2 months. Nineteen patients had cancer that was platinum-resistant or that returned after the chemo. Six of them, or 32 percent, saw their tumors shrink. The cancer of five, or 26 percent, stabilized for at least six months.
In addition, 12 patients achieved a 50 percent or greater reduction in levels of an ovarian cancer biomarker known as CA-125 protein.
“The encouraging anti-tumor activity that we recorded in patients with platinum-resistant or platinum-refractory high-grade serous ovarian carcinoma warrants further development in a randomized trial that includes assessment of patient-reported outcomes,” the researchers wrote.
During the study, all patients had at least one treatment-related adverse event. The most common severe or life-threatening events were low levels of immune cells known as neutrophils, low levels of white blood cells or platelets, and anemia. More serious events were temporary and manageable. One patient died during the study period when her tumor worsened.
Overall, the researchers concluded that “prexasertib monotherapy was tolerable and clinically active” in heavily treated patients with recurrent HGSOC not associated with BRCA mutations.
Researchers are now recruiting patients with BRCA mutations for the second part of the trial. The team expects to complete enrollment by the end of 2018. This part of the trial will “provide insight into the possible usefulness of prexasertib in patients with germline BRCA mutations,” the researchers wrote.