A phase 2 study of talazoparib found that it shrank tumors in breast cancer patients not previously indicated for the treatment
DALLAS – A drug approved to treat breast cancer patients with mutations in the BRCA1 or BRCA2 genes may also benefit people who have other genetic mutations.
Researchers at UT Southwestern reported in the journal Nature Cancer that talazoparib successfully shrank the tumors of breast cancer patients with mutations in the PALB2 gene. Patients with this mutation would not have previously qualified for treatment with talazoparib, a type of cancer drug known as a PARP inhibitor.
Joshua Gruber, M.D., Ph.D.
“These patients would otherwise have very limited treatment options,” said Joshua Gruber, M.D., Ph.D., Assistant Professor of Internal Medicine at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center. “This study expands the patient population that can benefit from PARP inhibitors.”
Like other PARP inhibitors, talazoparib works by blocking a protein that usually helps cells repair damaged DNA. Without the ability to repair their DNA, cancer cells accumulate damage and eventually die. In cancers that have other defects in this process – including those with BRCA1/2 mutations – the drug is particularly effective, dealing a fatal second blow to the DNA repair machinery.
In a landmark 2018 study, researchers focused on advanced breast cancer patients with BRCA mutations – which account for 5% to 10% of all breast cancer cases – and found that talazoparib increased their survival time. The Food and Drug Administration approved the drug for that group, and follow-up studies have found that talazoparib also works for prostate and pancreatic cancer patients with BRCA mutations.
In the new phase 2 trial, Dr. Gruber and colleagues tested the effectiveness of talazoparib in advanced cancer patients with less common gene mutations associated with DNA repair. Previous data has suggested that more than 17% of all cancers have such mutations.
Twenty patients were enrolled in the trial at Stanford University, where Dr. Gruber previously served. Thirteen had breast cancer, three had pancreatic cancer, and four had other tumor types. The patients had mutations in eight DNA repair genes. On average, they took a daily talazoparib pill for 23.8 weeks.
Among all patients, the average survival time was 5.6 months, and 20% had at least partial shrinkage of tumors. Because this was a phase 2 trial, there was not a control group to compare these data to, but the results were especially striking for patients with the PALB2 mutations: They survived 6.9 months on average, and all six patients (five with breast cancer, one with pancreatic cancer) had tumor shrinkage.
What does this mean for patients? The trial demonstrates that patients with PALB2 mutations will benefit from talazoparib or the related PARP-inhibitor olaparib. Patients with metastatic breast cancer should have genomic sequencing to see if they have such mutations. These mutations are distinct from the more well-known BRCA1 and BRCA2 mutations and must be tested for specifically. Next, the team is planning a follow-up trial at UT Southwestern to further understand which patients gain the most benefit from talazoparib. In the long run, they will work toward FDA approval for talazoparib for PALB-mutation patients, Dr. Gruber said.