番茄社区

SAN ANTONIO -- An investigational drug that interferes with cancer cells' ability to repair themselves can delay the progression of advanced breast cancer with a mutated BRCA gene, a researcher said here.

In a randomized phase III open-label trial, the PARP inhibitor talazoparib outperformed a range of standard therapies, according to Jennifer Litton, MD, of MD Anderson Cancer Center in Houston.

The drug delayed tumor progression by a median of three months longer than other standard therapies selected by treating physicians, Litton told reporters at the

"The curves do separate early and the separation continues," Litton said.

Talazoparib is one in a class of drugs that block the poly-ADP ribose polymerase (PARP) enzyme, which plays a role in DNA repair. The cells of some types of cancer are more dependent on PARP than normal cells, making PARP inhibitors potentially valuable as therapeutic agents.

In breast cancer, the drugs have had a "rough road," commented C. Kent Osborne, MD, of Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston, who was not part of the study but who moderated a media briefing at which it was discussed.

The study by Litton and colleagues is "one of the first steps in addressing DNA repair as a target for treatment" of breast cancer, he told 番茄社区.

"The concept has been shown to work in some patients," Osborne said. He noted that the drug yielded a "modest advantage, although there were some patients for whom the advantage was quite prolonged."

"Now the trick is to find out who is going to respond best and to find out what the mechanisms of resistance are," Osborne said.

The drug had promising results in earlier studies, Litton said, so she and colleagues conducted an international trial in women with locally advanced or metastatic HER2-negative breast cancer with a germline mutation in either the BRCA1 or BRCA2 gene.

The 431 patients were randomly assigned to get talazoparib or a standard therapy with capecitabine, eribulin, gemcitabine, or vinorelbine, depending on the treating physician's choice (PCT).

Treatment continued on 21-day cycles until progression or unacceptable toxicity, Litton said.

The study's primary endpoint was progression-free survival, defined by the so-called RECIST criteria and adjudicated by a blinded central review, she said, and the key secondary endpoints were overall survival, objective response rate, and safety.

After a median follow-up of 11.2 months, Litton reported, patients getting the investigational drug had a median time before progression of 8.6 months, compared with 5.6 months for those getting PCT.

The numbers yielded a highly significant hazard ratio for progression of 0.54, favoring talazoparib, Litton said.

The benefit was seen in almost all subgroups, with the exception of those with prior treatment with platinum-based chemotherapy, where the confidence interval crossed unity, she said.

The overall survival analysis is still immature, Litton said, but the curves have begun to separate and hazard ratio -- not yet significant -- was 0.76.

On the other hand, the objective response rate, as determined by the investigators, was 62.6% for talazoparib and 27.2% for PCT, a difference that yielded an odds ratio of 4.99 in favor of the investigational drug, she reported.

In an encouraging exploratory endpoint, Litton said, the duration of response was longer for talazoparib, with some patients still responding after 33 months. The one-year probability of a sustained response was 23% versus 0% for PCT.

Overall, she said, non-hematologic adverse events were similar between the arms, with 98.6% of talazoparib patients and 97.6% of PCT patients reporting at least one of any grade. Grades 3 and 4 events were also similar, with 38.1% of patients reporting them in each arm.

Hematologic adverse events were reported by 67.8% of those on talazoparib and 50% of those on PCT. Anemia was more common in the talazoparib arm while neutropenia was more common among PCT patients. Febrile neutropenia was rare in both arms.

The investigators also looked at patient-reported quality of life and found a statistically significant difference -- a 3.0-point improvement for those on talazoparib and a 5.4-point worsening for those on PCT.

The median time to clinically meaningful deterioration was 24.3 months in the talazoparib arm and 6.3 months in the PCT arm, a difference that yielded a hazard ratio of 0.38, Litton said.

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