SAN ANTONIO – In women with advanced HER2-negative breast cancer with germline BRCA mutations, an investigational oral PARP inhibitor talazoparib was associated with a near doubling in progression-free survival (PFS) when compared with single-agent chemotherapy, results of the phase 3 EMBRACA trial show.
After a median follow-up of 11.2 months, the median PFS by blinded central review – the primary endpoint – was 8.6 months for patients assigned to receive talazoparib, compared with 5.6 months for patients randomized to receive the physician’s choice of either capecitabine, eribulin, gemcitabine, or vinorelbine, reported Jennifer K. Litton, MD, from the University of Texas MD Anderson Cancer Center in Houston.
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Dr. Jennifer Litton
“Patients who were assigned to talazoparib had an improvement in their global health status versus patients who had deterioration when randomized.”
Talazoparib is an oral inhibitor of poly ADP-ribose polymerase (PARP) with a dual mechanism of action: It both inhibits the PARP enzyme directly and traps PARP on single-stranded DNA breaks, preventing repair of DNA damage and leading to the death of malignant cells.
In the phase 2 ABRAZO trial, the PARP inhibitor showed “encouraging” efficacy and safety in patients with germline BRCA1/BRCA2 mutations who had received platinum-based chemotherapy or at least three prior cytotoxic regimens.
Dr. Litton reported results of the EMBRACA trial, a phase 3 study in patients with locally advanced or metastatic HER2 negative breast cancer a germline BRCA1 or BRCA2 mutation. Patients were stratified by number of prior chemotherapy regimens, by having triple-negative breast cancer or hormone receptor-positive breast cancer, and by having a history of either central nervous system metastases or no CNS metastases; they were then randomized on a 2:1 basis to either oral talazoparib 1 mg daily (287 patients) or to the physician’s choice of therapy with one of the agents noted before.
The patient characteristics were generally well balanced, although there was a higher percentage of patients aged younger than 50 years in the talazoparib group than in the group treated with other agents (63.4% vs. 46.5%, respectively), slightly more CNS metastases (15% vs. 13.9%), and a higher percentage of patients with a disease-free interval (time from initial diagnosis to advanced breast cancer) shorter than 12 months (37.6% vs. 29.2%).
The primary endpoint of PFS by blinded central review showed the aforementioned significant benefit of talazoparib. A PFS by subgroup analysis showed that talazoparib was significantly better in all parameters except for patients who had previously received platinum-based therapy.
The trial was also powered to show overall survival as a secondary endpoint, but the data are not mature, Dr. Litton said. An interim OS analysis showed an apparent trend favoring the PARP inhibitor, with a median of 22.3 months, compared with 19.5 months with physician’s choice of treatment.
The 24- and 36-month probabilities of survival were 45% and 34% respectively for patients treated with talazoparib, compared with 37% and 0% for patients treated with other agents.
The objective response rate by investigator rating was 62.6% with talazoparib, compared with 27.2% for other drugs (odds ratio, 4.99; P less than .0001).
Anemia was the most common hematologic adverse event, with grade 3 or greater occurring in 39.2% of patients on the PARP inhibitor, compared with 4.8% of patients treated with other agents.
Talazoparib, unlike other PARP inhibitors, was also associated with grade 1 or 2 alopecia, which occurred in 25.2% of those patients, compared with 27.8% of those receiving the physician’s choice of treatment.
Grade 3 or 4 serious adverse events occurred in about 25.5% of patients in each study arm. Events leading to permanent drug discontinuation were more common with physician’s choice agents at 9.5%, compared with 7.7% of patients treated with talazoparib.
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Dr. Kent Osborne
Kent Osborne, MD, the director of the Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston, who moderated a briefing where Dr. Litton presented the data, commented that patients may not be as enthusiastic about the results as investigators seem to be.
“I’ve heard doctors like you and I say ‘This is really great, we’ve got some activity from a PARP inhibitor;’ patients look at it and say ‘Gee, a few more responses and a 3-month prolongation on average of my time to progression is not a very big advantage,’ ” he said to Dr. Litton.
“So what’s the next step in the development of these drugs? Are they going to be used in combinations? Are we going to come up with a mechanism of resistance that we can then overcome to extend the duration of their benefit?” he asked.
Dr. Litton replied that she was encouraged by fact that the tails of the survival curves appear to be separating and that some patients have complete responses and some have relatively durable responses.
“One of the things that we’re going to be looking at are the correlatives, trying to identify who these extraordinary responders are and the mechanisms of resistance as best we can,” she said.
This study was funded by Pfizer, which developed the inhibitor. Dr. Litton has disclosed research funding with EMD Serono, AstraZeneca, Pfizer, Genentech, and GlaxoSmithKline, and serves on advisory boards for Pfizer and AstraZeneca, all uncompensated.
SOURCE: Litton et al. SABCS 2017 Abstract GS6-07.