PARP Inhibitor Talazoparib Benefit in BRCA+ Breast Cancer

Pam Harrison

August 27, 2018

The now published results from the EMBRACA study confirm that talazoparib (in development by Pfizer), a poly adenosine diphosphate-ribose polymerase (PARP) inhibitor, prolongs progression-free survival (PFS) in advanced BRCA-positive breast cancer patients compared to single-agent chemotherapy alone and that it also significantly improves quality of life.

"This is the largest randomized trial in BRCA mutation carriers [ever undertaken] and demonstrates PARP efficacy," Jennifer Litton, MD, associate professor in the Department of Breast Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, told Medscape Medical News in an email.

"I think what was really striking was that patients felt better on [talazoparib] than on chemotherapy, and the time to meaningful deterioration was significantly improved on talazoparib than on standard chemotherapy," she added.

"The next steps will be to look beyond BRCA mutation carriers with combinations that may expand who may benefit or prolong their activity," Litton said.

The study was published online on August 23 in the New England Journal of Medicine .

The study has now been submitted as part of an approval application to the US Food and Drug Administration (FDA) and also the European Medicines Agency. The FDA recently granted a priority review designation to Pfizer for talazoparib for the treatment of BRCA-mutated, HER2-negative, locally advanced or metastatic breast cancer.

EMBRACA Study Design

As previously reported, 287 patients received talazoparib 1 mg/day, and 144 patients received single-agent chemotherapy of their physician's choice. The chemotherapy could consist of either capecitabine (Xeloda, Genentech), eribulin (Halaven, Eissai Co), gemcitabine (Gemzar, Pfizer) or vinorelbine (Navelbine, Pfizer), given in continuous 21-day cycles.

Patients had either locally advanced or metastatic breast cancer with either the BRRA1 mutation or the BRCA2 counterpart.

"The primary end point was radiologic progression-free survival," the investigators note. Patients were treated until disease progression or until they developed unacceptable side effects.

PFS was 46% longer for patients in the talazoparib arm than for patients in the single-agent chemotherapy comparator arm, at 8.6 months vs 5.6 months (P < .001).

In addition, 37% of patients treated with the PARP inhibitor experienced disease progression or death at 1 year, compared with 20% of patients in the single-agent chemotherapy group.

The response rate to the PARP inhibitor was also numerically higher, at 62.6%, compared with 27.2% for standard therapy. In addition, 5.5% of patients treated with talazoparib achieved a complete response. In contrast, no patient in the standard-therapy group achieved a complete response.

The median duration of response was also longer, at 5.4 months in the talazoparib arm compared with 3.1 months for those who received standard chemotherapy.

At the time of the interim analysis, median overall survival was 22.3 months in the talazoparib group compared with 19.5 months in the standard-therapy group, a difference between the two groups that was not statistically significant (P = .11).

Regardless of the subgroup analyzed, the hazard ratios (HRs) for disease progression or death were in favor of talazoparib compared to the single-agent chemotherapy arm.

Table. HRs for Disease Progression or Death by Subgroup, Talazoparib vs Single-Agent Chemotherapy

BRCA1 mutation 0.59
BRCA2 mutation 0.47
Triple-negative breast cancer 0.60
Hormone receptor– positive breast cancer 0.47
History of CNS metastasis: Yes 0.32
History of CNS metastasis: No 0.58
CNS, central nervous sytem

Patient-Reported Outcomes

The investigators also assessed patient-reported outcomes through the use of the European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) as well as the breast cancer—specific QLQ-BR23 at baseline, at the beginning of each treatment cycle, and at the end of treatment.

On the basis of estimated overall mean change from baseline in scores on the EORTC QLQ-C30 scale, patients treated with talazoparib had a significant improvement from baseline to treatment endpoint, with a score of +3.0, compared to a significant deterioration in the standard therapy group, at a score of -5.4 (P < .001).

"As compared with standard therapy, treatment with talazoparib resulted in a significant delay in the onset of clinically meaningful deterioration according to the global health status-quality-of-life scale," the study authors report.

The investigators also observed a significant improvement from baseline to treatment endpoint in scores on the EORTC QLQ-BR23 scale in the talazoparib arm compared with a nonsignificant change in the single-agent chemotherapy arm, at -5.1 vs -0.1 (P = .002).

Grade 3 or 4 hematologic toxicities were recorded in 55% of PARP inhibitor recipients, compared to 38% of those treated with single-agent chemotherapy.

However, "most grade 3-4 toxic effects associated with the use of talazoparib were hematologic laboratory abnormalities, were not associated with substantial clinical sequelae, and did not result in drug discontinuation," the investigators observe.

"And the majority of nonhematologic adverse events in the talazoparib group were grade 1 in severity," they indicate.

In commenting on the study when originally presented at the San Antonio Breast Cancer Symposium last year, Kent Osborne, MD, director of the Dan L. Duncan Cancer Center at the Baylor College of Medicine in Houston, Texas, suggested that the study should be viewed as a first step in addressing DNA repair as a target for treatment in the setting of BCRA-positive breast cancer.

As the investigators explain, inhibition of the PARP enzyme in cells expressing the BRCA1/2 mutation causes cell death, owing to accumulation of irreparable DNA damage.

"Several other PARP inhibitors have shown positive results, so I think the concept has been shown to work in some of these patients," Osborne said at the meeting. These include olaparib (Lynparza, AstraZeneca), which was recently approved by the FDA as the first drug specifically indicated for use in BRCA-mutated breast cancer.

However, Osborne cautioned that investigators still need to identify which patients will respond best to PARP inhibitor therapy and to characterize mechanisms of PARP drug resistance, because in some cases, "tumor cells are able to repair the BRCA mutation, and if there is no longer any mutation, the drug is no longer going to work," he said.

Litton noted that studies focusing on which patients will benefit the most from PARP inhibition as well as key mechanisms of resistance are ongoing.

The study was funded by Medivation (Pfizer). Dr Litton has received research funding from EMD Serono, AstraZeneca, Pfizer, Genentech, and GlaxoSmithKline and serves on advisory boards for Pfizer and AstraZeneca. Dr Osborne has financial ties to multiple pharmaceutical companies, including AstraZeneca, Genentech, and Gilead Sciences.

N Engl J Med. Published online August 23, 2018. Abstract

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