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Talazoparib provides significant benefit for germline BRCA-mutated breast cancer
Single-agent talazoparib significantly improved PFS and objective response rates compared with standard chemotherapy among women with advanced breast cancer and a germline BRCA1/BRCA2 mutation, according to results from the global phase 3 EMBRACA trial.
Patient-reported outcomes also appeared superior in the talazoparib (BMN-673, Medivation/Pfizer) treatment arm.
Talazoparib — an oral poly ADP ribose polymerase (PARP) inhibitor — is not yet approved for any indication.
“Talazoparib had been shown to be effective in earlier stage studies and preclinical work showed it was the most potent of the PARP inhibitors, especially with PARP trapping in research models,” Jennifer K. Litton, MD, associate professor in the department of breast medical oncology at The University of Texas MD Anderson Cancer Center, told HemOnc Today.
The open label trial of talazoparib included 431 patients with advanced breast cancer with a germline mutation in BRCA1 and BRCA2 detected by BRACAnalysis (Myriad Genetics) across 145 sites in 16 countries.
Litton and colleagues randomly assigned patients 2:1 to talazoparib 1 mg once daily (n = 287; median age, 45 years) or physician’s choice standard single-agent chemotherapy (n = 144; median age, 50 years) — which included capecitabine (44%), eribulin (40%; Halaven, Eisai), gemcitabine (10%) or vinorelbine (7%) — in continuous 21-day cycles.
All patients previously received no more than three cytotoxic regimens for the treatment of advanced breast cancer.
Efficacy outcomes
As HemOnc Today previously reported, researchers presented results from the EMBRACA trial at the San Antonio Breast Cancer Symposium last year.
Median follow-up was 11.2 months.
Radiologic PFS served as the study’s primary endpoint.
Results showed a median PFS of 8.6 months (95% CI, 7.2-9.3) among patients assigned talazoparib compared with 5.6 months (95% CI, 4.2-6.7) among those treated with standard chemotherapy (HR = 0.54; 95% CI, 0.41-0.71).
Thirty-seven percent of patients assigned talazoparib and 20% assigned standard therapy did not have disease progression or death at 1 year.
Across all clinically relevant subgroups, the risk for disease progression appeared lower among patients treated with talazoparib compared with those who received chemotherapy.
Median OS was 22.3 months (95% CI, 18.1-26.2) in the talazoparib arm compared with 19.5 months (95% CI, 16.3-22.4) in the standard therapy group (HR = 0.76; 95% CI, 0.55-1.06).
The objective response rate also appeared higher among those treated with talazoparib (62.6% vs. 27.2%; OR = 5; 95% CI, 2.9-8.8).
Median time to response was 2.6 months in the talazoparib group compared with 1.7 months in the standard therapy group.
In the analysis of patient-reported outcomes, researchers observed significantly improved profiles from baseline among those treated with talazoparib. Results showed a mean increase in EORTC-QLQ-C30 scores of three points (95% CI, 1.2-4.8) among those treated with talazoparib compared with a mean decline of 5.4 points (95% CI, –8.8 to –2) among those treated with chemotherapy (P < .001).
“Being able to provide a once-daily oral pill for treatment of metastatic breast cancer, including triple-negative cancer, would be novel,” Litton told HemOnc Today. “The study also demonstrated improvement in quality-of-life measures, as well as improved time to clinical deterioration.”
Safety outcomes
Fifty-five percent of patients in the talazoparib group experienced grade 3 to grade 4 hematologic adverse events compared with 38% of the standard therapy group. However, more patients in the standard therapy group had grade 3 nonhematologic adverse events than those in the treatment arm (38% vs. 32%). Most nonhematologic adverse events in the talazoparib group were grade 1.
Adverse events led to treatment discontinuation among 5.9% of those assigned talazoparib compared with 8.7% among those who received chemotherapy.
“In conclusion, talazoparib resulted in a significantly longer PFS than standard-of-care chemotherapy,” the researchers wrote. “Treatment-associated myelotoxicity was managed by dose modifications or delays. Improvements in patient-reported outcomes indicated that talazoparib had a good side effect profile.”
Limitations of the study included the open-label design necessitated by the mix of oral and IV chemotherapy options, as well as that more patients in the standard therapy group withdrew consent before receiving treatment.
“Future studies are looking at intriguing combinations that may expand the efficacy to other cancer patients as well as immuno-oncology combinations that are current enrolling patients,” Litton said. “A neoadjuvant trial is now enrolling for patients with a BRCA mutation and triple-negative breast cancer for single-agent talazoparib based off the pilot study presented at ASCO Annual Meeting in 2018.”
In June, the FDA granted talazoparib priority review designation for the treatment of patients with germline BRCA-mutated HER-2-negative locally advanced or metastatic breast cancer based on the results of this trial. – by Cassie Homer
For more information:
Jennifer K. Litton, MD, can be reached at Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1354, Houston, TX 77030; email: jlitton@mdanderson.org.
Disclosures: Medivation, a Pfizer company, funded this study. Litton reports grant support from AstraZeneca, EMD Serono, Genentech, GlaxoSmithKline, Medivation and Pfizer. Please see the study for all other authors’ relevant financial disclosures.
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Litton JK, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1802905.