Safety data from the phase III EMBRACA trial were recently published. Talazoparib appears to be safe with manageable toxicities in patients with germline BRCA-mutated HER2-negative advanced breast cancer.
The PARP inhibitor talazoparib (Talzenna) was generally well-tolerated in patients with germline BRCA-mutated HER2-negative advanced breast cancer in the phase III EMBRACA trial. Toxicities associated with talazoparib were manageable with necessary dose modifications and supportive care. Toxicities were most commonly hematologic and only rarely resulted in permanent drug discontinuation, according to the results of a new safety analysis published recently in The Oncologist.1
Overall, 431 patients were included in the safety population and received either talazoparib (n = 236) or physician's choice of chemotherapy (n = 126; PCT). The median treatment-emergent (TE) period, defined as the time from the first study drug dose through 30 days after the last study drug dose or the day before antineplastic therapy, was 7.0 months (range, 0.8-36.9 months) for talazoparib and 4.5 months (range, 0.5-18.3 months) for PCT.
Laboratory data showed that patients who received PCT had a higher probability of lower neutrophil counts. Patients who received talazoparib were more likely to have lower hemoglobin and platelets counts. The median time to recovery for patients with low hemoglobin was 8 days (range 2-47 days) with talazoparib and 8 days (7-115 days) with PCT. The median time to recovery from low neutrophils was 9 days (range, 1-32 days) in the talazoparib group and 9 days (range, 2-57 days) in the PCT group. For platelet counts, the median time to recovery was 9 days (range, 5-21 days) with talazoparib and not available for the PCT group.
Hematologic adverse events (AEs) occurred in about two-thirds of patients in the talazoparib group (n = 195, 68.2%) and typically occurred within the first 3–4 months of starting treatment with talazoparib. Grade 3-4 anemia lasted approximately 7 days in both the talazoparib and chemotherapy arms.
Less than 2% of talazaporib patients discontinued treatment permanently due to hematologic AEs. Few patients experienced overlapping grade 3-4 hematologic AEs with talazoparib, although higher talazoparib exposure was associated with grade ≥3 anemia. Approximately half of patients (n = 150, 52.4%) who received talazoparib developed AEs that led to dose reduction.
Hematologic toxicities were managed by supportive care medication (including transfusion) and dose modifications. Patient-reported outcomes favored talazporib among patients who had anemia, nausea and/or vomiting. Talazoparib was generally associated with a lower rate of hospitalization and the use of supportive care medication compared with chemotherapy after accounting for the treatment-emergent period.
The most common (≥20%) AEs of any grade reported for talazoparib included fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, and decreased appetite.
“Positive PROs [patient-reported outcomes] of talazoparib-treated patients with reported anemia or nausea and vomiting AE suggests that these AEs are manageable and that patients’ QoL [quality of life] improved versus PCT [physician’s choice therapy]-treated patients,” wrote the authors, led by Sara A. Hurvitz, MD, of the University of California, Los Angeles. “Altogether, the findings of this study support the incorporation of talazoparib in clinical practice as a favorable treatment option for patients with locally advanced or metastatic breast cancer with gBRCA mutation.”
EMBRACA (ClinicalTrials.gov identifier: NCT01945775) is an ongoing open-label, randomized, international, study that compares the efficacy, patient-reported outcomes, and safety of oral talazoparib to physician’s choice chemotherapy consisting of either capecitabine, eribulin, gemcitabine, or vinorelbine. Efficacy results for EMBRACA were originally published in The New England Journal of Medicine in August 2018.2
In October 2018, the FDA approved talazoparib for patients with deleterious or suspected deleterious germline BRCA-mutated HER2‑negative locally advanced or metastatic breast cancer on the strength of EMBRACA’s results.
EMBRACA’s hematologic inclusion criteria were hemoglobin ≥9.0 g/dL with last the transfusion ≥14 days before randomization, neutrophils ≥1500 × 106/L, and platelets ≥100 × 109/L. During the study, the authors amended talazoparib dosing guidance for managing AEs, primarily affecting the management of grade ≥3 hematologic toxicities. Study treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or per the discretion of investigator.1
The primary endpoint was radiographic progression-free survival (PFS) by blinded independent central review. Secondary and exploratory endpoints included safety, overall survival, objective response rate, duration of response, clinical benefit rate, patient-reported outcomes, and pharmacokinetics.
With talazoparib, the most common hematologic AEs were anemia (any grade 52.8%), neutropenia (any grade 34.6%), and thrombocytopenia (any grade 26.9%). The chemotherapy group had higher rates of neutropenia (any grade 42.9%) and lower rates of anemia (any grade 18.3%) and thrombocytopenia (any grade 7.1%).
All hematologic AEs declined over time. The cumulative risk of any grade anemia increased more steeply than that of neutropenia and thrombocytopenia with talazoparib treatment. The authors reported that all three generally plateaued by week 25. The onset of hematologic toxicities mostly occurred within the first 16 weeks of talazoparib.
Hurvitz et al reported that all-grade anemia and thrombocytopenia had a slightly shorter median duration with talazoparib. Anemia lasted 21 days in the talazoparib group compared with 29 days in the chemotherapy group. For thrombocytopenia, the comparison was 15 days in the talazoparib group compared with 24 days in the chemotherapy group. Grade 3-4 thrombocytopenia was 8 days for talazoparib versus 18 days in the chemotherapy group.
The investigators observed a similar incidence of serious AEs with both treatments. Slightly less than one-third of patients in each group experienced serious AEs: 91 patients (31.8%) in the talazoparib group and 37 patients (29.4%) in the chemotherapy group. The incidence of study drug-related serious AEs was slightly higher in the talazoparib group: 26 patients (9.1%) versus 11 patients (8.7%) in the chemotherapy group. Anemia was the most frequently reported drug-related serious AE in the talazoparib group (n = 15, 5.2%), while neutropenia was the most frequently reported drug-related serious AE in the chemotherapy group (n = 4, 3.2%).
A total of 10 patients experienced fatal AEs, 6 patients (2.1%) in the talazoparib group and 4 patients (3.2%) in the chemotherapy group. Of these, the investigators considered 1 case of veno-occlusive liver disease (talazoparib) and 1 case of sepsis (chemotherapy) to be study-related. “However, the sponsor considered veno-occlusive liver disease an unlikely etiology, a consideration supported by two hepatologist consultants to the sponsor who reviewed the case,” wrote Hurvitz et al.
1. Hurvitz SA, Gonçalves AA, Rugo HS, et al. Talazoparib in Patients with a Germline BRCA-Mutated Advanced Breast Cancer: Detailed Safety Analyses from the Phase III EMBRACA Trial. Oncologist. 2020;25:e439–e450. Published online November 25, 2019. http://dx.doi.org/10.1634/theoncologist.2019-0493
2. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018; 379:753-763. DOI: 10.1056/NEJMoa1802905 https://www.nejm.org/doi/full/10.1056/NEJMoa1802905