“Talazoparib for Advanced Germline BRCA-mutated Breast Cancer”

By J. Litton, H. Rugo, J. Ettl, S. Hurvitz, A. Gonçalves, Kyung-Hun Lee, L. Fehrenbacher, R. Yerushalmi, L. Mina, Miguel Martín and 8 more. New England Journal of Medicine, 2018

1,744 citations recorded by the source corpus.

BACKGROUND The poly(adenosine diphosphate‐ribose) inhibitor talazoparib has shown antitumor activity in patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2 (BRCA1/2). METHODS We conducted a randomized, open‐label, phase 3 trial in which patients with advanced breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive talazoparib (1 mg once daily) or standard single‐agent therapy of the physician's choice (capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21‐day cycles). The primary end point was progression‐free survival, which was assessed by blinded independent central review. RESULTS Of the 431 patients who underwent randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive standard therapy. Median progressionfree survival was significantly longer in the talazoparib group than in the standardtherapy group (8.6 months vs. 5.6 months; hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P<0.001). The interim median hazard ratio for death was 0.76 (95% CI, 0.55 to 1.06; P = 0.11 [57% of projected events]). The objective response rate was higher in the talazoparib group than in the standard‐therapy group (62.6% vs. 27.2%; odds ratio, 5.0; 95% CI, 2.9 to 8.8; P<0.001). Hematologic grade 3‐4 adverse events (primarily anemia) occurred in 55% of the patients who received talazoparib and in 38% of the patients who received standard therapy; nonhematologic grade 3 adverse events occurred in 32% and 38% of the patients, respectively. Patient‐reported outcomes favored talazoparib; significant overall improvements and significant delays in the time to clinically meaningful deterioration according to both the global health status‐quality‐of‐life and breast symptoms scales were observed. CONCLUSIONS Among patients with advanced breast cancer and a germline BRCA1/2 mutation, single‐agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression‐free survival. Patient‐reported outcomes were superior with talazoparib. (Funded by Medivation [Pfizer]; EMBRACA ClinicalTrials.gov number, NCT01945775.)

Subfields: Genetics, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/c4720b49cebd5439aa1855fc0e362a11fc6966fd

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In Genetics

1. J. Reis-Filho
2. C. Lord
3. N. Turner

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1. J. Reis-Filho
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Citations in the corpus

• PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance (2020, background): “Given this, the FDA approved Talazoparib as the second PARPi for the treatment of breast cancer (Litton et al., 2018).”
• Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: A report from the ESMO Precision Medicine Working Group. (2020, background): “Phase III studies reported a significant improvement of PFS with poly ADP ribose polymerase inhibitors (PARPi) in patients with germline BRCA1/2-mutated metastatic breast cancer (mBC).(70,71) It is currently estimated that somatic multigene sequencing cannot substitute germline testing for BRCA1/2 s”
• ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. (2021, background): “47,48 OS was not improved but a post hoc subset analysis of one study suggested improved OS in patients receiving olaparib who had not received prior ChT for metastatic disease.”
• Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study (2019, background): “Only a limited subset of patients with germline BReast CAncer gene (BRCA)-related TNBC benefit from poly (ADP-ribose) polymerase (PARP) inhibitors, the only available targeted therapy [3, 4].”
• A decade of clinical development of PARP inhibitors in perspective (2019, methodology): “This approach was validated in another phase III trial with talazoparib administered continuously compared with the same chemotherapy regimens [37], with a median PFS of 8.”