Abstract P1-19-29: An integrated safety analysis of talazoparib monotherapy from five clinical trials (phase 1-3) in advanced cancers
Authors: Ettl Joannes , Litton Jennifer , Rugo Hope S. , Mina Lida , Martin Miguel , Turner Nicholas , Roché Henri , Wainberg Zev , de Bono Johann , Usari Tiziana , Elmeliegy Mohamed , Lanzalone Silvana , Czibere Akos , DeAnnuntis Liza , Hurvitz Sara A. 
Published: March 2020

Abstract
Background: Talazoparib is a potent oral inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2, which significantly improved progression-free survival versus standard-of-care chemotherapy in patients with HER2-negative advanced breast cancer (ABC; locally advanced/metastatic breast cancer) and a germline BRCA1/2 mutation (gBRCA1/2mut) in the Phase 3 EMBRACA trial (Litton J, et al. N Engl J Med. 2018;379:753-763). An integrated analysis of five clinical trials (Phase 1-3) in multiple tumor types was performed to evaluate the safety of talazoparib administered at 1 mg/day (d). Methods: Data were pooled from the ongoing Phase 3 randomized EMBRACA trial in HER2-negative gBRCA1/2mut ABC (NCT01945775), the Phase 2 non-randomized ABRAZO trial in gBRCA1/2mut ABC (NCT02034916), the Phase 1 trial in advanced/recurrent solid tumors (NCT01286987), the Phase 1 cardiac repolarization trial in advanced solid tumors (NCT03042910), and an ongoing open-label extension trial (NCT02921919). Results: 494 patients who received talazoparib 1 mg/d were included (Table). The most common all-grade adverse drug reactions (≥20%) with talazoparib were ANEMIA (includes preferred terms: anemia, decreased hemoglobin, decreased hematocrit; 49.6%), fatigue (47.6%), nausea (44.3%), NEUTROPENIA (neutropenia, decreased neutrophil count; 30.2%), THROMBOCYTOPENIA (thrombocytopenia, decreased platelet count; 29.6%), headache (26.5%), diarrhea (22.7%), alopecia (22.3%; Grade 1, 20.6%; Grade 2, 1.6%), vomiting (22.3%), and decreased appetite (20.2%). Grade 3/4 toxicities (≥10%) with talazoparib were ANEMIA (35.2%), NEUTROPENIA (17.4%), and THROMBOCYTOPENIA (16.8%). Overall 24 patients (4.9%) died within 30 days after the last dose of study drug; the most common cause of death was disease progression (13 patients; 2.6%). Other causes of death were reported in 1 patient each (cerebral hemorrhage, dyspnea, lung infection, lung metastases, respiratory failure, suspected veno-occlusive liver disease, and worsening of neurological symptoms); cause of death was not reported for 4 patients. The most common treatment-related serious adverse event was anemia (4.3%). Median duration of talazoparib exposure was 5.4 months (range, 0.0-61.1). Median relative dose intensity (defined as actual-dose intensity/planned-dose intensity) was 92.8%. Dosing interruptions due to TEAEs were reported for 48.6% of patients receiving talazoparib; median duration of dosing interruption due to TEAEs was 8.0 days (range, 1.0-121.0). Hematologic TEAEs (≥5%) associated with dose modification (interruption or reduction) included anemia (33.0%), neutropenia (15.8%), thrombocytopenia (13.4%), and decreased platelet count (5.9%); non-hematologic TEAEs (≥2%) associated with dose modification included fatigue (4.3%), vomiting (2.6%), and nausea (2.0%). Only 18 patients (3.6%) permanently discontinued due to a TEAE (anemia, 3 patients [0.6%]; other events, 1 patient each [0.2%]). Conclusions: Talazoparib monotherapy at 1 mg/d was generally well tolerated with few patients permanently discontinuing talazoparib due to AEs. Common toxicities were primarily hematologic and were manageable through dosing modifications and/or standard supportive care. Funding: Pfizer Inc.
Table Summary of TEAEsPhase 3 EMBRACA trialOpen-label trialsTalazoparibTalazoparib mg/dTalazoparib 1 mg/d1 mg/d populationbTalazoparibPCTABRAZONCT01286987NCT03042910OLEaTotalN=286N=126N=83N=77N=37N=46N=494Any TEAE282 (98.6)123 (97.6)81 (97.6)75 (97.4)28 (75.7)39 (84.8)484 (98.0)Grade 3 or 4 TEAE193 (67.5)80 (63.5)54 (65.1)52 (67.5)9 (24.3)21 (45.7)326 (66.0)Treatment-related Grade 3 or 4 TEAE159 (55.6)61 (48.4)48 (57.8)36 (46.8)3 (8.1)14 (30.4)260 (52.6)SAE91 (31.8)37 (29.4)23 (27.7)27 (35.1)3 (8.1)14 (30.4)156 (31.6)Treatment-related SAE26 (9.1)11 (8.7)11 (13.3)3 (3.9)1 (2.7)1 (2.2)42 (8.5)TEAE primary reason for permanent discontinuation13 (4.5)7 (5.6)3 (3.6)002 (4.3)18 (3.6)TEAE associated with dose modification190 (66.4)75 (59.5)55 (66.3)46 (59.7)4 (10.8)15 (32.6)308 (62.3)All data are number (%) of patients; d, day; OLE, open-label extension; PCT, physician’s choice of chemotherapy; SAE, serious adverse event; TEAE, treatment-emergent adverse event;aInitiated treatment with talazoparib; monotherapy (1 mg/d) in either the originating or the extension trial;b35 patients who initiated talazoparib 1 mg/d in two of the trials and continued in the OLE are counted only once in the total number of patients
Citation Format: Joannes Ettl, Jennifer Litton, Hope S. Rugo, Lida Mina, Miguel Martin, Nicholas Turner, Henri Roché, Zev Wainberg, Johann de Bono, Tiziana Usari, Mohamed Elmeliegy, Silvana Lanzalone, Akos Czibere, Liza DeAnnuntis, Sara A. Hurvitz. An integrated safety analysis of talazoparib monotherapy from five clinical trials (phase 1-3) in advanced cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-29.