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In EMBRACA, talazoparib prolonged progression-free survival versus chemotherapy (hazard ratio [HR] 0.542 [95% confidence interval (CI) 0.413-0.711]; P < 0.0001) and improved patient-reported outcomes (PRO) in germline BRCA1/2 (g BRCA1/2)-mutated advanced breast cancer (ABC). We report final overall survival (OS). This randomized phase III trial enrolled patients with g BRCA1/2 -mutated HER2-negative ABC. Patients received talazoparib or physician's choice of chemotherapy. OS was analyzed using stratified HR and log-rank test and prespecified rank-preserving structural failure time model to account for subsequent treatments. A total of 431 patients were entered in a randomized study (287 talazoparib/144 chemotherapy) with 412 patients treated (286 talazoparib/126 chemotherapy). By 30 September 2019, 216 deaths (75.3%) occurred for talazoparib and 108 (75.0%) chemotherapy; median follow-up was 44.9 and 36.8 months, respectively. HR for OS with talazoparib versus chemotherapy was 0.848 (95% CI 0.670-1.073; P = 0.17); median (95% CI) 19.3 months (16.6-22.5 months) versus 19.5 months (17.4-22.4 months). Kaplan–Meier survival percentages (95% CI) for talazoparib versus chemotherapy: month 12, 71% (66% to 76%)/74% (66% to 81%); month 24, 42% (36% to 47%)/38% (30% to 47%); month 36, 27% (22% to 33%)/21% (14% to 29%). Most patients received subsequent treatments: for talazoparib and chemotherapy, 46.3%/41.7% received platinum and 4.5%/32.6% received a poly(ADP-ribose) polymerase (PARP) inhibitor, respectively. Adjusting for subsequent PARP and/or platinum use, HR for OS was 0.756 (95% bootstrap CI 0.503-1.029). Grade 3-4 adverse events occurred in 69.6% (talazoparib) and 64.3% (chemotherapy) patients, consistent with previous reports. Extended follow-up showed significant overall improvement and delay in time to definitive clinically meaningful deterioration in global health status/quality of life and breast symptoms favoring talazoparib versus chemotherapy (P < 0.01 for all), consistent with initial analyses. In g BRCA1/2 -mutated HER2-negative ABC, talazoparib did not significantly improve OS over chemotherapy; subsequent treatments may have impacted analysis. Safety was consistent with previous observations. PRO continued to favor talazoparib. • In BRCA1/2 -mutated advanced breast cancer, talazoparib did not significantly improve overall survival (OS) versus chemotherapy. • OS was generally consistent across subgroups including by prior platinum, hormone-receptor status, or line of treatment. • Most patients received subsequent systemic treatments, which may have confounded the survival outcome. • Toxicities were managed by supportive care medication/dose modifications; safety was consistent with previous observations. • Extended follow-up of patient-reported outcomes continued to favor talazoparib over chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract Background Talazoparib (1 mg/day) exhibited promising efficacy and safety in patients with advanced breast cancer during ABRAZO (NCT02034916); this study evaluated patient-reported outcomes (PROs). Patients and methods ABRAZO is a two-cohort, two-stage, phase 2 study of talazoparib in patients with advanced breast cancer after a response to prior platinum-based therapy (cohort 1 [C1], n = 49) or ≥3 platinum-free cytotoxic-based regimens (cohort 2 [C2], n = 35). PROs were assessed on day 1 (baseline), every 6 weeks for an initial 24 weeks, and every 12 weeks thereafter until progression, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and its breast cancer module, QLQ-BR23. Results Global health status/quality of life (GHS/QoL) was maintained from baseline across all time points for both C1 and C2. For C1 and C2, median time to deterioration (TTD) of GHS/QoL (95% confidence interval [CI]) was 2.8 (2.1, 3.0) and 5.5 (4.2, 5.7) months, respectively. Median TTD for all QLQ-C30 functional scales for C1 and C2 ranged 2.1–3.1 months and 4.2–5.6 months, respectively; median TTD for all QLQ-BR23 symptom scales ranged 2.6–4.0 months and 4.2–5.6 months, respectively. There were no statistically significant differences in estimated overall change from baseline in the GHS/QoL scale for both cohorts (C1: −2.6 [95% CI, −7.8, 2.5]; C2: 1.2 [95% CI, −5.5, 8.0]). Significant overall improvements in the breast symptoms and arm symptoms and the future perspective of patients in C1 and C2 were observed, despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2). Conclusion Despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2), patients in both C1 and C2 reported significant overall improvements in their breast symptoms, arm symptoms and future perspective, and their GHS/QoL was maintained from baseline. Highlights • ABRAZO is a two-cohort, two-stage, phase 2 study of talazoparib in advanced breast cancer/germline BRCA mutation. • Patient-reported global health status/quality of life (GHS/QoL) was maintained from baseline among talazoparib patients. • These findings are the first-ever detailed patient-reported outcomes for talazoparib in advanced breast cancer patients. • The encouraging efficacy achieved with talazoparib is accompanied by maintaining patient-reported GHS/QoL. [ABSTRACT FROM AUTHOR]

Objectives Cyclin D–cyclin-dependent kinase (CDK) 4/6–inhibitor of CDK4/6–retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting. Materials and methods Postmenopausal women ( N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2–) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling. Results Mean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38–100%; n = 2), Arm 2 96% (range 78–100%; n = 6), Arm 3 92% (range 75–100%; n = 3). Decreased phosphorylated Rb levels and CDK4 , CDK6 , CCND2 , CCND3 , and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment. Conclusion The results suggest absence of a drug–drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2– BC (NCT01919229). [ABSTRACT FROM AUTHOR]

CHEMOTHERAPY (CT) SUBGROUPS A significant estimated overall change from baseline in pain symptoms favored TALA vs PCT for both subgroups with (P<0.001) and without (P =0.01) prior CT. A significant delay in TTD favoring TALA was observed in pain symptoms for both subgroups with (P<0.001) and without (P=0.002) prior CT. [Extracted from the article]