EMBRACA Trial Research Articles

Characteristics, Treatment, and Outcomes of Real-World Talazoparib-Treated Patients With Germline BRCA-Mutated Advanced HER2-Negative Breast Cancer.

Talazoparib is a poly (adenosine diphosphate-ribose) polymerase inhibitor approved for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative, locally advanced or metastatic breast cancer (LA/mBC), with approval based on the EMBRACA trial. To date, there are no published data on talazoparib use in the real-world United States (USA) setting. Characteristics, treatment patterns, and clinical outcomes of real-world US patients with gBRCAm HER2-negative LA/mBC treated with talazoparib monotherapy were collected via retrospective chart review and summarized using descriptive statistics. Among 84 eligible patients, 35.7% had hormone receptor-positive tumors and 64.3% had triple-negative LA/mBC (TNBC). At talazoparib initiation, 29.8% had ECOG PS of ≥2 and 19.0% had brain metastasis. Mutations in gBRCA1 or 2 were detected among 64.3% and 35.7% of patients, respectively. Talazoparib was given as 1st-line therapy in 14.3% of patients, 2nd-line in 40.5%, and 3rd- or 4th-line in 45.2%. Median time to talazoparib treatment failure was 8.5 months (95% CI, 8.0-9.7), median progression-free survival was 8.7 months (95% CI, 8.0-9.9), the median time from initiation to chemotherapy was 12.2 months (95% CI, 10.5-20.1), and the overall response rate was 63.1%. No differences in clinical outcomes were observed between patients with HR-positive/HER2-negative LA/mBC and patients with TNBC by using unadjusted statistical comparisons. Brain metastasis and ECOG PS ≥2 at talazoparib initiation were associated with treatment failure and progression or mortality. Overall, talazoparib clinical outcomes in this real-world population are consistent with findings from EMBRACA.

Abstract P1-18-28: Phase IV study evaluating effectiveness and safety of talazoparib in patients with locally advanced or metastatic HER2 negative breast cancer and a BRCA1 or BRCA2 mutation (ViTAL)

Abstract Background: Talazoparib (TALA) is a highly potent PARP inhibitor that has demonstrated clinical benefit in the phase III EMBRACA trial for patients with germline BRCA1 or BRCA2-mutation and a locally advanced or metastatic HER2 negative (HER2-) breast cancer (BC). Methods: ViTAL is an ambispective, multi-center longitudinal, phase IV study that aims to ensure the effectiveness and safety of TALA in the real-world setting among patients with locally advanced or metastatic HER2- BC, with somatic or germline BRCA mutation (sBRCA or gBRCA). This study includes two cohorts: - Cohort 1: patients treated through the French Early Access Program from November 2018 to September 2019. Inclusion of patients with sBRCA mutation was allowed. - Cohort 2: patients treated according to the European Marketing Approval granted 21/09/2021. The primary endpoint is Time to Treatment Discontinuation (TTD) for TALA defined as Time between the date of first dose of TALA and the date of last dose or death. Results: We present the results of Cohort 1 in which includes 85 patients. Patients’ characteristics are as follows: median age 50 years; 46% triple negative BC and 54% ER+ BC; 47% BRCA1-mutated and 53% BRCA2-mutated; 94% gBRCA and 6% sBRCA; 95% ECOG PS 0 or 1; 31% premenopausal status; 40% de novo metastatic BC (mBC). Visceral, bones and central nervous system metastases were found in 61%, 54% and 11% of patients, respectively. No breast or ovarian cancer in first degree relative was found in 35 patients (41%). The median number of prior cytotoxic regimen was 2, 15% were chemo-naïve for mBC; 35% received prior platinum in the neoadjuvant, adjuvant or metastatic setting. For patients with ER+/HER2- mBC the median number of prior endocrine therapy was 2 and 74% of these patients received a CDK4/6 inhibitor prior to TALA. The median follow-up was 17.4 months [range 15.7-20.5]. Of 85 treated patients, 66 patients (78%) experienced permanent discontinuation of TALA due to progressive disease (88%), toxicity (8%), cancer-related death (3%), or other reasons (1.5%). The median TTD for TALA was 9.0 months [range 6.0-11.0] with 35% of patients still in under treatment at 12 months. At least one adverse event (AEs) was recorded in 71% of patients. Hematologic AEs (any grade) occurred in 44% of patients (anemia for 26%, thrombocytopenia for 9%, neutropenia for 8%). The most common non-hematologic AEs were alopecia (6%) and asthenia (5%). Related serious hematologic AEs occurred in 7 (8%) patients including 6 (7%) with anemia. Related serious non-hematologic AEs (vomiting, pyelonephritis) were seen in 2 patients (2%). AEs associated with temporary drug interruption, dose modification and permanent drug discontinuation occurred in 32 (38%), 16 (19%), and 5 (8%) patients respectively. After discontinuation of TALA, 83% of patients received a subsequent treatment with a TTD of 2.4 months [range 1.7-3.3]. The most common subsequent treatments were non-platinum chemotherapy (64%) and platinum therapy (24%). Conclusions: The TTD of 9 months is consistent with the outcomes and safety results of the EMBRACA study. ViTAL, the first real-word study with TALA confirms its interest in locally advanced or metastatic HER2- BC. Analysis of Cohort 2 will occur when data are mature. (Ref Litton JK, Rugo HR, Ellt J et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018; 379:753-763. Citation Format: Delphine Loirat, Marie Duboys de Labarre, Christine Essner, Ioana Hrab, Jean-Christophe Thery, Christelle Jouannaud, Cristian Villanueva, Perrine Vuagnat, Pauline Soibinet-Oudot, Anne Creisson, Audrey Mailliez, Jean-Loup Mouysset, Laura Salabert, Nadine Dohollou, Jean-David Fumet, Thibault De La Motte Rouge, Jean-Michel Vauthier, Maylis Decrop, Pascal Pujol. Phase IV study evaluating effectiveness and safety of talazoparib in patients with locally advanced or metastatic HER2 negative breast cancer and a BRCA1 or BRCA2 mutation (ViTAL) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-28.

Determinants of Response to Talazoparib in Patients with HER2-Negative, Germline BRCA1/2-Mutated Breast Cancer.

PARP inhibitors (PARPi) have demonstrated efficacy in tumors with germline breast cancer susceptibility genes (gBRCA) 1 and 2 mutations, but further factors influencing response to PARPi are poorly understood. Breast cancer tumor tissue from patients with gBRCA1/2 mutations from the phase III EMBRACA trial of the PARPi talazoparib versus chemotherapy was sequenced using FoundationOne CDx. In the evaluable intent-to-treat population, 96.1% (296/308) had ≥1 tumor BRCA (tBRCA) mutation and there was strong concordance (95.3%) between tBRCA and gBRCA mutational status. Genetic/genomic characteristics including BRCA loss of heterozygosity (LOH; identified in 82.6% of evaluable patients), DNA damage response (DDR) gene mutational burden, and tumor homologous recombination deficiency [assessed by genomic LOH (gLOH)] demonstrated no association with talazoparib efficacy. Overall, BRCA LOH status, DDR gene mutational burden, and gLOH were not associated with talazoparib efficacy; however, these conclusions are qualified by population heterogeneity and low patient numbers in some subgroups. Further investigation in larger patient populations is warranted.

272P Outcomes of patients (pts) who had received prior platinum (PP) therapy in the phase III EMBRACA trial of talazoparib (TALA) vs physician’s choice of chemotherapy (PCT) in patients with germline BRCA1/2 mutated (gBRCA1/2mut) advanced breast cancer (ABC)

TALA is a poly (ADP-ribose) polymerase inhibitor approved in the US, EU, and other countries for the treatment of deleterious/suspected deleterious gBRCA1/2mut HER2-negative ABC. While TALA treatment in the phase 3 EMBRACA trial (NCT01945775) benefited pts regardless of PP, greater improvements in clinical outcomes for TALA vs PCT (capecitabine, eribulin, gemcitabine, or vinorelbine) were seen for pts not treated with PP (PFS hazard ratio [95% CI] 0.76 [0.40–1.45], P = 0.41 for PP vs 0.52 [0.39–0.71], P < 0.0001 for no-PP subgroups).

269P Patient-reported outcomes (PRO) with talazoparib (TALA) vs physician’s choice chemotherapy (PCT) in patients (pts) with HER2- advanced breast cancer (ABC) and a germline BRCA1/2 mutation (gBRCAm): Subgroup analysis of pts with and without TALA dose reductions vs PCT in the EMBRACA trial

In EMBRACA, TALA vs PCT demonstrated significant improvement in progression-free survival, a manageable adverse event (AE) profile, and quality of life (QoL) improvement. AEs were managed with supportive care and dose modifications. This post hoc analysis evaluated PROs in TALA pts without/with dose reductions vs PCT.

273P Talazoparib (TALA) for patients with germline BRCA1/2 mutated (gBRCA1/2mut) advanced breast cancer (ABC): Characteristics of patients who experienced hematologic toxicity in the phase III EMBRACA trial

In the EMBRACA trial (NCT01945775), TALA significantly improved progression-free survival (HR=0.54; 95% CI: 0.41–0.71; P < 0.001) and quality of life vs physician’s choice of chemotherapy (PCT) while having a manageable safety profile. The most common adverse events (AEs) with TALA were hematologic (68%) but few resulted in permanent discontinuation (<2%). After accounting for the treatment-emergent periods to normalize for longer exposure due to increased efficacy, the serious AE-associated hospitalization rate was lower for TALA vs PCT.

Development of the PARP inhibitor talazoparib for the treatment of advanced BRCA1 and BRCA2 mutated breast cancer

ABSTRACT Introduction BRCA1 and BRCA2 (BRCA1/2) mutation breast cancers constitute an uncommon, but unique group of breast cancers that present at a younger age, and are underscored by genomic instability and accumulation of DNA damage. Talazoparib is a potent poly(ADP-ribose) polymerase (PARP) inhibitor that exploits impaired DNA damage response mechanisms in this population of patients and results in significant efficacy. Based on the results of the EMBRACA trial, talazoparib was approved for the treatment of patients with advanced germline BRCA1/2 mutant breast cancer. Areas covered In this review, the authors highlight the relevant clinical trials of talazoparib, as well as, safety, tolerability, and quality of life considerations. They also examine putative response and resistance mechanisms, and rational combinatorial therapeutic strategies under development. Expert opinion Talazoparib has been a major advance in the treatment of germline BRCA1/2 mutation breast cancer with both clinical efficacy and improvement in quality of life compared to standard cytotoxic chemotherapy. To date, the optimal sequencing of talazoparib administration in the metastatic setting has not yet been established. A deeper understanding of response and resistance mechanisms, and more broadly, the DNA repair pathway, will lead to additional opportunities in targeting this pathway and open up therapeutic indications to a broader patient population.

Clinical outcomes in patients (pts) with a history of central nervous system (CNS) metastases receiving talazoparib (TALA) or physician’s choice of chemotherapy (PCT) in the phase 3 EMBRACA trial.

1090 Background: In the EMBRACA trial (NCT01945775) of pts with germline BRCA1/2-mutated HER2-negative locally advanced/metastatic breast cancer (ABC), the poly(ADP-ribose) polymerase (PARP) inhibitor TALA significantly improved progression-free survival (PFS) vs PCT (8.6 vs 5.6 mo; HR [95% CI] 0.54 [0.41-0.71]; P &lt; 0.0001). Patient-reported outcomes favored TALA, and most common adverse events included anemia, fatigue, and nausea. Previous subgroup analyses found that pts with a history of CNS metastases had improved PFS for TALA vs PCT (HR [95% CI] 0.32 [0.15-0.68]; P = 0.0016) and improved objective response rate (ORR) 63.2% vs 15.8%, respectively (odds ratio [95% CI] 8.95 [1.86-52.26]; P = 0.0013). This retrospective subgroup analysis further explored the clinical characteristics and outcomes in pts with a history of CNS metastases in EMBRACA. Methods: Pts were randomized 2:1 to TALA or PCT. Pts with adequately treated and stable CNS metastases not requiring corticosteroids were included. This analysis assessed intracranial ORR and best overall response (BOR) based on investigator assessment per RECIST 1.1 in pts with intracranial disease at baseline (data cutoff 15-Sep-17), and overall survival (OS; data cutoff 30-Sep-19). Results: In the intent-to-treat (ITT) population, 63 pts (43/287 [15.0%] TALA and 20/144 [13.9%] PCT) had a history of CNS metastases, of which 33 (11.5%) pts (TALA) and 15 (10.4%) pts (PCT) had intracranial disease at baseline. Additional baseline characteristics are shown in the table. Intracranial ORR in pts with intracranial disease at baseline and unconfirmed complete or partial response was 18.2% (TALA) vs 20.0% (PCT) (odds ratio [95% CI] 0.78 [0.13-5.80]; P = 0.765). In pts with intracranial disease at baseline, an intracranial BOR of stable disease was 69.7% for TALA vs 33.3% for PCT. Median OS in pts with a history of CNS metastases was 12.9 mo (95% CI 9.4-15.6) for TALA and 13.4 mo (95% CI 8.8-17.6) for PCT (HR [95% CI] 0.67 [0.37-1.2]; P = 0.1936 [stratified log-rank test]). In the safety population ([n = 43, TALA]; [n = 19, PCT]), median treatment duration (range) with TALA was 5.0 (0.1-36.0) mo compared with 2.1 (0.4-6.9) mo for PCT. Conclusions: In this subgroup analysis, baseline characteristics between pts with a history of CNS metastases treated with TALA or PCT were comparable. More pts with intracranial disease at baseline treated with TALA vs PCT experienced stable disease. Intracranial ORR in pts with intracranial disease was 18.2% for TALA vs 20.0% for PCT. Treatment options for pts with a history of CNS metastases are limited and further investigation in larger data sets is warranted. Clinical trial information: NCT01945775 .[Table: see text]

Characterization of long-term responders following treatment with talazoparib (TALA) or physician’s choice of chemotherapy (PCT) in the phase 3 embraca trial.

1029 Background: In the EMBRACA trial (NCT01945775), the poly(ADP-ribose) polymerase inhibitor (PARPi) TALA significantly improved progression-free survival (PFS) versus PCT in patients (pts) with germline BRCA1/2-mutated HER2-negative locally advanced/metastatic breast cancer (BC) (8.6 vs 5.6 months [mo]; hazard ratio [HR, 95% CI] 0.54 [0.41-0.71]; P &lt; 0.0001). Predictive markers for response to PARPi, other than germline BRCA1/2 mutational status, are largely unknown. A previous analysis investigated biomarkers associated with long and short responders in EMBRACA. Here, we report the clinical characteristics of long and short responders. Methods: Pts were randomized 2:1 to TALA or PCT. In this retrospective analysis, pts in the intent-to-treat (ITT) population were mapped into two groups based on response: LONG (pts in TALA arm with overall survival [OS] ≥30 mo and duration of treatment ≥24 mo; pts in PCT arm with OS ≥30 mo); SHORT (pts in either arm with a PFS event [progressive disease by Independent Radiological Facility or death] ≤12 wks). Data cutoff date was Sept 30, 2019. Results: Of 431 pts randomized, 412 pts were treated (286 received TALA; 126 received PCT). In the ITT population, 37 pts receiving TALA and 34 pts receiving PCT were identified as LONG responders; 40 pts receiving TALA and 32 pts receiving PCT were SHORT responders. The Table shows a summary of pt characteristics for LONG and SHORT responders. More pts with HR+ BC and no prior CT for ABC were associated with LONG response; more pts with TNBC and ≥2 prior CT regimens or platinum were associated with SHORT response (Table). Median treatment duration for LONG responders (n = 37, TALA; n = 31, PCT) was 33.5 (24.0-61.4) mo for TALA and 7.6 (1.1-36.3) mo for PCT; 51.4% receiving TALA and 91.2% receiving PCT had subsequent therapy. In SHORT responders, median treatment duration was 2.0 (0.1-5.5) mo (TALA) and 1.4 (0.2-5.6) mo (PCT); 67.5% and 68.8% received subsequent therapy following TALA or PCT, respectively. Conclusions: In this clinical characterization of responders from the EMBRACA study, a higher number of LONG responders had HR+ BC and received no prior CT for ABC. A greater proportion of SHORT responders had TNBC and received ≥2 prior CT regimens or platinum. Further investigation is warranted in a larger number of pts. Clinical trial information: NCT01945775 .[Table: see text]

Abstract SP085: Metastatic TNBC - What’s new on the horizon?

Abstract Until very recently, the treatment for locally advanced or metastatic breast cancer revolved solely around sequential chemotherapies, alone or in combination. With the increasing recognition that triple negative breast cancers are a very heterogeneous group of tumors, exciting new strategies have emerged. Here we review some of the recent advances to standard chemotherapy now in clinical use as well discuss new strategies in development. Immunotherapy: There is currently an indication for nab-paclitaxel and atezolizumab for patients with locally advanced or metastatic triple negative breast cancer with PD-L1 positive tumor-infiltrating immune cells. The Impassion130 study first presented a median PFS of 7.2 months with nab-paclitaxel and atezolizumab vs. 5.5 months of nab-paclitaxel and placebo (HR 0.80; 95% confidence interval (CI) 0.69-0.92). Further analyses showed no benefit in the PD-L1 negative group.1 An exploratory overall survival analysis in the PD-L1+ subset showed an increase in the atezolizumab group of 25 months vs 18 in the control group.2 Immunotherapy for metastatic breast cancer will be presented in greater detail in another talk in this session. Sacituzumab govitecan: Sacituzumab govitecan is an antibody-drug conjugate (ADC) targeting Trop-2 and linked with SN-38, the active metabolite of irinotecan and a potent DNA- damaging agent. Trop-2 has been estimated to be expressed in up to 90% of TNBC, making it an attractive target for an ADC. Sacituzumab govitecan was conditionally approved for use after the Phase I/II trial demonstrated and objective response rate of 33.3% and a median overall survival of 13.0 months.3 The recently presented phase III ASCENT trial evaluated patients with metastatic TNBC who had at least 2 previous lines of therapy in the metastatic setting. There was an improvement in median PFS from 1.7 to 5.6 months for patients who received sacituzumab vs. physician’s choice of therapy. The HR for PFS was 0.41; 95% CI: 0.32-0.52) Additionally, there was an improvement in median OS of 6.7 to 12.1 months (HR 0.48; 95%CI:0.38-0.59).4PARP Inhibitors: There are now 2 PARP inhibitors that have FDA approval for use for patients with metastatic breast cancer and a germline BRCA pathogenic variant.5,6 Both Olaparib and Talazoparib demonstrated improvements in PFS which led to FDA approval. While neither the OlympiAD (olaparib) nor the EMBRACA (talazoparib) trial showed statistically significant improvement in OS, both trials showed a significant improvement in quality of life measures. Future Directions: Ongoing trials evaluating further ADCs, targeted therapies and drugs targeting DNA Damage Repair pathways for both germline and somatic pathogenic variants will be discussed 1.Schmid P, Adams S, Rugo HS, et al: Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. NEJM 379:2108-2121, 20182.Schmid P, Rugo HS, Adams S, et al: Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer The Lancet Oncology 21:44-59, 20203.Bardia A, Mayer IA, Diamond JR, et al: Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer. J Clin Oncol 35:2141-2148, 20174.Bardia A, Tolaney S, Loirat D, et al: ASCENT: A randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Annals of Oncology 31:S1142-S1215. 10.1016/annonc/annonc325, 20205.Robson M, Im S-A, Senkus E, et al: Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. NEJM 377:523-533, 20176.Litton JK, Rugo HS, Ettl J, et al: Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. NEJM 379:753-763, 2018 Citation Format: J Litton. Metastatic TNBC - What’s new on the horizon? [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP085.

Abstract CT071: Talazoparib (TALA) in germline BRCA1/2 (gBRCA1/2)-mutated human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC): Final overall survival (OS) results from randomized Phase 3 EMBRACA trial

Abstract Background: TALA significantly prolonged progression-free survival vs physician's choice of chemotherapy (PCT) (hazard ratio [HR] 0.54 [95% CI 0.41-0.71]; P &amp;lt; 0.001) and improved patient-reported outcomes (PRO) in patients (pts) with HER2- ABC (locally advanced/metastatic) with a gBRCA1/2 mutation. We report results of the final OS analysis (secondary endpoint). Methods: Pts randomized 2:1 to TALA or PCT. OS HR was based on stratified Cox regression model (treatment as covariate); P value on stratified log-rank test. Results: 431 pts were randomized (287 TALA/144 PCT), 412 treated (286 TALA/126 PCT). By Sept 30, 2019, 216 deaths (75.3%) occurred for TALA and 108 deaths (75.0%) PCT; median follow-up 44.9 and 36.8 months, respectively. HR for OS was 0.85 (95% CI 0.67-1.07; P = 0.17); survival probability was higher for pts receiving TALA at 24, 36, and 48 months (Table 1). OS results were consistent across subgroups, eg by prior platinum or hormone receptor status. Most pts received post-study therapies; 32.6% of pts in the PCT arm received a PARP inhibitor post-study (4.5% for TALA arm). Grade 3-4 AEs occurred in 69.6% (TALA) and 64.3% (PCT) pts; AEs leading to permanent treatment discontinuation (excluding progressive disease) occurred in 5.9% and 8.7% of pts. Extended follow-up showed statistically significant overall improvements and delays in time to definitive clinically meaningful deterioration in both global health status/QoL and breast symptoms scales favoring TALA vs PCT (P &amp;lt; 0.01 for all), consistent with initial PRO analyses. Table 1.OS and post-study therapy (intent-to-treat)Talazopariboral 1 mg QDN = 287PCTaN = 144Deaths (%)216 (75.3)108 (75.0)HR (95% CI)0.85 (0.67-1.07); P = 0.17Median, mo. (95% CI)b19.3 (16.6-22.5)19.5 (17.4-22.4)Survival probability (95% CI) at Monthc120.71 (0.66-0.76)0.74 (0.66-0.81)240.42 (0.36-0.47)0.38 (0.30-0.47)360.27 (0.22-0.33)0.21 (0.14-0.29)480.19 (0.14-0.25)0.07 (0.02-0.15)Post-study antineoplastic therapy, n (%)233 (81.2)110 (76.4)PARP inhibitor, n (%)13 (4.5)47 (32.6)Platinum-based therapy, n (%)133 (46.3)60 (41.7)CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier; mo., months; OS, overall survival; PARP, poly(ADP-ribose) polymerase; QD, once daily.aPCT, physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine, vinorelbine).bDuration of OS based on KM estimates.cProbability estimated from the KM curve and CI calculated with product-limit method. Conclusions: In gBRCA1/2-mutated HER2- ABC, TALA did not significantly improve OS over PCT (HR 0.85; 95% CI 0.67-1.07; P = 0.17); analysis not adjusted for subsequent therapies. TALA was generally well-tolerated with no new safety signals. PRO continued to favor TALA. Funding: Pfizer (Medivation) Citation Format: Jennifer K. Litton, Sara A. Hurvitz, Lida A. Mina, Hope S. Rugo, Kyung-Hun Lee, Anthony Gonçalves, Sami Diab, Natasha Woodward, Annabel Goodwin, Rinat Yerushalmi, Henri Roché, Young-Hyuck Im, Wolfgang Eiermann, Ruben G. Quek, Tiziana Usari, Silvana Lanzalone, Akos Czibere, Joanne L. Blum, Miguel Martin, Johannes Ettl. Talazoparib (TALA) in germline BRCA1/2 (gBRCA1/2)-mutated human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC): Final overall survival (OS) results from randomized Phase 3 EMBRACA trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT071.

Abstract P1-19-29: An integrated safety analysis of talazoparib monotherapy from five clinical trials (phase 1-3) in advanced cancers

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.

357P - Patient Reported Outcomes (PRO) in patients (pts) with HER2- advanced breast cancer (ABC) and a germline BRCA1/2 mutation (gBRCAm) receiving talazoparib (TALA) vs physician’s choice chemotherapy (PCT) in the EMBRACA trial: A focus on subgroups with/ without visceral disease

BackgroundAs part of the key subgroup analyses of EMBRACA, a randomized 2:1 open-label phase 3 study (NCT01945775), improvements in PFS with TALA vs PCT were observed in both subgroups: HER2- gBRCAm ABC pts with/without visceral disease at baseline; these post hoc analyses evaluated PRO. MethodsPRO was assessed on baseline, at start of each 3-week cycle, and at end of treatment, using the EORTC QLQ-C30 and breast cancer module, QLQ-BR23. Higher scores indicate better functioning/global health status (GHS)/QoL or worse symptom severity. PRO analyses performed separately in pts with/without visceral disease, for GHS/QoL, functional and symptom scales include: Overall mean change from baseline (per longitudinal repeated measures mixed-effects model) and time to definitive clinically meaningful deterioration (TTD) (per survival analysis methods). Between-arm comparisons of TTD were made using stratified log-rank test and Cox proportional hazards model. ResultsBaseline scores were similar between arms. A statistically significant estimated overall change from baseline in GHS/QoL favored TALA vs PCT for both subgroups with {8.8 [95%CI: (4.1, 13.5)] P<0.001} and without {7.4 [95%CI: (0.4, 14.3)] P=0.04} visceral disease. A statistically significant estimated overall change from baseline in patient reported pain symptoms favored TALA vs PCT for both subgroups with (P<0.001) and without (P=0.03) visceral disease. A statistically significant delay in TTD favoring TALA was observed in GHS/QoL for both subgroups with [median: 21.1 vs 6.0 mos, HR=0.36 (95%CI: 0.23, 0.57); P<0.001] and without [median: 26.3 vs 12.2 mos, HR=0.38 (95%CI: 0.18, 0.80); P=0.009] visceral disease. A statistically significant delay in TTD favoring TALA was observed in pain symptoms for both subgroups with (P<0.001) and without (P=0.002) visceral disease. ConclusionsIn HER2- gBRCAm ABC, TALA (vs PCT) resulted in significantly better change from baseline and delayed TTD in GHS/QoL and pain in both pts subgroups with/without visceral disease. Clinical trial identificationNCT01945775. Editorial acknowledgementEditorial/writing support was provided by Chantel Cadwell, PhD, and Dena McWain at Ashfield Healthcare Communications, Middletown, CT. Legal entity responsible for the studyPfizer Inc. FundingPfizer Inc. DisclosureJ. Ettl: Honoraria (self), Advisory / Consultancy: Lily; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Eisai; Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self): TEVA; Honoraria (self): AstraZeneca. R.G.W. Quek: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. H. Bhattacharyya: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. H.S. Rugo: Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OBI Pharma; Research grant / Funding (institution): Pfizer Inc.; Research grant / Funding (institution): Plexxikon; Travel / Accommodation / Expenses: Mylan; Travel / Accommodation / Expenses: Puma; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OBI Pharma; Research grant / Funding (institution): Pfizer Inc.; Research grant / Funding (institution): Plexxikon; Travel / Accommodation / Expenses: Mylan; Travel / Accommodation / Expenses: Puma. S.A. Hurvitz: Research grant / Funding (institution): Ambryx; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): BI Pharma; Research grant / Funding (institution): Biomarin; Research grant / Funding (institution): Cascadian; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Dignitana; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Merrimack; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: OBI Pharma; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pieris; Research grant / Funding (institution): PUMA; Research grant / Funding (institution): Roche, Seattle Genetics. A. Gonçalves: Travel / Accommodation / Expenses: Pfizer Inc.; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Boehringer Ingelheim.

Outcomes of talazoparib (TALA) versus physician's choice of chemotherapy (PCT) in patients (pts) with advanced breast cancer (ABC) and a germline BRCA (gBRCA) mutation by line of chemotherapy (CT) in the EMBRACA trial.

1071 Background: The PARP inhibitor TALA was approved in the US for treatment of g BRCA-mutated ABC based in part on the EMBRACA study. Understanding the outcomes of EMBRACA pts relative to prior CT is a current unmet need. Methods: EMBRACA was a randomized Phase 3 trial comparing TALA 1 mg daily vs PCT (capecitabine, eribulin, gemcitabine, vinorelbine) in g BRCA-mutated ABC. Clinical outcomes were assessed by line of prior CT for ABC in intent-to-treat (ITT), triple-negative breast cancer (TNBC), and hormone receptor-positive (HR+) breast cancer cohorts. Results: 431 pts were randomized (ITT; TALA 287; PCT: 144). TALA was generally more effective than PCT across efficacy endpoints regardless of line of CT (Table). For the ITT population, TALA improved progression-free survival (PFS) and objective response rate (ORR) vs PCT for each line of CT assessed. Other prespecified subgroups (TNBC and HR+) will be presented. Conclusions: In pts with g BRCA-mutated ABC, TALA demonstrated improvements in clinical outcomes compared with PCT regardless of prior lines of CT. Clinical trial information: NCT01945775. [Table: see text]

Efficacy and safety of talazoparib (TALA) or physician's choice of therapy (PCT) in United States patients (pts) with HER2- germline BRCA1/2-mutated (gBRCAm) locally advanced/metastatic breast cancer (LA/MBC) in the EMBRACA study.

1044 Background: TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor approved in the US for HER2- g BRCAm LA/MBC. Approval was based on results from the Phase 3 EMBRACA trial comparing efficacy/safety of TALA (1 mg/d) to PCT (capecitabine, eribulin, gemcitabine, vinorelbine) in HER2- g BRCAm LA/MBC pts. This analysis describes outcomes in US pts included in the pivotal study. Methods: Clinical findings from US pts enrolled in EMBRACA were analyzed. Pt characteristics, progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), and safety/adverse events (AEs) were among the parameters assessed. Results: Of 431 randomized pts, 156 pts (36%) were from the US (TALA: 99; PCT: 57). Pt characteristics were balanced, although a higher percentage in the TALA arm had more poor prognostic features (eg, triple-negative breast cancer, disease-free interval &lt; 12 mo, and more disease sites). TALA improved PFS, ORR, CBR, and duration of response (DOR) vs PCT (Table). 22% of pts in the TALA arm had a continued objective response at month 12 vs 0 pts in the PCT arm. The most common AEs in the TALA arm included anemia, neutropenia, thrombocytopenia, fatigue, nausea, alopecia, and headache; hematologic grade 3/4 AEs occurred more often than nonhematologic AEs. Conclusions: In US pts with HER2- g BRCAm LA/MBC, TALA demonstrated significant improvements in outcomes vs PCT with a manageable safety profile. Clinical trial information: NCT01945775. [Table: see text]

154O - Impact of objective response (OR) on patient-reported outcomes (PRO) in patients (pts) with advanced breast cancer (ABC) and a germline BRCA1/2 (gBRCA) mutation in the phase III EMBRACA trial

154O - Impact of objective response (OR) on patient-reported outcomes (PRO) in patients (pts) with advanced breast cancer (ABC) and a germline BRCA1/2 (gBRCA) mutation in the phase III EMBRACA trial

Abstract OT3-03-02: A phase 2, open-label, single-arm, multi-center study of talazoparib for neoadjuvant treatment of germline BRCA1/2 mutation patients with early-stage triple-negative breast cancer (TNBC)

Abstract Background: Approximately 15% of all breast cancers are triple negative and deleterious BRCA1/2 mutations are found in ˜11% of unselected TNBC. In the phase 3 EMBRACA trial (NCT01945775), the poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib was superior to chemotherapy in prolonging progression-free survival in BRCA1/2 mutation patients with advanced breast cancer. A recent pilot study (NCT02282345) of 20 patients, explored the feasibility of neoadjuvant talazoparib in BRCA1/2 mutation patients; pathologic complete response (pCR) was reported at 53% with 6 months of single agent talazoparib. Trial Design: This phase 2, single-arm, open-label, multi-center study has a Simon 2-stage design. Eligible pts have stage I-III invasive TNBC (ER and PR &amp;lt;10%), with germline BRCA1/2 mutations who are suitable for neoadjuvant therapy. Pts will receive talazoparib 1 mg daily for 24 weeks, followed by breast surgery, which should occur within 4 to 6 weeks of the last dose. Ultrasound will be performed serially to assess tumor response. The primary objective is to evaluate pCR after 24 weeks of neoadjuvant talazoparib. pCR (ypT0/is ypN0) will be assessed by independent central review. Safety will also be assessed. Pts will be followed for at least 5 years to assess long term outcomes (event-free and overall survival). After surgery, any further adjuvant therapy will be given at the discretion of the treating physician. Pt reported outcomes will be assessed electronically including the global health status/quality of life, functions, and symptoms using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and BR23. Plasma pharmacokinetic (PK) samples for determination of talazoparib concentrations will be collected at defined timepoints to describe the steady-state PK of talazoparib. Exploratory biomarker research will also take place. Approximately 122 men and women will be enrolled in the study, of which 112 evaluable pts are planned. With 112 evaluable pts and one interim futility look, the null hypothesis that the true pCR rate is 35% will be tested against a 1-sided alternative. This design yields a 1-sided type 1 error rate of 2.5% and power of 90% when the true pCR rate is 50%. An interim analysis will be performed to evaluate the efficacy of talazoparib after 28 evaluable pts undergo talazoparib treatment for 24 weeks, followed by surgery, and are assessed for pCR by central review. This trial is currently recruiting and is registered at clinicaltrials.gov (NCT03499353). Funding: This study is sponsored by Pfizer, Inc. Citation Format: Litton J, Symmans F, Gogineni K, Saltzman M, Telli ML, Usha L, Chakrabarti J, Tudor IC, Quek RG, Czibere A. A phase 2, open-label, single-arm, multi-center study of talazoparib for neoadjuvant treatment of germline BRCA1/2 mutation patients with early-stage triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-03-02.

305P - Exposure-efficacy progression-free survival (PFS) analyses of breast cancer patients with germline BRCA1/2 mutations receiving talazoparib in the phase III EMBRACA trial

305P - Exposure-efficacy progression-free survival (PFS) analyses of breast cancer patients with germline BRCA1/2 mutations receiving talazoparib in the phase III EMBRACA trial

Abstract P5-19-05: Health-related quality of life during a phase 2 study of talazoparib in patients with advanced breast cancer and germline BRCA1/2 mutations (ABRAZO)

Abstract Background: Talazoparib (TALA; 1 mg/d) was well tolerated and exhibited promising antitumor activity in ABRAZO, a 2-cohort, 2-stage, open-label phase 2 study (NCT02034916) in patients (pts) with locally advanced or metastatic breast cancer and gBRCA1/2 mutations following platinum-based therapy (cohort 1 [C1]) or ≥3 platinum-free cytotoxic-based regimens (cohort 2 [C2]). This analysis evaluates health-related quality of life (QoL) for both cohorts. Methods: QoL was assessed on day 1 (baseline) and every 6 weeks for the initial 24 weeks and every 12 weeks thereafter, or sooner if progression was clinically suspected, using the EORTC QLQ-C30 and its breast cancer module, QLQ-BR23. For all scales, results were summarized using descriptive statistics for each cohort and at each time point, based on Characters (max 3400 including title, body and table [including spaces]): 3363 No abbreviations in title; title sentence case; define acronyms; no figures Category: Psychosocial, QOL, and Educational Aspects – Other 2 observed values and changes from baseline (clinically meaningful defined as ≥10-point change from baseline). Time to deterioration (TTD; defined as ≥10-point decrease in global health status [GHS]/functional scales or increase in symptom scales) analyses using survival analysis methods were carried out on the GHS/functional scales of QLQ-C30 and symptom scales of QLQ-BR23. Results:GHS was maintained from baseline across all time points for both C1 and C2 except at week 24 in C2, when a statistically significant but not clinically meaningful improvement in GHS was observed. In C1, statistically significant and clinically meaningful improvement was observed at specific time points in 4 functional scales (body image, week 6; sexual functioning, week 24; sexual enjoyment, week 36; and future perspective, weeks 6, 18, and 24) and in 3 symptom scales (dyspnea, week 24; insomnia, week 24; and breast symptoms, weeks 6 and 36). Statistically significant and clinically meaningful deterioration in C1 was observed in 2 functional scales (emotional functioning, week 12 and end of treatment, and role functioning, end of treatment) and in 1 symptom scale (fatigue, week 6). In C2, statistically significant and clinically meaningful improvement was observed at specific time points in 4 functional scales (role functioning, week 24; social functioning, week 24; sexual enjoyment, week 18; and future perspective, weeks 6, 12, and 18) and in 5 symptom scales (nausea/vomiting, week 18; pain, weeks 12, 18, and 24; insomnia, week 24; breast symptoms, weeks 12 and 18; and arm symptoms, week 48). For C2, no statistically significant and clinically meaningful deterioration was observed for any functional or symptoms scales across all time points, except in the dyspnea symptom scale at week 18. For C1 and C2, the median (95% confidence interval) TTD of GHS was 2.8 (2.1-3.0) and 5.5 (4.2-5.7) months, respectively. The median TTD for all QLQ-C30 functional scales for C1 and C2 ranged 2.1-3.1 and 4.2-5.6 months, respectively; the median TTD for all QLQ-BR23 symptoms scales ranged 2.6-4.0 and 4.2-5.6 months, respectively. Conclusions: The QoL of TALA-treated patients during ABRAZO was maintained. QoL is being evaluated among atients with germline BRCA1/2 mutated advanced BC treated with TALA vs physician's choice chemotherapy in the phase 3 EMBRACA trial (NCT01945775). Citation Format: Hurvitz SA, Turner NC, Telli ML, Rugo HS, Mailliez A, Ettl J, Grischke E-M, Mina LA, Balmaña J, Fasching PA, Tudor C, Quek RGW, Hannah AL, Robson ME, Wardley AM. Health-related quality of life during a phase 2 study of talazoparib in patients with advanced breast cancer and germline BRCA1/2 mutations (ABRAZO) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-19-05.

Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline BRCA1/2 mutations (ABRAZO).

1007 Background: TALA is a dual-mechanism PARP inhibitor that traps PARP on DNA. This study was designed to assess the activity of TALA in pts with g BRCA1/2mutation previously exposed to platinum or multiple prior cytotoxic regimens. Methods: ABRAZO (NCT02034916) is a 2-cohort, 2-stage phase 2 study of TALA (1 mg/d) following platinum-based therapy (Cohort 1 [C1]) or ≥ 3 platinum-free cytotoxic-based regimens (Cohort 2 [C2]) in pts with locally advanced or metastatic breast cancer (MBC) and g BRCA1/2mutation. Pts had ECOG PS ≤ 1 and measurable disease by RECIST v1.1. Five responses per cohort were required in ≤ 35 pts to progress to stage 2. The primary endpoint was confirmed ORR by independent radiology facility (IRF). Secondary endpoints: clinical benefit rate ≥ 24 weeks (CBR24), DOR, PFS, and OS. Results: From May 2014 to Feb 2016, 84 pts were enrolled (C1, n = 49; C2, n = 35). At data cutoff (1 Sep 2016), 9 pts continued on treatment. Both cohorts proceeded to stage 2 before enrollment closed. Median age was 50 (range, 31–75) years; 58% of pts had an ECOG PS of 0. TNBC/HR+ incidence in C1 and C2 was 59%/41% and 17%/83%, respectively. Median number of prior cytotoxic regimens administered for advanced disease was 2 in C1 and 4 in C2. ORR by IRF for BRCA1/BRCA2 was 24%/34%, and ORR by IRF for TNBC/HR+ was 26%/29%. Common all grade AEs: anemia (52%), fatigue (45%), nausea (42%), diarrhea (33%), thrombocytopenia (33%), and neutropenia (27%). Grade ≥ 3 AEs: anemia (35%), thrombocytopenia (19%), and neutropenia (15%). Nonhematological AEs grade ≥ 3 did not occur. AEs related to TALA led to drug discontinuation in 3 pts (4%); 4 AEs resulted in death, none related to TALA. Conclusions: TALA was well tolerated in MBC pts with a g BRCA1/2 mutation, exhibiting promising antitumor activity in C1 and C2. TALA vs physician’s choice of treatment in g BRCA1/2-mutated MBC is being evaluated in the phase 3 EMBRACA trial (NCT01945775). Clinical trial information: NCT02034916. [Table: see text]