Talazoparib Research Articles

EMBRACA: Efficacy outcomes in clinically relevant subgroups comparing talazoparib (TALA), an oral poly ADP ribose polymerase (PARP) inhibitor, to physician's choice of therapy (PCT) in patients with advanced breast cancer and a germline BRCA mutation.

1069Background: TALA is a dual-mechanism PARP inhibitor that traps PARP on DNA, preventing DNA damage repair and causing cell death in BRCA1/2-mutated cells. Methods: EMBRACA (NCT01945775) is an open-label, randomized, 2-arm, phase 3 trial comparing the efficacy and safety of TALA (1 mg/day) with standard single-agent PCT (capecitabine, eribulin, gemcitabine, or vinorelbine) in pts with advanced breast cancer (aBC) and a germline BRCA1/2 mutation (gBRCAmut). PFS by blinded independent central review (BICR) and ORR by investigator were investigated in clinically important subgroups. Results: Of 431 pts randomized, 287 were assigned to receive TALA and 144 to PCT. PFS and ORR are shown (Table). Conclusions: In pts with advanced gBRCAmut breast cancer, TALA demonstrated a statistically significant improvement in both ORR and PFS in clinically relevant subgroups compared with PCT, including pts with CNS metastases, poor performance status, younger age, and visceral disease. Clinical trial information: NCT0194...

Analysis of germline BRCA1/2 mutated (gBRCAmut) hormone receptor-positive (HR+) and triple negative breast cancer (TNBC) treated with talazoparib (TALA).

1070Background: TALA is a dual-mechanism PARP inhibitor that traps PARP on DNA in BRCA1/2-mutated cells, preventing DNA damage repair and causing cell death. Methods: EMBRACA (NCT01945775) is a ran...

Talapro-2: A 2-part, placebo-controlled phase 3 study of talazoparib (TALA) with background enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC) with DNA damage repair deficiencies.

TPS5091Background: ENZA is approved to treat men with mCRPC. TALA is a dual-mechanism PARP inhibitor that inhibits PARP1 and PARP2 catalytic activity and traps PARP on DNA, preventing DNA damage re...

Abstract GS6-07: EMBRACA: A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician's choice of therapy in patients with advanced breast cancer and a germline BRCA mutation

Abstract Background: Talazoparib (TALA) is a highly potent, dual-mechanism PARP inhibitor that inhibits the PARP enzyme and effectively traps PARP on single-stranded DNA breaks, preventing DNA damage repair and causing cell death in BRCA1/2-mutated cells. Methods: EMBRACA is an open-label, randomized, 2-arm, phase 3 trial comparing the efficacy and safety of TALA (1 mg/day) with standard single-agent physician's choice of therapy (PCT) (capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with advanced breast cancer (aBC) and a germline BRCA1/2 mutation (gBRCAmut). The primary objective was PFS assessed by blinded independent central review (BICR). Secondary objectives: OS, ORR, CBR at 24 weeks (CBR24), and safety. Exploratory objectives: patient-reported QoL and DOR. Eligibility criteria: age ≥ 18 years; HER2-negative aBC; deleterious or suspected deleterious gBRCAmut; ≤ 3 prior cytotoxic regimens for aBC; and ECOG PS ≤ 2. Prior platinum was allowed. Patients were randomized 2:1 and stratified by receptor status, extent of prior therapy, and CNS metastases (NCT01945775). Results: 431 patients were randomized (median age 46 years; 54% hormone-receptor [HR]+ BC; 45% BRCA1+ and 55% BRCA2+; 55% ECOG PS = 0; 38% chemo-naïve for aBC; 18% prior platinum; 15% CNS metastases); 287 were assigned to TALA and 144 to PCT (1 TALA, 18 PCT patients were not treated). Median duration of exposure was 6.1 and 3.9 months, respectively; TALA had a relative dose intensity of 87%. At 62% PFS data maturity: TALAPCTHazard Ratio/Odds Ratio (P value)PFS by BICR, mo (95% CI)8.6 (7.2-9.3); n = 2875.6 (4.2-6.7); n = 1440.542 (< 0.0001)OS [interim], mo (95% CI)22.3 (18.1-26.2); n = 28719.5 (16.3-22.4); n = 1440.761 (0.105)ORR by INV, % (95% CI)62.6% (55.8-69.0); n = 21927.2% (19.3-36.3); n = 1144.99 (< 0.0001)DOR by INV, mo (IQR)5.4 (2.8-11.2); n = 1373.1 (2.4-6.7); n = 310.431 (0.0005)*CBR24 by INV, % (95% CI)68.6% (62.9-74.0); n = 28736.1% (28.3-44.5); n = 1444.28 (≤0.0001) INV, investigator. *Not a randomized subset. Improved clinical benefit was seen in all subsets including those with HR+ BC (HR 0.47; 95% CI 0.32-0.71) and CNS metastasis (HR 0.32; 95% CI 0.15-0.88). There was a significant delay in the time to deterioration in global health status (GHS)/QoL for TALA vs PCT (HR 0.38; 95% CI 0.26-0.55; P < 0.0001]. Grade 3-4 hematologic adverse events (AEs) occurred in 55% TALA (mainly anemia)/39% PCT (mainly neutropenia). Grade 3-4 non-hematologic AEs were seen in 32% TALA/38% PCT; TALA was associated with fewer gastrointestinal disorders (5.6% vs 11.9%) and skin/subcutaneous tissue disorders (0.7% vs 5.6%) than PCT. Grade 3-4 serious AEs were observed in 26% TALA/25% PCT. AEs associated with permanent study drug discontinuation occurred in 8% TALA/10% PCT. AE resulting in death occurred in 2.1% TALA/3.2% PCT.Conclusions: Single-agent TALA significantly prolonged PFS by BICR in HER2-negative aBC patients with a gBRCAmut compared to PCT; all key secondary efficacy endpoints demonstrated benefit with TALA, with a significant delay in time to deterioration in GHS/QoL. TALA was generally well tolerated with minimal non-hematologic toxicity and few AEs associated with treatment discontinuations. Citation Format: Litton J, Rugo HS, Ettl J, Hurvitz S, Gonçalves A, Lee K-H, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roché H, Im Y-H, Quek RGW, Tudor IC, Hannah AL, Eiermann W, Blum JL. EMBRACA: A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician's choice of therapy in patients with advanced breast cancer and a germline BRCA mutation [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 GS6-07.

Abstract P1-14-03: ABRAZO: Exposure-efficacy and -safety analyses of breast cancer patients with germline BRCA1/2 mutations receiving talazoparib in a phase 2 open-label trial

Abstract Background: Talazoparib (TALA) is a dual-mechanism poly (ADP-ribose) polymerase (PARP) inhibitor that traps PARP on DNA. Efficacy results of this phase 2 trial were previously presented (Turner et al, ASCO 2017, abstract 1007). This study included sparse pharmacokinetic (PK) sampling for patients through cycle 4 of therapy. Exploratory analyses included assessment of exposure versus parameters of efficacy and safety. Methods: ABRAZO (NCT02034916) was a parallel-cohort, open-label phase 2 study of TALA (1 mg/d) following (i) platinum-based therapy (cohort 1) or (ii) ≥3 platinum-free cytotoxic-based regimens (cohort 2) in patients with locally advanced or metastatic breast cancer and germline BRCA1/2 mutation. Sparse PK sampling was performed on day 1 of cycles 1-4, consisting of a predose sample collected ≤60 minutes prior to dosing and 2 postdose samples collected ≥30 minutes after dosing (time of food ingestion prior to the dose was collected). The collection times of the 2 postdose samples were separated by ≥2 hours. Efficacy parameters included radiographic progression-free survival (rPFS) by central review and objective response rate (ORR). Safety parameters included incidence of overall adverse events (AEs) and grade ≥3 AEs. Individual AUCs (area under concentration-time curves) for exposure-response analyses were predicted by population PK analyses. Results: Patients were divided into AUC tertiles: low (median, 109.0 ng*hr/mL; n=27), intermediate (median, 170.8 ng*hr/mL; n=27), and high (median, 219.2 ng*hr/mL; n=27). Median rPFS was 5.3 months (95% confidence interval [CI], 3.1, 8.3) in the lowest AUC tertile, 5.6 months (95% CI, 3.7, 8.4) in the intermediate AUC tertile, and 5.3 months (95% CI, 3.9, 5.6) in the highest AUC tertile. The ORR was 22.2% (95% CI, 8.6, 42.3) in the lowest AUC tertile, 25.9% (95% CI, 11.1, 46.3) in the intermediate AUC tertile, and 37.0% (95% CI, 19.4, 57.6) in the highest AUC tertile. AEs of any grade were reported in 11 patients (40.7%) in the lowest AUC tertile, 21 patients (77.8%) in the intermediate AUC tertile, and 22 patients (81.5%) in the highest AUC tertile. Grade ≥3 AEs were reported in 8 patients (29.6%) in the lowest AUC tertile and in 18 patients (66.7%) in the intermediate and highest AUC tertiles. The most common AEs in all 3 exposure tertiles were anemia, thrombocytopenia, and neutropenia. Conclusions: Median rPFS did not change with increasing systemic exposure. There may be a trend to higher ORR in patients with highest systemic exposure. A larger percentage of patients experienced AEs with elevated systemic exposure. Increased response rates with greater exposure does not translate to improved rPFS. These results should be interpreted with caution due to the low patient numbers in each cohort. Citation Format: Telli ML, Turner NC, Mailliez A, Ettl J, Grischke E-M, Mina LA, Balmaña J, Hurvitz SA, Wardley AM, Fasching PA, Tudor C, Nguyen L, Hannah AL, Robson ME, Rugo HS. ABRAZO: Exposure-efficacy and -safety analyses of breast cancer patients with germline BRCA1/2 mutations receiving talazoparib in a phase 2 open-label trial [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 P1-14-03.

Abstract B36: A biomarker-guided approach to combining PARP inhibitors with radiotherapy in pediatric sarcomas

Abstract Background: Ewing sarcoma (EWS) expresses high levels of Schlafen-11 (SLFN11). SLFN11 disrupts checkpoint maintenance and may serve as a biomarker to assess sensitivity to Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi). The goal of this study is to evaluate SLFN11 protein expression in a panel of pediatric solid tumors and correlate levels of protein with sensitivity to PARP inhibition combined with ionizing radiation (IR), a component of therapy for many pediatric sarcomas and a potent inducer of DNA damage. Methods: SLFN11 mRNA and protein levels were assessed by quantitative RT-PCR, and immunohistochemistry, Western blot, and immunofluorescence microscopy, respectively. PARPi included talazoparib (TAL), niraparib (NIR), veliparib (VEL), and olaparib (OLA). Approximately 30 minutes after addition of systemic therapy, graded doses of radiation were delivered and viability across a panel of pediatric solid tumor cell lines was measured using the ATP-based Cell TiterGlo assay and confirmed with the colony formation assay. Results: We found that SLFN11 mRNA and protein is expressed at high levels in EWS, and SLFN11 is also variably present in a subset of other pediatric sarcomas, including desmoplastic small round cell tumor, osteosarcoma, and rhabdomyosarcoma. In all tumor cells with detectable SLFN11 expression, viability was reduced by greater than 90% when exposed to 2 Gy IR and 1-10 nM TAL, whereas cells with undetectable levels of SLFN11 were 5-10 times less sensitive. Intriguingly, variation in the potentiation between specific PARPi and IR correlated with the ability to form drug-induced PARP-DNA adducts, with the strong PARP trapper TAL showing ~10-fold higher potency compared to the moderate trapper NIR, and ~300-fold more potency relative to the weak trapper VEL. Consistent with our PARPi findings, the toposiomerase 1 inhibitor irinotecan, which also forms DNA adducts, potentiated with IR similarly to TAL at concentrations <10 nM in tumor cells expressing detectable levels of SLFN11. Conclusion: SLFN11 is present in select pediatric sarcomas and may induce a DNA repair defect that is best exploited by combining low doses of TAL and irinotecan with IR. Citation Format: Anang A. Shelat, Christopher L. Tinkle, Elizabeth Stewart, Sara Michele Federico, Brandon Bianski, Marcia Mellado-Lagarde. A biomarker-guided approach to combining PARP inhibitors with radiotherapy in pediatric sarcomas [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B36.

P3.15-008 [F18]PARPi PET as an In Vivo Pharmacodynamic Biomarker of PARP Inhibitor Therapy in Patient-Derived Xenografts of Small Cell Lung Cancer

Inadequate drug delivered to target tumors contributes to ineffective treatment. However, the delivered drug concentration is difficult to assess in patients in a timely and clinically-relevant manner. To address this barrier to PARP inhibitor (PARPi) therapy, we evaluated a radiolabeled PARP inhibitor ([F18]PARPi) as a pharmacodynamic biomarker. We hypothesized that [F18]PARPi PET imaging can measure PARP inhibitor concentration and activity intratumorally, thereby, predicting therapeutic efficacy. Here, we applied this approach to patient-derived xenografts (PDX) of small cell lung cancer (SCLC). To study [F18]PARPi PET as a biomarker of talazoparib (TAL), SCRX-Lu149 PDXs were orally gauged with different doses of TAL. Mice were injected with [F18]PARPi and imaged with PET, with the expectation that TAL would competitively block [F18]PARPi binding to PARP. Organ retrieval and gamma counting was performed for drug and radiotracer biodistribution. Ex vivo PARP enzymatic activity was measured by ELISA of PAR levels. Differences in PET uptake and the tumor volumetric endpoint (time to reach 1000 mm3) were analyzed by student t-test and the log-rank test, respectively. In PK PET imaging with 0.2 mg/kg TAL, greatest blocking of the radiotracer was noted at 1 hour after gavage with less blocking as time from dosing was extended (avg of 3 mice: 4.5, 2.2, 2.7, 3.1, and 3.4% max injected dose per gram [ID/g] for untreated, 1, 3, 6, and 24 h after drug, respectively). [F18]PARPi PET differentiated between doses of 0.1 and 0.3 mg/kg TAL at 3 h after dosing (3.9 vs 2.1% ID/g or 13% vs 53% relative blocking, respectively; p=0.003). No differences were noted in heart, lung, esophagus, muscle, or bone. PET uptake correlated with ex vivo enzymatic inhibition/PAR levels (p=0.0009). PET measured differences in drug doses corresponded with improved outcomes for PDXs treated with 0.3 mg/kg in combination with radiotherapy (RT; median 84 days, p=0.04) but not 0.1 mg/kg + IR (66 days) compared to RT alone (52 days). [F18]PARPi PET can differentiate between multiple doses and timing of orally administered TAL and correlates with drug efficacy. This likely reflects differences in intratumoral drug level and demonstrates the potential of this PET radiotracer to assess differences in drug delivery and efficacy for patients treated with PARP inhibitors.

Development and validation of a high-performance liquid chromatography method for the quantification of talazoparib in rat plasma: Application to plasma protein binding studies.

A sensitive and selective RP-HPLC method has been developed and validated for the quantification of a highly potent poly ADP ribose polymerase inhibitor talazoparib (TZP) in rat plasma. Chromatographic separation was performed with isocratic elution method. Absorbance for TZP was measured with a UV detector (SPD-20A UV-vis) at a λmax of 227 nm. Protein precipitation was used to extract the drug from plasma samples using methanol-acetonitrile (65:35) as the precipitating solvent. The method proved to be sensitive and reproducible over a 100-2000 ng/mL linearity range with a lower limit of quantification (LLQC) of 100 ng/mL. TZP recovery was found to be >85%. Following analytical method development and validation, it was successfully employed to determine the plasma protein binding of TZP. TZP has a high level of protein binding in rat plasma (95.76 ± 0.38%) as determined by dialysis method.

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]

Phase I study of talazoparib and irinotecan in children and young adults with recurrent/refractory solid tumors.

10542 Background: Poly (ADP-ribose) Polymerase inhibitors (PARPi) target tumors with deficiencies in DNA repair mechanisms. Talazoparib (TAL), a potent PARP inhibitor, demonstrated significant efficacy in a Ewing sarcoma model when combined with DNA-damaging irinotecan (IRN). We performed a phase I trial to determine the maximum tolerated doses (MTDs) of TAL and IRN in pediatric patients with solid tumors. Methods: Cohorts of 3-6 eligible patients (pts) with recurrent/refractory solid tumors received escalating doses of oral (PO) TAL and intravenous (IV) IRN in a 3+3 design (Table 1). Each course was 21 days. Serum for TAL and IRN pharmacokinetics (PK) were obtained. Toxicities were assessed using CTCAE v.4 and responses were evaluated by RECIST v.1.1. Results: Twenty-four pts (9 male; median age, 11 years; 18 recurrent) received a median of 2 courses (range, 1-18). Fifteen pts had prior exposure to IRN. Table 1 summarizes the dose-limiting toxicities (DLTs) in course 1. The most common grade 3 or higher non-hematologic and hematologic toxicities in 82 evaluable courses were febrile neutropenia (5), elevated gamma-glutamyltransferase (GGT, 4), neutropenia (22) and lymphopenia (17). Two of 22 evaluable patients had a response (CR Ewing sarcoma, 18 courses; PR synovial sarcoma, 10 courses) and 9 had disease stabilization, median 4 courses (range, 4-10). Results of PK tests will be presented. Conclusions: The recommended phase II doses are TAL 600mcg/m2 (max 1000mcg/dose) days 1-6 and IRN 40mg/m2/day days 2-6. This regimen is feasible with evidence of anti-tumor activity and warrants further investigation. Clinical trial information: NCT02392793. [Table: see text]

A biomarker-guided approach to combining PARP inhibitors with radiotherapy in pediatric solid tumors.

10556 Background: Ewing sarcoma (EWS) expresses high levels of Schlafen-11 (SLFN11). SLFN11 disrupts checkpoint maintenance and may serve as a biomarker to assess sensitivity to Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi). The goal of this study is to evaluate SLFN11 protein expression in a panel of pediatric solid tumors and correlate levels of protein with sensitivity to PARP inhibition combined with ionizing radiation (IR), a component of therapy for many pediatric solid tumors and a potent inducer of DNA damage. Methods: SLFN11 mRNA and protein levels were assessed by quantitative RT-PCR, and immunohistochemistry, Western blot, and immunofluorescence microscopy, respectively. PARPi included: talazoparib (TAL), niraparib (NIR), veliparib (VEL), and olaparib (OLA). Approximately 30 minutes after addition of systemic therapy, graded doses of radiation were delivered and viability across a panel of pediatric solid tumor cell lines was measured using the ATP-based Cell TiterGlo assay and confirmed with the colony formation assay. Results: We found that SLFN11 mRNA and protein is expressed at high levels in EWS, and SLFN11 is also variably present in a subset of other pediatric solid tumor lines, including desmoplastic small round cell tumor, osteosarcoma, and rhabdomyosarcoma. In all tumor cells with detectable SLFN11 expression, viability was reduced by greater than 90% when exposed to 2Gy IR and 1-10nM TAL, whereas cells with undetectable levels of SLFN11 were 5-10 times less sensitive. Intriguingly, variation in the potentiation between specific PARPi and IR correlated with the ability to form drug-induced PARP-DNA adducts, with the strong PARP trapper TAL showing ~10-fold higher potency compared to the moderate trapper NIR, and ~300-fold more potency relative to the weak trapper VEL. Consistent with our PARPi findings, the toposiomerase 1 inhibitor irinotecan, which also forms DNA adducts, potentiated with IR similarly to TAL at concentrations < 10nM in tumor cells expressing detectable levels of SLFN11. Conclusions: SLFN11 is present in select pediatric solid tumors and may induce a DNA repair defect that is best exploited by combining low-doses of TAL and irinotecan with IR.

Abstract 340: Talazoparib enhances low-dose temozolomide efficacy in flank glioblastoma models, but intracranial efficacy is constrained by limited brain distribution

Abstract BACKGROUND: Talazoparib (TAL) is a potent poly (ADP-ribose) polymerase (PARP) inhibitor that robustly enhances in vitro sensitivity to temozolomide (TMZ) in several tumor models. We assessed the in vitro and in vivo efficacy of TAL combined with TMZ in glioblastoma (GBM) models. METHODS: Established glioma cell lines (T98G, U251) and the GBM12 patient derived xenograft (PDX) line were treated in vitro with TAL (1-10 nM) ± TMZ (2-300 μM). Antitumor efficacy was assessed with CyQUANT, clonogenic and primary neurosphere assays; cell cycle analysis with flow cytometry; DNA damage signaling with phospho-specific western blots for pKap1, pChk1, pChk2 and fluorescent immunocytochemistry for γH2AX and replication protein A foci. Brain and plasma concentrations of TAL in wild-type (WT), Mdr1a/b(-/-), Bcrp(-/-) and Mdr1a/b(-/-)Bcrp(-/-) knockout (KO) mice were assessed with LC-MS/MS. The tolerability of TAL (0.05 - 0.30 mg/kg/day orally, divided twice daily (div. bid)) and TMZ (5-50 mg/kg/day orally) was tested in athymic nude mice. Subsequently, in vivo combination TAL/TMZ efficacy was assessed with survival analyses in intracranial and flank GBM12 PDX models. RESULTS: TAL 1-3 nM sensitizes the TMZ resistant T98G glioma cell line to TMZ at high TMZ concentrations (30-300 μM) and is associated with G2 cell cycle arrest and enhanced DNA damage signaling. TAL 1-3 nM also enhances the cytotoxic efficacy of lower concentrations of TMZ (10-30 μM) in the TMZ sensitive U251 cell line. At least 3 nM TAL is required to enhance the in vitro efficacy of low TMZ concentrations (2-10 μM) in the TMZ sensitive GBM12 PDX line. PK studies in non-tumor bearing WT FVB mice treated with a single dose of TAL 0.15 mg/kg revealed mean brain and plasma concentrations of 0.49 ng/g (1.3 nM) and 25.5 ng/ml (67.1 nM) respectively at 2 hours. The mean brain/plasma ratio at 2 hours was unchanged in Bcrp(-/-) KO mice compared to WT mice (1.2% vs. 2.0%), but was significantly increased in Mdr1a/b(-/-) KO mice (22.8%) and Mdr1a/b(-/-)Bcrp(-/-) KO mice (23.9%). Standard doses of TMZ (50 mg/kg/day, days 1-5) combined with low doses of TAL (0.05 mg/kg/day, div. bid) were toxic in nude mice. Higher doses of TAL (0.30 mg/kg/day, div. bid) required substantial TMZ dose reductions (5 mg/kg/day, days 1-5) for tolerability. The addition of TAL (0.30 mg/kg/day, div. bid) to low-dose TMZ (5 mg/kg/day) prolonged tumor stasis in flank GBM12 xenografts (median time to endpoint 76 vs. 50 days, p = 0.005). However this regimen was ineffective in intracranial GBM12 xenografts (median survival 37 vs. 30 days, p = 0.93). CONCLUSIONS: TAL is a potent PARP inhibitor that enhances the efficacy of TMZ in both in vitro GBM models and flank GBM12 PDX models, but not in the corresponding GBM12 intracranial xenografts. This lack of intracranial efficacy is associated with limited brain distribution due to active efflux mediated by Mdr1 at the blood-brain barrier. Citation Format: Sani H. Kizilbash, Kenneth Chang, Shiv K. Gupta, Ryo Kawashima, Karen Parrish, Ann C. Mladek, Brett L. Carlson, Katrina K. Bakken, Mark A. Schroeder, Gaspar J. Kitange, Paul A. Decker, Yuqiao Shen, William F. Elmquist, Jann N. Sarkaria. Talazoparib enhances low-dose temozolomide efficacy in flank glioblastoma models, but intracranial efficacy is constrained by limited brain distribution. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 340.