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.

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

“…Both studies showed improvement of median PFS with the PARP inhibitor of ~ 3 months and greater tolerability, with no overall survival benefit evident as yet. Among patients with measurable disease, the objective response rates were approximately 60% with the PARP inhibitor compared to approximately 30% in physician choice (need to check talazaparib) [18,19]. The FDA approved olaparib for the treatment of germline BRCA1/2 metastatic breast cancer in January 2018.…”

PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside

“…Several early phase studies with the other PARPis demonstrated similar signals of efficacy in BRCAmutant breast cancer ( Table 2). [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] Multiple phase 2 studies further demonstrated activity of olaparib in patients who had metastatic breast cancer with germline BRCA mutations. [30][31][32] In a phase 2 study, Tutt et al investigated the effects of olaparib monotherapy in 54 patients who had centrally confirmed, germline BRCA-mutant breast cancer.…”

“…Recently, the activity of talazoparib in BRCA ‐mutant breast cancer was demonstrated in the phase 3 EMBRACA trial . Initial results from that trial demonstrated a median PFS of 8.6 months in patients who received talazoparib compared with 5.6 months in those who received chemotherapy ( P < .0001).…”

“…Overall, patient-reported qualityof-life metrics (the European Organization for Research and Treatment of Cancer Core 30 Quality-of-Life Recently, the activity of talazoparib in BRCAmutant breast cancer was demonstrated in the phase 3 EMBRACA trial. 39 Initial results from that trial demonstrated a median PFS of 8.6 months in patients who received talazoparib compared with 5.6 months in those who received chemotherapy (P < .0001). In addition, the ORR in the talazoparib group was more than twice that of the control arm (62.6% vs 27.2% for chemotherapy; P < .0001).…”

Optimizing poly (ADP‐ribose) polymerase inhibition through combined epigenetic and immunotherapy

“…Despite longer PFS and higher response rates, the median duration of response was only 5.4 months and OS, at an interim analysis after 51% of the projected events, was not significantly different between groups (hazard ratio, 0.76; P = .10). 13 Despite impressive responses and PFS benefit, development of resistance to PARPi was almost ubiquitous, hampering the duration of response and perhaps even OS. Furthermore, PFS benefit was in the range of 2-4 months with PARPi, even in germline BRCA-mutant patients.…”