PDF file - 93K, Distribution of the PAM50 intrinsic subtypes based on RORP score groups.

PDF file - 44K, Clinical-pathological comparison of the NOAH and the transNOAH gene expression (GEP) tumor samples.

PDF file, 66K, Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the treatment effect of conventional versus response-guided neoadjuvant chemotherapy as measured by mean disease-free survival according to overlapping subpopulations defined by percentages of Ki67 at surgery in patients with hormone-receptor-positive (A) and hormone-receptor-negative (B) disease.

PDF file - 105K, Ability of the high RORP group to predict pCR in 91 patients with clinically HER2-positive disease treated with trastuzumab-based chemotherapy in the ISPY-1, MDACC and XeNA studies.

PDF file - 102K, Clinical-pathological characteristics of the various pathology-defined subtypes.

PDF file - 57K, Quality control profiles of the samples.

PDF file - 104K, Ability of the HER2-E subtype to predict pCR in 91 patients with clinically HER2-positive disease treated with trastuzumab-based chemotherapy in the ISPY-1, MDACC and XeNA studies.

PDF file - 104K, Association of the PAM50 Proliferation, RORS and RORP continuous scores with response and event-free survival (EFS).

PDF file - 92K, Affymetrix U133A 2.0 probes used for in this study for PAM50 subtyping.

Background: Loss-of-function mutations in genes encoding components of the homologous recombination DNA damage response (DDR) machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). In EMBRACA, the PARPi TALA improved progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P<0.001) vs chemotherapy (CT) in germline BRCA-mutated (gBRCAm) HER2− advanced breast cancer. BRCA1/2 deficiency is associated with elevated PD-L1 expression in ovarian cancers, and PARP inhibition has been associated with PD-L1 upregulation in nonclinical models (Stewart et al, Cancer Res 2018;78:6717-25). Little is known about the potential for PD-L1 expression to modulate sensitivity to PARPi monotherapy in the clinic. Recently, a neoadjuvant study of olaparib in unselected, primary triple-negative breast cancer (TNBC), demonstrated a significant correlation between PD-L1 expression (using the 22C3 antibody) and response to olaparib (Eikesdal et al, Ann Oncol 2021;32:240-9). In contrast, this EMBRACA analysis assessed the contribution of PD-L1 status to TALA sensitivity in a uniformly gBRCAm patient (pt) population. Methods: Available baseline tumor tissue blocks from 120 of 431 EMBRACA pts (28% of intent-to-treat) were sectioned and slides immunostained using SP142/Ventana anti-PD-L1 at HistoGeneX (Naperville, Illinois). PD-L1 immunohistochemistry (IHC) status was assessed as the proportion of tumor area occupied by PD-L1 stained immune cells (IC) of any intensity, with ≥1% defined as PD-L1+. The overall response rate (ORR), defined as unconfirmed complete or partial response (CR/PR), was assessed by investigators. PFS was assessed by an Independent Review Facility. Results: 92/120 (77%) tumors were evaluable for PD-L1 IHC status. Of these 92 evaluable tumors, 9/36 (25%) TNBC and 15/56 (27%) hormone receptor-positive (HR+) tumors were PD-L1+ (24/92, 26% combined TNBC and HR+). In the TALA arm, the ORR was similar for PD-L1+ and PD-L1− tumors for TNBC pts: 2/5 (40%) and 6/19 (32%), respectively. In contrast, the ORR was higher for PD-L1+ vs PD-L1− tumors for HR+ pts: 11/12 (92%) vs 12/31 (39%), exact P value=0.002 (for combined TNBC and HR+, 13/17 [76%] vs 18/50 [36%], P=0.005). For the CT arm, the limited numbers evaluable for both PD-L1 and response (n=25 total), with only one response, precluded similar analysis. Based on the imbalanced results in ORR according to PD-L1 status in pts with HR+ disease, Cox regression analysis was used to explore potential associations of PD-L1 status with PFS. In the TALA arm, median PFS was similar for TNBC independent of PD-L1 status (6.3 mo and 7.0 mo, respectively; HR [95% CI] 1.207 [0.371-3.929]). Median PFS was numerically longer for PD-L1+ vs PD-L1− for HR+ tumors; this difference was not significant (20.2 mo vs 9.2 mo; HR [95% CI] 1.154 [0.395-3.367]). In the CT arm, PD-L1 status was not associated with PFS, although the PD-L1 subgroups were small (For HR+: PD-L1+, n=3; PD-L1−, n=10). Conclusions: Based on these exploratory, retrospective subgroup analyses, PD-L1 positivity by SP142/Ventana was lower in EMBRACA than previously reported in TNBC using the same scoring algorithm: 24/92 (26%) vs 369/902 (41%) in IMpassion130 (Schmid et al, Lancet Oncol 2020;21:44-59). PD-L1+ status was associated with higher ORR in HR+ EMBRACA pts receiving TALA. Interestingly, the enhanced responsiveness for PD-L1+ was not associated with improved PFS, although this assessment is complicated by low pt numbers. Further research is warranted to explore the relationship between baseline tumor PD-L1 status and sensitivity to PARPi, particularly in light of ongoing clinical studies evaluating combinations of immunotherapy and PARPi. Citation Format: Hope S. Rugo, Joanne L. Blum, A. Douglas Laird, Sara A. Hurvitz, Johannes Ettl, Lida A. Mina, Kyung-Hun Lee, Anthony Gonçalves, Rinat Yerushalmi, Young-Hyuck Im, Miguel Martin, Louis Fehrenbacher, Henri H. Roché, Ying Chen, Silvana Lanzalone, Jijumon Chelliserry, Wolfgang Eiermann, Jennifer K. Litton. Identification of PD-L1+ status as a candidate predictive biomarker of response to talazoparib (TALA) in the phase 3 EMBRACA study [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 P5-13-08.

AbstractPurpose: Cardiac toxicity is a serious potential complication of HER2-directed therapies and anthracyclines. HER2 codon 655 and SLC28A3 gene polymorphisms have been reported to be associated with cardiac toxicity from anti-HER2 and anthracycline therapy, respectively. Association of the polymorphism at HER2 codon 655 with prognosis has also been reported. Experimental Design: Whole blood samples from patients treated on a randomized adjuvant breast cancer trial (BCIRG-006) that compared chemotherapy with or without trastuzumab plus either anthracycline or nonanthracycline chemotherapy were tested for genetic polymorphisms in HER2 codon 655 and SLC28A3. Genotypes were correlated with cardiac function and disease-free survival (DFS) outcomes. Results: Of 3,222 patients enrolled in BCIRG-006, 662 patient samples were successfully genotyped for the rs1136201 allele in HER2 (codon 655): 424 (64%) were AA, 30 (4.5%) were GG, and 208 (31%) were AG genotype. In addition, 665 patient samples were successfully genotyped for the rs7853758 allele in the SLC28A3 gene: 19 (3%) were AA, 475 (71%) were GG, and 171 (26%) were AG genotype. Follow-up time was 10 years. No correlation between DFS, cardiac event rate, or mean left ventricular ejection fraction (LVEF) and rs1136201 genotype was seen in the trastuzumab-treated or non–trastuzumab-treated patients. Moreover, mean LVEF and cardiac event rates were similar in all rs7853758 genotype groups treated with anthracycline-based therapy. Conclusions: In the largest study to date to evaluate whether two polymorphisms are associated with DFS and/or cardiac toxicity in HER2-positive breast cancer treated with trastuzumab and/or anthracyclines, we observed no correlation.

Background The TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses. Methods In total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0–N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT. Results Local recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt . Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17–0.88) P = 0.0091. Conclusion TARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect. Trial registration ISRCTN34086741 (21/7/2004), NCT00983684 (24/9/2009).

Abstract Introduction: Although HER2+ breast cancer (BC) is considered a moderately immunogenic tumor, several studies have shown a role of pre-existing immunity associated with favorable long-term prognosis and better response to treatment. In this study, we performed exploratory analyses to assess whether the efficacy of HER2 targeted treatment in the MARIANNE trial correlated with immune gene expression. Methods: MARIANNE (NCT01120184) is a phase 3 study in patients (pts) with centrally confirmed HER2+ local advanced/metastatic BC naïve to prior treatments in the advanced disease. Pts were randomized (1:1:1) to trastuzumab+taxane (HT), T-DM1, or T-DM1+Petuzumab (P) and the trial showed noninferior PFS of T-DM1 and T-DM1+P vs HT. Gene expression (RNA) analysis was performed on tumor samples by a custom 800-gene codeset on the nCounter platform. PD-L1, CD8 expressions and immune gene signatures (sign) analyses were assessed by multivariate Cox regression models using median (cut-off) as categorical variable and adjusted by prior HT, presence of visceral disease, world region, baseline ECOG, measureable disease at baseline, therapy setting, HER2 mRNA expression, PIK3CA mutation status. Results: MARIANNE randomized 1095 pts (HT, n=365; T-DM1, n=367; T-DM1+P, n=363). Gene expression results were available for 671 pts (61.3% of the intent-to-treat [ITT] population) which was representative of ITT. In ITT, HR below 1 was observed when comparing pts with high (>median) vs low (≤median) immune gene expression by clinical outcome suggesting a potential association of high immune marker expression with improved PFS (Table 1) and to some extent with OS (data not shown). This association was primarily observed in the T-DM1 arm where the HR suggested a risk reduction of disease progression(PD)/death especially in the high Teff, high PD-L1 and high CD8 subgroups, and to some extent in the HT arm (Table 1). When assessing the predictive impact on PFS by comparing T-DM1 vs HT, HR below 1 was observed especially in pts with high Teff signature, high PD-L1 and high CD8 expressions (HR 0.67 (95% CI (0.47-0.95)), HR 0.68 (95% CI (0.48-0.97), and HR 0.64 (95%CI 0.44-0.93), respectively). When comparing T-DM1+P vs. HT, HR below 1 was observed especially in pts with low Teff signature and low PD-L1 expression (HR 0.70 (95% CI (0.50-0.99), and HR 0.68 (95% CI (0.48-0.96) respectively). No clear differences between immune gene expression subgroups was observed when comparing treatment arms in regards to OS (data not shown). Conclusions: In the exploratory analysis from the MARIANNE study, high immune gene expression, especially in the high PD-L1, CD8 and Teff subgroups, showed an association with improved clinical benefit with HRs reflecting for a risk reduction of PD/death for PFS and partially for OS. This association was less obvious in the T-DM1+P arm. When comparing the treatments effect, the data showed a potential impact of high Teff signature, and high CD8 and PD-L1 expressions on T-DM1 and less on HT. The potential opposite association of low Teff signature and low PD-L1 expression with improved benefit in the T-DM1+P arm was unexpected and needs further investigation. Table 1: Prognostic biomarker effect on PFSBiomarker by categories (>Median vs ≤Median)HR (95% CI) ITT n=671HR (95% CI) HT n=220HR (95% CI) T-DM1 n=227HR (95% CI) T-DM1+P n=224Teff sign0.89 (0.73-1.09)0.97 (0.68-1.38)0.64 (0.45-0.91)1.09 (0.75-1.58)Th1 cytokine sign0.91 (0.74-1.11)0.92 (0.64-1.31)0.78 (0.55-1.11)0.96 (0.67-1.36)Checkpoint inhibitor sign0.95 (0.78-1.15)0.91 (0.64-1.29)0.90 (0.64-1.26)1.02 (0.71-1.47)PD-L10.80 (0.66-0.98)0.79 (0.55-1.13)0.62 (0.44-0.87)1.07 (0.74-1.55)CD80.91 (0.75-1.11)1.10 (0.77-1.57)0.66 (0.46-0.93)0.98 (0.68-1.41) Citation Format: Edith A Perez, Sanne Lysbet de Haas, Carlos H Barrios, Wolfgang Eiermann, Masakazu Toi, Young-Hyuck Im, Pier Franco Conte, Miguel Martin, Tadeusz Pienkowski, Xavier B Pivot, Howard A Burris III, Chiara Lambertini, Silke Hoersch, Monika Patre, Paul Anthony Ellis. Association of immune gene expression with outcome in the MARIANNE phase 3 clinical trial in HER2-positive metastatic breast cancer (MBC) [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 PD5-11.

AbstractObjectiveTo determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast external beam radiotherapy for early breast cancer.DesignProspective, open label, randomised controlled clinical trial.Setting32 centres in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada.Participants2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1, eligible for breast conservation and randomised before lumpectomy (1:1 ratio, blocks stratified by centre) to either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT).InterventionsRandom allocation was to the EBRT arm, which consisted of a standard daily fractionated course (three to six weeks) of whole breast radiotherapy, or the TARGIT-IORT arm. TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic and was the only radiotherapy for most patients (around 80%). TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients).Main outcome measuresNon-inferiority with a margin of 2.5% for the absolute difference between the five year local recurrence rates of the two arms, and long term survival outcomes.ResultsBetween 24 March 2000 and 25 June 2012, 1140 patients were randomised to TARGIT-IORT and 1158 to EBRT. TARGIT-IORT was non-inferior to EBRT: the local recurrence risk at five year complete follow-up was 2.11% for TARGIT-IORT compared with 0.95% for EBRT (difference 1.16%, 90% confidence interval 0.32 to 1.99). In the first five years, 13 additional local recurrences were reported (24/1140 v 11/1158) but 14 fewer deaths (42/1140 v 56/1158) for TARGIT-IORT compared with EBRT. With long term follow-up (median 8.6 years, maximum 18.90 years, interquartile range 7.0-10.6) no statistically significant difference was found for local recurrence-free survival (hazard ratio 1.13, 95% confidence interval 0.91 to 1.41, P=0.28), mastectomy-free survival (0.96, 0.78 to 1.19, P=0.74), distant disease-free survival (0.88, 0.69 to 1.12, P=0.30), overall survival (0.82, 0.63 to 1.05, P=0.13), and breast cancer mortality (1.12, 0.78 to 1.60, P=0.54). Mortality from other causes was significantly lower (0.59, 0.40 to 0.86, P=0.005).ConclusionFor patients with early breast cancer who met our trial selection criteria, risk adapted immediate single dose TARGIT-IORT during lumpectomy was an effective alternative to EBRT, with comparable long term efficacy for cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned.Trial registrationISRCTN34086741, NCT00983684.

Importance Conventional adjuvant radiotherapy for breast cancer given daily for several weeks is onerous and expensive. Some patients may be obliged to choose a mastectomy instead, and some may forgo radiotherapy altogether. We proposed a clinical trial to test whether radiotherapy could be safely limited to the tumor bed. Objective To determine whether delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) is noninferior to whole-breast external beam radiotherapy (EBRT) in terms of local control. Design, Setting, and Participants In this prospective, randomized (1:1 ratio) noninferiority trial, 1153 patients aged 45 years or older with invasive ductal breast carcinoma smaller than 3.5 cm treated with breast conservation were enrolled from 28 centers in 9 countries. Data were locked in on July 3, 2019. Interventions The TARGIT-A trial was started in March 2000; patients were randomized after needle biopsy to receive TARGIT-IORT immediately after lumpectomy under the same anesthetic vs EBRT and results have been shown to be noninferior. A parallel study, described in this article, was initiated in 2004; patients who had their cancer excised were randomly allocated using separate randomization tables to receive EBRT or delayed TARGIT-IORT given as a second procedure by reopening the lumpectomy wound. Main Outcomes and Measures A noninferiority margin for local recurrence rate of 2.5% at 5 years, and long-term survival outcomes. Results Overall, 581 women (mean [SD] age, 63 [7] years) were randomized to delayed TARGIT-IORT and 572 patients (mean [SD] age, 63 [8] years) were randomized to EBRT. Sixty patients (5%) had tumors larger than 2 cm, or had positive nodes and only 32 (2.7%) were younger than 50 years. Delayed TARGIT-IORT was not noninferior to EBRT. The local recurrence rates at 5-year complete follow-up were: delayed TARGIT-IORT vs EBRT (23/581 [3.96%] vs 6/572 [1.05%], respectively; difference, 2.91%; upper 90% CI, 4.4%). With long-term follow-up (median [IQR], 9.0 [7.5-10.5] years), there was no statistically significant difference in local recurrence-free survival (HR, 0.75; 95% CI, 0.57-1.003;P = .052), mastectomy-free survival (HR, 0.88; 95% CI, 0.65-1.18;P = .38), distant disease-free survival (HR, 1.00; 95% CI, 0.72-1.39;P = .98), or overall survival (HR, 0.96; 95% CI, 0.68-1.35;P = .80). Conclusions and Relevance These long-term data show that despite an increase in the number of local recurrences with delayed TARGIT-IORT, there was no statistically significant decrease in mastectomy-free survival, distant disease-free survival, or overall survival. Trial Registration ISRCTN34086741, ClinicalTrials.gov Identifier:NCT00983684

1018 Background: Loss-of-function mutations in genes encoding components of the homologous recombination DNA damage response (DDR) machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). In EMBRACA, the PARPi TALA showed an improvement in progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P < 0.001) vs physician's choice of chemotherapy (PCT) in g BRCAm HER2− ABC. Methods: Baseline tumor tissue from 308 pts (71%; intent-to-treat) was sequenced using the FoundationOne CDx panel. Mutations summarized below were known/likely pathogenic single-nucleotide variants, insertions, deletions, or rearrangements. Best tumor response (BOR) was using RECIST 1.1 by Investigator (confirmation of CR or PR not required). Results: 296/308 (96%) of evaluable pts exhibited ≥1 tumor BRCA mutation, with 7 of the remaining 12 exhibiting BRCA copy number alterations deemed pathogenic. Mutations in other genes implicated in DDR and/or potential sensitization to PARPi were rare, with mutations detected in BARD1, CDK12, FANCG, STAG2 (each 0.3%), ATR, BRD4, FANCC, PALB2, RAD51B (0.6%), ATM, BRIP1 (1.0%), NBN (1.3%), CHEK2, FANCA (1.6%), and ARID1A (2.3%). No association was observed between total number of DDR mutations, including BRCA1/2, and best tumor response (BOR) [odds ratio of 1 vs ≥2 DDR mutations (95% CI): TALA, 0.76 (0.31-1.87), P = 0.55; PCT, 0.98 (0.27-3.51), P = 0.97]. TP53 and PIK3CA were the most commonly mutated non- BRCA genes in BRCAm tumors (52.0 and 10.8%, respectively). TP53 mutations were more prevalent in BRCA1m vs BRCA2m tumors (85.2 vs 24.8%). PIK3CA mutations were more prevalent in BRCA2m vs BRCA1m tumors (15.9 vs 5.2%). With TALA, PFS was significantly shorter in pts with TP53 mutations than without [HR (95% CI) 1.693 (1.186-2.418), P = 0.0033]. A similar, non-significant, trend was evident with PCT [HR (95% CI) 1.439 (0.859-2.411), P = 0.1614]. PIK3CA mutational status had no impact on PFS in either arm. Conclusions: Selection based on g BRCA mutational status is appropriate to identify HER2─ ABC pts with potential for clinical benefit from TALA, with the total number of tumor mutations in BRCA1/2 and other DDR genes not impacting response (within the g BRCAm subset). TP53 mutations were associated with shorter PFS, likely reflecting the worse outcomes observed in g BRCA1m patients. Additional correlative analyses are ongoing. Clinical trial information: NCT01945775 .

Abstract Background: Loss-of-function mutations in genes encoding components of the homologous recombination machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. In EMBRACA, the PARP inhibitor talazoparib (TALA) demonstrated a significant improvement in the primary endpoint of progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P < 0.001) vs physician's choice of chemotherapy (PCT) in pts with HER2− ABC and a gBRCA1/2 mutation. Methods: Baseline tumor tissue (primary or metastatic sites) from 308 pts (71%) in the intent-to-treat population was sequenced using the FoundationOne CDx NGS panel. Mutations summarized below were known/likely pathogenic single-nucleotide variants, insertions, deletions, or rearrangements. Additional exploratory computational analyses pertinent to homologous recombination deficiency were performed, including somatic-germline-zygosity (SGZ) and gLOH assessments. Results: 296/308 (96%) of evaluable pts exhibited ≥1 tumor BRCA mutation, with BRCA1 and BRCA2 mutations mainly mutually exclusive (4/308 [1%] pts had both BRCA1 and BRCA2 mutations). Of 12 pts with no apparent BRCA mutations, 7 exhibited tumor BRCA copy number alterations deemed pathogenic and 2 had BRCA single-nucleotide variants deemed of unknown pathogenicity. 195/236 (83%) BRCA-mutant (BRCAm) pts evaluable for BRCA LOH status were predicted to exhibit BRCA LOH by SGZ analysis. The potential impact of tumor BRCA mutational zygosity on PFS was explored in the TALA arm calculating HR by Cox proportional hazards model, comparing 122 pts with BRCA LOH with 27 pts without BRCA LOH. This analysis demonstrated no difference in PFS [HR (95% CI): 1.152 (0.680-1.951); P = 0.597)]. gLOH scores were variable, but mostly high: median (range), 21.8% (0.0, 52.7) and 20.5% (0.2, 40.5) for TALA and PCT arms, respectively. The potential association of gLOH scores with selected measures of efficacy was explored. Within both arms gLOH was similar in those pts achieving vs pts not achieving clinical benefit as defined by complete response, partial response, or stable disease ≥24 wks per RECIST v.1.1 as determined by investigator (P = 0.976 and 0.492, respectively, using 2-tailed t-test). In both arms, pts with gLOH ≥ median vs gLOH < median exhibited similar PFS: HR (95% CI) 1.247 (0.828-1.879) for TALA; 1.238 (0.693-2.211) for PCT, with HR <1 favoring gLOH ≥ median. Conclusions: Selection based on gBRCA mutational status is appropriate to identify HER2− ABC pts with potential for clinical benefit with PARP inhibitors, with tumor BRCA zygosity and gLOH not impacting outcome (within the gBRCAm subset). Additional exploratory correlative analyses are ongoing and will be reported. Citation Format: Jennifer K. Litton, A. Douglas Laird, Hope S. Rugo, Johannes Ettl, Sara A. Hurvitz, Miguel Martin, Henri Roché, Young-Hyuck Im, Annabel Goodwin, Joanne L. Blum, Wolfgang Eiermann, Ying Chen, Silvana Lanzalone, Jijumon Chelliserry, Akos Czibere, Lee A. Albacker, Garrett M. Frampton, Lida A. Mina. Exploration of impact of tumor BRCA zygosity and genomic loss-of-heterozygosity (gLOH) on efficacy in Phase 3 EMBRACA study of talazoparib in patients (pts) with HER2-negative (HER2−) advanced breast cancer (ABC) and a germline BRCA1/2 (gBRCA1/2) mutation [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 CT072.

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 < 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 < 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.

Background: 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 (gBRCA1/2)-mutated advanced breast cancer (ABC). We report final overall survival (OS). Patients and methods: This randomized phase III trial enrolled patients with gBRCA1/2-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. Results: 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). KaplaneMeier 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. Conclusions: In gBRCA1/2-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.