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Efficacy and safety of first-line veliparib and carboplatin–paclitaxel in patients with HER2− advanced germline BRCA+ breast cancer: Subgroup analysis of a randomised clinical trial

Open AccessPublished:July 06, 2021DOI:https://doi.org/10.1016/j.ejca.2021.05.037

      Highlights

      • BROCADE3 showed veliparib plus platinum efficacy for BRCA+ advanced breast cancer.
      • This subanalysis was in patients without prior chemotherapy for metastatic disease.
      • Addition of veliparib to carboplatin–paclitaxel led to durable disease control.
      • The data suggest a benefit of veliparib plus platinum in early lines of therapy.

      Abstract

      Background

      Addition of veliparib to carboplatin–paclitaxel, with continuation of veliparib monotherapy if carboplatin–paclitaxel was discontinued, improved progression-free survival (PFS) in patients with germline BRCA-associated locally advanced/metastatic HER2− breast cancer and ≤2 lines of previous cytotoxic therapy for metastatic disease in BROCADE3. A pre-planned subgroup analysis evaluated efficacy and safety in patients without previous cytotoxic therapy for metastatic disease.

      Methods

      Patients were randomised 2:1 to receive veliparib (120 mg orally BID) or placebo on days −2 to 5. Carboplatin (AUC 6) was administered on day 1, and paclitaxel (80 mg/m2) on days 1, 8 and 15 (21-day cycles). Patients discontinuing carboplatin–paclitaxel for reasons besides progression could continue veliparib/placebo monotherapy (300 mg BID, increasing to 400 mg BID if tolerated) until progression. The primary end-point was PFS assessed by investigator.

      Results

      Of 509 patients in the intention-to-treat population (98.6% female; mean age 47, standard deviation 11), 413 (81%) had no previous cytotoxic therapy for metastatic disease (274, veliparib; 139, placebo). In the first-line subgroup, median PFS was 16.6 months (95% confidence interval [CI] 13.4–18.7) versus 13.1 months (95% CI 11.4–14.5) for the veliparib versus control groups (hazard ratio 0.70, 95% CI 0.54–0.89, P = .004). More patients were alive and progression-free at 2 years (36% versus 23.2%) and 3 years (27.9% versus 13.3%) in the veliparib versus control group. Adverse events unrelated to progression leading to study drug discontinuation occurred in 25 (9.1%) and 8 (5.8%) patients.

      Conclusions

      Veliparib with carboplatin–paclitaxel led to durable disease control among first-line patients, suggesting a benefit of this treatment approach in early lines.

      Clinical trial registration

      NCT02163694.

      Keywords

      1. Introduction

      Patients with germline breast cancer gene (BRCA) (gBRCA) mutation-associated breast cancer are generally diagnosed at a younger age, and are more likely to have triple-negative breast cancer (TNBC), or tumours with aggressive luminal B features if their tumours are hormone receptor positive [
      • Atchely D.P.
      • et al.
      Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer.
      ,
      • Larsen M.J.
      • Kruse T.A.
      • Tan Q.
      • et al.
      Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling.
      ]. gBRCA mutation-associated metastatic breast cancers are particularly sensitive to platinum chemotherapy [
      • Tutt A.
      • Tovey H.
      • Cheang M.C.U.
      • et al.
      Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial.
      ,
      • Isakoff S.J.
      • Mayer E.L.
      • He L.
      • et al.
      TBCRC009: a multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer.
      ] and inhibitors of poly(adenosine diphosphate-ribose) polymerase (PARP) [
      • Bryant H.E.
      • Schultz N.
      • Thomas H.D.
      • et al.
      Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
      ,
      • Farmer H.
      • McCabe N.
      • Lord C.J.
      • et al.
      Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
      ]. Clinical data suggest that PARP inhibitors and platinum have increased activity in earlier lines of therapy prior to development of acquired resistance [
      • Isakoff S.J.
      • Mayer E.L.
      • He L.
      • et al.
      TBCRC009: a multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer.
      ,
      • Robson M.E.
      • Tung N.
      • Conte P.
      • et al.
      OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.
      ,
      • Kaufman B.
      • Shapira-Frommer R.
      • Schmutzler R.K.
      • et al.
      Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
      ].
      Veliparib is a potent, orally bioavailable, selective PARP1/2 inhibitor that potentiated platinum activity in preclinical studies [
      • Donawho C.K.
      • Luo Y.
      • Luo Y.
      • et al.
      ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models.
      ]. Veliparib has shown activity and acceptable toxicity as a single agent [
      • Somlo G.
      • Frankel P.H.
      • Arun B.K.
      • et al.
      Efficacy of the PARP inhibitor veliparib with carboplatin or as a single agent in patients with germline BRCA1- or BRCA2-associated metastatic breast cancer: California Cancer Consortium Trial NCT01149083.
      ] and combined with carboplatin and paclitaxel (carboplatin–paclitaxel) in patients with BRCA-mutated advanced breast cancer [
      • Appleman L.J.
      • Beumer J.H.
      • Jiang Y.X.
      • et al.
      A phase I study of veliparib (ABT-888) in combination with carboplatin and paclitaxel in advanced solid malignancies.
      ,
      • Pahuja S.
      • Beumer J.H.
      • Appleman L.J.
      • et al.
      A phase I study of veliparib (ABT-888) in combination with weekly carboplatin and paclitaxel in advanced solid malignancies and enriched for triple-negative breast cancer (TNBC).
      ]. The phase II randomised, placebo-controlled BROCADE trial (NCT01506609) enrolled patients with locally recurrent/metastatic gBRCA mutation-associated breast cancer; the majority of patients had no previous chemotherapy for metastatic disease. The addition of veliparib to carboplatin–paclitaxel resulted in numerical increases in median progression-free survival (PFS) and overall survival (OS) versus carboplatin–paclitaxel alone, without substantial additional toxicity [
      • Han H.S.
      • Dieras V.
      • Robson M.
      • et al.
      Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study.
      ].
      The phase III BROCADE3 trial (NCT02163694) further evaluated veliparib with carboplatin–paclitaxel in patients with human epidermal growth factor receptor 2 negative (HER2-negative) locally advanced/metastatic breast cancer and a gBRCA1/2 mutation [
      • Diéras V.
      • Han H.S.
      • Kaufman B.
      • et al.
      Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer: a randomised, double-blind, placebo-controlled, phase 3 trial.
      ]. Addition of veliparib to carboplatin–paclitaxel improved PFS compared to placebo plus carboplatin–paclitaxel (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.57–0.88, p = 0.002) [
      • Diéras V.
      • Han H.S.
      • Kaufman B.
      • et al.
      Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer: a randomised, double-blind, placebo-controlled, phase 3 trial.
      ]. This pre-planned subgroup analysis evaluated the efficacy and safety of veliparib plus carboplatin–paclitaxel, compared to carboplatin–paclitaxel alone, in BROCADE3 patients without previous cytotoxic therapy in the metastatic setting.

      2. Methods

      2.1 Study design

      This study reports a pre-planned subgroup analysis of BROCADE3, an international, double-blind, placebo-controlled phase III trial at 147 hospitals in 36 countries; patients were screened from 30th July 2014 to 17th January 2018 and efficacy analysis data cut-off was on 5th April 2019 [
      • Diéras V.
      • Han H.S.
      • Kaufman B.
      • et al.
      Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer: a randomised, double-blind, placebo-controlled, phase 3 trial.
      ].

      2.2 Patients

      Eligible patients had metastatic/locally advanced unresectable HER2-negative breast cancer, suspected deleterious/deleterious gBRCA1/2 mutations and Eastern Cooperative Oncology Group performance status 0–2. Patients had received ≤2 previous lines of cytotoxic therapy for metastatic breast cancer, ≤1 previous line of platinum without progression within 12 months of completing treatment and no PARP inhibitor therapy. Prior taxane in neoadjuvant or locally advanced setting was allowed if given >6 months before first dose on study; prior taxane in the metastatic setting was allowed if given >12 months before first dose or for ≤1 cycle without progression. Eligibility was not otherwise restricted based on time to progression on any other prior therapy in any setting. Time interval from primary diagnosis to study start for the enrolled population and the proportion of patients with de novo breast cancer in the study are not available.
      The study was conducted according to the protocol approved by institutional review boards at investigational sites, International Conference on Harmonization Good Clinical Practice guidelines, regulations governing clinical study conduct and ethical principles with their origin in the Declaration of Helsinki. All patients provided written informed consent. An independent data monitoring committee reviewed safety data. Eligibility and study design details were previously described [
      • Diéras V.
      • Han H.S.
      • Kaufman B.
      • et al.
      Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer: a randomised, double-blind, placebo-controlled, phase 3 trial.
      ].

      2.3 Treatment

      Patients were randomised (2:1) to receive carboplatin–paclitaxel with veliparib or carboplatin–paclitaxel with placebo. Randomisation was stratified according to oestrogen receptor (ER) and/or progesterone receptor (PgR) expression (positive or negative), previous platinum therapy (yes or no) and history of central nervous system (CNS) metastases (yes or no), and all parties were blinded to treatment assignment until investigator-assessed disease progression. Patients received veliparib (120 mg orally twice daily [BID]) or placebo on days −2 to 5, carboplatin area under the concentration curve (AUC 6 mg/mL/min intravenously) on day 1 and weekly paclitaxel (80 mg/m2 intravenously) on days 1, 8 and 15 (of 21-day cycles) until disease progression or unacceptable toxicity. Any of the three agents could be dose reduced or discontinued individually at investigator discretion to manage toxicity. Patients discontinuing both carboplatin and paclitaxel for reasons other than disease progression received continuous single-agent veliparib or placebo at 300 mg BID, increasing to 400 mg BID if tolerated. The control group could receive crossover open-label veliparib monotherapy after disease progression.

      2.4 End-points

      The primary end-point was PFS (time from randomisation to disease progression or death from any cause within 63 days of last tumour assessment) assessed by investigator per Response Evaluation Criteria in Solid Tumours version 1.1. Secondary end-points were OS, clinical benefit rate (CBR) at 24 weeks, objective response rate (ORR) and time from randomisation to disease progression on first subsequent therapy or death from any cause (PFS2). Duration of response (DOR) was a tertiary end-point. Adverse events (AEs) were monitored throughout study and graded per NCI Common Terminology Criteria for Adverse Events v4.03.

      2.5 Statistical analysis

      The overall study aimed to enrol 500 patients for a target of 344 PFS events to provide at least 90% power at two-sided alpha level of 0.05 (assuming HR 0.69) to detect a statistically significant treatment effect. Statistical analysis details were previously reported [
      • Diéras V.
      • Han H.S.
      • Kaufman B.
      • et al.
      Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer: a randomised, double-blind, placebo-controlled, phase 3 trial.
      ].
      Log-rank test and Cox proportional hazards model, stratified by previous platinum (yes versus no) and ER/PgR status (positive for one or both versus negative for both), were used to compare treatment groups for PFS, OS, PFS2 and DOR. A logistic regression model, adjusted by previous platinum therapy and ER/PgR status, was used to compare treatment groups for CBR and ORR. All P-values are two-sided and nominal. For comparisons of PFS and OS in the subgroup of patients with prior cytotoxic therapy for metastatic disease, analyses were stratified by ER/PgR status. Statistical analyses were conducted using SAS software v9.4 or later under the UNIX operating system.
      Efficacy analyses were performed on the intention-to-treat (ITT) population which included all randomised patients with a suspected deleterious or deleterious BRCA mutation confirmed by core laboratory (Myriad BRACAnalysis CDx assay). Safety analyses included all patients who received ≥1 dose of veliparib or placebo. Analysis of PFS in the subgroup of patients without previous cytotoxic therapy for metastatic disease was pre-planned but not powered for statistical significance.

      3. Results

      3.1 Patients

      In total, 513 patients were randomised in BROCADE3 (509 in ITT population; 337 veliparib group, 172 control group); 81% of patients in each group had no previous cytotoxic therapy for metastatic disease [
      • Diéras V.
      • Han H.S.
      • Kaufman B.
      • et al.
      Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer: a randomised, double-blind, placebo-controlled, phase 3 trial.
      ]. In this subgroup, 274 were randomised to veliparib and 139 to control (Fig. 1). Baseline characteristics were generally balanced between groups (Table S1). Time interval from primary diagnosis to study start for the enrolled population and the proportion of patients with de novo breast cancer are not available.
      Fig. 1
      Fig. 1CONSORT diagram. Patient allocation for the BROCADE3 study and subgroup analysis. AE, adverse event; C/P, carboplatin and paclitaxel; ITT, intention-to-treat; PD, progressive disease.

      3.2 Efficacy

      It was previously reported that veliparib added to carboplatin–paclitaxel significantly improved PFS compared to placebo plus carboplatin–paclitaxel in the overall patient population [
      • Diéras V.
      • Han H.S.
      • Kaufman B.
      • et al.
      Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer: a randomised, double-blind, placebo-controlled, phase 3 trial.
      ]. Analyses of PFS within subgroups generally favoured the veliparib group, including in the subgroup of patients without previous chemotherapy in the metastatic setting.
      Within the subgroup of patients with no previous chemotherapy for metastatic disease, patients in both treatment groups received a similar duration of chemotherapy. Patients without previous chemotherapy for metastatic disease received a mean (standard deviation [SD]) of 11 (9) cycles and 11 (8) cycles of carboplatin in the veliparib and control groups, respectively; mean cycles of paclitaxel were 12 (10) and 11 (9) cycles for the veliparib and control groups (Table S2). The proportion of patients who discontinued both carboplatin and paclitaxel for reasons other than disease progression and then received blinded monotherapy during the study was 42.5% and 32.4% in the veliparib and control groups, respectively.
      Within this subgroup, PFS events had been recorded in 62% (171/274) of patients in the veliparib group versus 74% (103/139) of patients in the control group at the time of data cut-off. Median PFS per investigator was 16.6 months (95% CI 13.4–18.7) in the veliparib group versus 13.1 months (95% CI 11.4–14.5) in the control group (HR 0.70, 95% CI 0.54–0.89, two-sided log-rank p = 0.004) (Fig. 2A). More patients were alive and progression-free in the veliparib compared to control group at 2 years (36% versus 23%) and 3 years (28% versus 13%). PFS by blinded independent central review showed similar results (HR 0.63, 95% CI 0.47–0.84, log-rank p = 0.002) (Fig. 2B).
      Fig. 2
      Fig. 2Kaplan–Meier estimates of PFS by investigator assessment (A), PFS by central assessment (B), and interim OS (C) for patients with no previous cytotoxic therapy in the metastatic setting. Kaplan–Meier estimates of the proportion of patients alive and progression-free at 24 and 36 months are shown. P-values were by 2-sided log-rank test. P-values were by a stratified Cox proportional hazards model (stratified by prior platinum therapy [yes versus no] and receptor status [oestrogen and/or progesterone receptor positive versus ER/PgR negative]). BICR, blinded independent central review; CI, confidence interval; C/P, carboplatin and paclitaxel; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; ER, oestrogen receptor; PgR, progesterone receptor.
      Fig. 2
      Fig. 2Kaplan–Meier estimates of PFS by investigator assessment (A), PFS by central assessment (B), and interim OS (C) for patients with no previous cytotoxic therapy in the metastatic setting. Kaplan–Meier estimates of the proportion of patients alive and progression-free at 24 and 36 months are shown. P-values were by 2-sided log-rank test. P-values were by a stratified Cox proportional hazards model (stratified by prior platinum therapy [yes versus no] and receptor status [oestrogen and/or progesterone receptor positive versus ER/PgR negative]). BICR, blinded independent central review; CI, confidence interval; C/P, carboplatin and paclitaxel; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; ER, oestrogen receptor; PgR, progesterone receptor.
      At the pre-planned interim analysis, OS was 36.0 months (95% CI 32.0–43.1) for the veliparib group and 29.9 months (95% CI 26.0–39.3) for the control group (HR 0.92, 95% CI 0.68–1.24, p = 0.570; 127 [46%] events in 274 patients versus 67 [48%] events in 139 patients) (Fig. 2C) within the subgroup. At the time of this analysis, 43.2% (60/139) of patients randomly assigned to the control group had received open-label veliparib (crossover) as the first subsequent therapy.
      Within the subgroup, investigator-assessed CBR at week 24 and ORR were high and similar between treatment groups (Table 1). Median DOR in patients with a confirmed complete or partial response was 16.5 months for the veliparib group versus 11.3 months for the control group (HR 0.63, 95% CI 0.46–0.85, p = 0.003). Median PFS2 was 23.7 versus 17.9 months (HR 0.71, 95% CI 0.55–0.93, p = 0.011). Subsequent therapies are given in Table S3.
      Table 1Clinical benefit rate and overall response rate for patients with no previous cytotoxic therapy for metastatic disease.
      Veliparib plus carboplatin–paclitaxel (n = 274)Placebo plus carboplatin–paclitaxel (n = 139)
      CBR at 24 weeks, % (95% CI)92.8 (90.0, 94.9)93.4 (89.1, 96.0)
      ORR
       % (95% CI)79.7 (74.0, 84.7)76.3 (67.4, 83.8)
       n/N185/23287/114
      PFS2
       Events150/27490/139
       Median PFS2, months (95% CI)23.7 (20.5–32.1)17.9 (16.6–20.8)
       Hazard ratio (95% CI)0.71 (0.55–0.93)
      DOR
       Events106/18568/87
       Median DOR, months (95% CI)16.5 (12.5–20.5)11.3 (10.2–12.3)
       Hazard ratio (95% CI)0.63 (0.46–0.85)
      CBR, clinical benefit rate; CI, confidence interval; ORR, objective response rate; PFS2, progression-free survival on subsequent therapy; DOR, duration of response.
      An exploratory analysis of PFS was conducted among patients without previous cytotoxic therapy in the metastatic setting in subgroups defined by hormone receptor status. Among ER and/or PgR positive patients, PFS HR was 0.67 (95% CI 0.48–0.93) (median PFS 15.1 months [95% CI 12.5–18.7] versus 12.6 months [95% CI 10.4–14.4] in the veliparib and control groups, respectively). Among ER and PgR negative patients, PFS HR was 0.72 (95% CI 0.50–1.04) (median PFS 17.7 months [95% CI 13.4–24.9] versus 14.4 months [95% CI 10.6–16.6]).
      Efficacy in patients without previous cytotoxic therapy in any setting was evaluated in an exploratory analysis. Median PFS and OS were longer in the veliparib group. HR for PFS by investigator was 0.55 (95% CI 0.33–0.91) (Fig. 3A). Results per central review were consistent (Fig. S1). OS HR was 0.76 (95% CI 0.41–1.43) (Fig. 3B). ORR and CBR were comparable between treatment groups, but PFS2 and DOR were improved in the veliparib group (Table S4). Additional baseline characteristics, treatment exposure and subsequent therapies for this subgroup are given in Tables S5–S7.
      Fig. 3
      Fig. 3Kaplan–Meier estimates of PFS by investigator assessment (A) and OS (B) for patients with no previous cytotoxic therapy in any setting. Kaplan–Meier estimates of the proportion of patients alive and progression-free at 24 and 36 months are shown. P-values were by a stratified Cox proportional hazards model (stratified by prior platinum therapy [yes versus no] and receptor status [oestrogen and/or progesterone receptor positive versus ER/PgR negative]). CI, confidence interval; C/P, carboplatin and paclitaxel; HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival; ER, oestrogen receptor; PgR, progesterone receptor.
      Sixty-three patients (18.7%) and 33 patients (19.2%) of the ITT population had prior chemotherapy in the metastatic setting in the veliparib and control arms, respectively. Among these patients, the PFS by investigator was 9.5 months (95% CI 8.3–12.5) in the veliparib group and 10.3 months (95% CI 8.3–14.5) in the control group (HR 0.80, 95% CI 0.50–1.3, p = 0.34). The interim OS was 21.4 months (95% CI 17.8–28.8) and 22.5 months (95% CI 17.1–32.7) (HR 1.09, 95% CI 0.63–1.86, p = 0.77).

      3.3 Safety

      AEs occurring in ≥20% of patients for the subgroup of patients without previous cytotoxic therapy for metastatic disease are given in Table 2. Common any-grade AEs with >5% difference between the veliparib and control groups were anaemia (81%/69%), thrombocytopenia (80%/71%), nausea (74%/67%) and diarrhoea (48%/38%). Serious AEs occurred in 91 (33.1%) patients in the veliparib group and 43 (30.9%) in control group. The most common serious AE among patients in the veliparib group was anaemia, occurring in 13 patients (4.7%) compared to 5 patients (3.6%) in the control group (Table S8). AEs leading to discontinuation of study drug that were not related to progression occurred in 25 (9.1%) patients in the veliparib group and 8 (5.8%) patients in control group. AEs leading to death occurred in 5 patients (1.8%) in the veliparib group (malignant neoplasm progression in 4 patients and sepsis in 1 patient) and 3 patients (2.2%) in the control group (malignant neoplasm progression in 2 patients and pulmonary artery thrombosis in 1 patient); all were assessed as unrelated to veliparib/placebo by the investigator.
      Table 2Adverse events summary for patients with no previous cytotoxic therapy in the metastatic setting.
      n (%)Veliparib plus carboplatin–paclitaxel

      N = 275
      Placebo plus carboplatin–paclitaxel

      N = 139
      Any gradeGrade ≥3Any gradeGrade ≥3
      Any adverse event273 (99.3)267 (97.1)139 (100)133 (95.7)
      Any serious adverse event91 (33.1)NA43 (30.9)NA
      Any adverse event leading to study drug discontinuation43 (15.6)NA15 (10.8)NA
      Any adverse event leading to study drug discontinuation (not related to progression)25 (9.1)NA8 (5.8)NA
      Any adverse event leading to death5 (1.8)NA3 (2.2)NA
      Neutropenia251 (91.3)227 (82.5)124 (89.2)113 (81.3)
      Anaemia223 (81.1)114 (41.5)96 (69.1)52 (37.4)
      Thrombocytopenia219 (79.6)104 (37.8)98 (70.5)41 (29.5)
      Nausea202 (73.5)16 (5.8)93 (66.9)4 (2.9)
      Alopecia151 (54.9)071 (51.1)0
      Fatigue137 (49.8)20 (7.3)69 (49.6)7 (5.0)
      Peripheral sensory neuropathy132 (48.0)15 (5.5)71 (51.1)7 (5.0)
      Diarrhoea132 (48.0)14 (5.1)53 (38.1)5 (3.6)
      Leucopaenia106 (38.5)73 (26.5)53 (38.1)37 (26.6)
      Vomiting98 (35.6)10 (3.6)52 (37.4)1 (0.7)
      Constipation96 (34.9)1 (0.4)50 (36.0)1 (0.7)
      Asthenia77 (28.0)7 (2.5)35 (25.2)2 (1.4)
      Decreased appetite68 (24.7)2 (0.7)39 (28.1)0
      Headache96 (34.9)4 (1.5)48 (34.5)1 (0.7)
      Hypomagnesaemia69 (25.1)7 (2.5)32 (23.0)7 (5.0)
      Cough62 (22.5)026 (18.7)0
      Back pain58 (21.1)8 (2.9)35 (25.2)2 (1.4)
      Epistaxis57 (20.7)024 (17.3)0
      Arthralgia53 (19.3)034 (24.5)1 (0.7)
      Pyrexia51 (18.5)3 (1.1)31 (22.3)0
      Adverse events of any grade occurring in at least 20% of patients, and the corresponding grade ≥3 adverse events are shown. The adverse event rates include all adverse events during the treatment emergent period, which includes veliparib or placebo in combination with carboplatin and paclitaxel and veliparib or placebo single agent, if applicable.
      NA, not applicable.

      4. Discussion

      Tumours with BRCA mutations have deficiencies in homologous recombination repair, which render the cells more sensitive to DNA-damaging agents, such as platinum, and to PARP inhibitors. Efficacy of platinum and PARP inhibitors has been demonstrated in patients with BRCA-associated breast cancer [
      • Tutt A.
      • Tovey H.
      • Cheang M.C.U.
      • et al.
      Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial.
      ,
      • Isakoff S.J.
      • Mayer E.L.
      • He L.
      • et al.
      TBCRC009: a multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer.
      ,
      • Robson M.
      • Im S.A.
      • Senkus E.
      • et al.
      Olaparib for metastatic breast cancer in patients with a germline BRCA mutation.
      ]. Emerging data suggest that both platinum and PARP inhibitors may be particularly beneficial in earlier lines of therapy. An exploratory subgroup analysis in a single-arm phase II study of platinum monotherapy for metastatic TNBC suggested improved response rates for first- versus second-line treatment [
      • Isakoff S.J.
      • Mayer E.L.
      • He L.
      • et al.
      TBCRC009: a multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer.
      ]. In a phase III study of olaparib versus single-agent non-platinum chemotherapy in patients with BRCA1/2-mutated metastatic breast cancer, subgroup analysis suggested greater OS benefit among patients without previous chemotherapy for metastatic breast cancer for olaparib versus control [
      • Robson M.E.
      • Tung N.
      • Conte P.
      • et al.
      OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.
      ]. Additionally, a phase II study demonstrated that ORR with olaparib improved when used in earlier treatment lines for patients with advanced cancer and gBRCA1/2 mutations [
      • Kaufman B.
      • Shapira-Frommer R.
      • Schmutzler R.K.
      • et al.
      Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
      ]. PARP inhibitor maintenance administered after platinum-based chemotherapy also resulted in substantial increases in PFS in patients with newly diagnosed ovarian cancer and gBRCA1/2 mutations [
      • Ray-Coquard I.
      • Pautier P.
      • Pignata S.
      • et al.
      Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
      ,
      • Moore K.
      • Colombo N.
      • Scambia G.
      • et al.
      Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.
      ,
      • González-Martín A.
      • Pothuri B.
      • Vergote I.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ,
      • Coleman R.L.
      • Fleming G.F.
      • Brady M.F.
      • et al.
      Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.
      ].
      The subgroup analysis presented here evaluated the efficacy and safety of veliparib plus carboplatin–paclitaxel compared to placebo plus carboplatin–paclitaxel in patients without previous chemotherapy for metastatic disease. Veliparib added to carboplatin–paclitaxel reduced the risk of progression by 30%. This improvement in PFS was versus a highly active comparator. Median PFS was 13.1 months in the placebo plus carboplatin–paclitaxel group, increasing to 16.6 months in the veliparib plus carboplatin–paclitaxel group. The proportion of patients alive and progression-free at 3 years was more than doubled in the veliparib–carboplatin–paclitaxel group compared to placebo–carboplatin–paclitaxel (27.9% versus 13.0%). The durable PFS observed in this subgroup supports the hypothesis that platinum and PARP inhibitors may be particularly beneficial in earlier lines of treatment. The safety profile for this subgroup was consistent with the overall study population [
      • Diéras V.
      • Han H.S.
      • Kaufman B.
      • et al.
      Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer: a randomised, double-blind, placebo-controlled, phase 3 trial.
      ].
      An increase in OS with single-agent olaparib versus physician’s choice of capecitabine, vinorelbine or eribulin was reported for the subgroup of patients in the phase III OlympiAD trial without previous chemotherapy for metastatic breast cancer (HR 0.51, 95% CI 0.29–0.90; and median OS 22.6 versus 14.7 months) [
      • Robson M.E.
      • Tung N.
      • Conte P.
      • et al.
      OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.
      ]. For patients in BROCADE3 without previous chemotherapy for metastatic disease, median OS exceeded 2 years in both treatment arms. Although the comparison was not statistically significant, there was a numerical increase in median OS for veliparib versus control (36.0 versus 29.9 months). These data further suggest the potential benefit of a treatment strategy that incorporates both platinum and PARP inhibitor when used in earlier treatment lines. Multiple mechanisms conferring resistance to both platinum and PARP inhibitor have been described [
      • Lord C.J.
      • Ashworth A.
      PARP inhibitors: synthetic lethality in the clinic.
      ]. Using both of these agents in the first-line metastatic setting may yield long-term benefit by allowing patients to receive two classes of agents to which they are particularly susceptible.
      Sequential single-agent therapy has been recommended for the treatment of advanced breast cancer. In BROCADE3, a different treatment strategy was evaluated that comprised a combination regimen of carboplatin and paclitaxel with or without the addition of veliparib during combination treatment and continued if chemotherapy is discontinued without disease progression. Given the high ORR that approached 80% in both arms, 3-year PFS rate of 27.9% in the veliparib group versus 13% in the control group and median OS of greater than 2 years in both arms and of 3 years in the veliparib group, such a treatment strategy may be suitable for patients with metastatic breast cancer, particularly those with gBRCA mutations.
      For tumour types including ovarian, treatment regimens consisting of induction chemotherapy followed by maintenance are commonly used. In the current study, a portion of patients discontinued chemotherapy prior to progression and continued veliparib/placebo as monotherapy at an increased dose. The PFS curves exhibit delayed separation, and veliparib treatment after chemotherapy was discontinued for this subset of patients which may contribute to this late observation of benefit. However, the study was not designed to isolate the benefit of veliparib given in combination compared to maintenance monotherapy. Treatment strategies including induction and maintenance warrant further investigation in advanced breast cancer.
      Although this study enrolled both patients with ER and/or PgR positive disease and patients with ER and PgR negative disease, the durable PFS observed in the first-line subgroup was not confined to patients with a particular hormone receptor status. Within these groups, HRs for progression were comparable, as were median PFS times at 15.1 and 17.7 months for ER and/or PgR+ and TNBC patients receiving the veliparib plus carboplatin–paclitaxel regimen, respectively.
      Additional exploratory subgroup analysis in patients without previous chemotherapy in any setting showed HRs for PFS and OS of 0.55 (95% CI 0.33–0.91) and 0.76 (95% CI 0.41–1.43) in favour of the veliparib-containing arm, suggesting this regimen may be particularly effective in chemotherapy-naïve patients. A previous trial of veliparib with carboplatin–paclitaxel for treatment of metastatic TNBC in the neoadjuvant setting did not meet the primary end-point of increased pathologic complete response. However, this study used a lower veliparib dose and did not select for patients with BRCA mutations. Its outcome therefore may not reflect the potential of this combination regimen for the current population.
      The majority of patients in the BROCADE3 study had no prior chemotherapy for metastatic disease. Among those patients who had received prior chemotherapy for metastatic disease, median PFS and median OS observed were numerically shorter than among first-line patients as expected for a more heavily pre-treated population. The HR for PFS in this subgroup suggested a comparable treatment effect as in the first-line subgroup. However, the subgroup of patients with previous chemotherapy for metastatic disease was small and the HR for PFS had a nominal p value >0.05.
      The current analysis is limited by the lack of power for significance in the comparison between treatment groups in the subgroup of patients without previous cytotoxic therapy for metastatic disease, although it was pre-planned. Results in patient groups defined by receptor status within the first-line subgroup or by the lack of previous cytotoxic therapy in any setting were exploratory and limited by small numbers. Time interval from primary diagnosis to study start and the proportion of patients with de novo breast cancer are not available; potential imbalances in these characteristics may introduce bias and limit interpretation of results.

      5. Conclusions

      These results indicate that veliparib plus carboplatin–paclitaxel was an effective treatment in patients without previous cytotoxic therapy for metastatic disease. Addition of veliparib improved PFS, with long median PFS and OS times observed. These results suggest a benefit of this treatment approach in early lines for patients with advanced/metastatic gBRCA mutation-associated breast cancer when chemotherapy is indicated.

      Author contributions

      All authors contributed to study conception, design and recruitment. BKA, HSH, BK, HW, MF, J-PA, SLP and VD contributed to provision of patients and patient care. All authors contributed to data analysis, collection and interpretation, and were responsible for writing the manuscript and approval of the final version.

      Funding statement

      AbbVie provided financial support for the study and participated in the design, study conduct, analysis and interpretation of data as well as the writing, review and approval of the manuscript. No honoraria or payments were made for authorship.

      Availability of data and material

      AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g. protocols and Clinical Study Reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
      This clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html.

      Conflict of interest statement

      BK Arun has received research support to her institution from AbbVie, PharmaMar, Astra Zeneca and Invitae, and is a Steering Committee (non-paid) member for AbbVie.
      HS Han has received research funding to her institution from AbbVie, Arvinas, Prescient, Horizon, Karyopharm, BMS, Novartis, Pfizer, GSK, Marker Therapeutics, Seattle Genetics and Zymeworks. She has received a grant from the Department of Defense and is on the speakers’ bureau for Lilly.
      B Kaufman is an Advisory Board member for AbbVie, Astra Zeneca, Roche, Novartis and Pfizer.
      H Wildiers’ institution received consulting fees and honoraria from Roche, Astra Zeneca, Amgen, Lilly, Novartis, AbbVie, Vifor Pharma, Pfizer, Celldex Therapeutics, Janssen-CILAG, TRM Oncology, PUMA Biotechnology, ORION Corporation and an unrestricted research grant from Roche. He received travel support from Roche and Pfizer.
      M Friedlander reports a consulting/advisory role for AstraZeneca, MSD, AbbVie, Lilly, Takeda and Novartis. He is on the speakers’ bureau for AstraZeneca. He has received honoraria from AstraZeneca, MSD, Lilly, Takeda, Novartis and GSK, and has received research funding from BeiGene, AstraZeneca and Novartis.
      JP Ayoub has received research funding to his instituion from AbbVie and Boston Biomedical. He is a consultant for Astra Zeneca, Eisai, Eli Lilly, Novartis, Pfizer, Puma and Roche.
      SL Puhalla is a consultant for AbbVie, MedImmune, Celldex, Puma, Pfizer, AstraZeneca, Eisai and Nanostring. She has received research funding to her institution from AbbVie, Pfizer, Lilly, Novartis, Incyte, Covance-Bayer, Astra Zeneca, Genentech and Medivation.
      VC Diéras reports a consulting/advisory role to Roche/Genentech, Novartis, Lilly, Pfizer, Astellas, AbbVie, MSD, Tesaro, Daiichi Sankyo, Odonate, Seattle Genetics and Astra Zeneca.
      KM Bell-McGuinn, BA Bach, CK Ratajczak and D Maag are AbbVie employees and own stock.
      M Kundu is a former AbbVie employee and may own stock.

      Acknowledgements

      AbbVie and the authors thank all the trial investigators and the patients who participated in this clinical trial, and their families, study coordinators, and support staff. Medical writing support was provided by Ana Mrejeru, Ph.D., of AbbVie.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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