Abstract PS10-41: PARP inhibitors for treatment of BRCA positive metastatic breast cancer: A systematic review and meta-analysis
Authors: Kunwor Ranju , Silver Daniel P , Bhattacharya Saveri , Jaslow Rebecca , Fellin Frederick , Lopez Ana Maria , Abu-Khalaf Maysa M 
Published: February 2021

Background: PARP Inhibitors (inh), Olaparib and Talazoparib, are approved for deleterious germline BRCA mutated (gBRCA+) metastatic breast cancer (MBC). This approval was based on a progression-free survival (PFS) benefit seen in two randomized controlled trials (RCTs). Other PARP inh such as Veliparib and Niraparib have also been studied. We conducted this meta-analysis of RCTs aiming to assess PFS and OS of PARP inh in gBRCA+ MBC.

Methods: We performed a systematic search for RCTs using Cochrane Library, PubMed, Embase, and Web of Science up to June 2020. Only phase II and III RCTs evaluating PFS for PARP inh alone or in combination with chemotherapy (CT) to standard CT were eligible for this meta-analysis. The pooled analysis of hazard ratio (HR) was performed with RevMan 5.4 software using random effect model.

Results: A total of 5 RCTs including 1563 patients were included in this meta-analysis. Baseline study characteristics are listed in Table 1. The pooled HR for PFS was 0.77 (95%CI 0.55-1.09) and the pooled HR for OS was 0.96 (95%CI 0.80-1.16). The only statistically significant adverse event more common in PARP inh group was anemia (Odds Ratio, 3.01; CI95%, 1.14-7.93, P=0.03). (Table 2)

Conclusion: The results of our meta-analysis confirmed the previously reported PFS benefit of PARP inh either alone or with standard CT when compared to standard CT alone in gBRCA+ MBC. PARP inh when combined with temozolomide did not show PFS benefit. OS benefit is not seen with PARP inh alone or with standard CT. Ongoing trials are evaluating the benefit of PARP inh in early stage gBRCA+ BC.

Table 1: Baseline study characteristics as experimental group vs. control groupVCP: veliparib with carboplatin/paclitaxelVT: veliparib with temozolomidePCP: placebo plus carboplatin/paclitaxelNA: Not available** Subgroup germline BRCA+ pts (n=37, 13 vs 24) is used for PFS and OS analysis in this study.TrialsSample sizeExperimental groupControl groupECOG PS % (0/1/2)Previous CT no. (%)Previous platinum no. (%)Median PFS (mo)Median OS (mo)OlympiAD302 (205 Vs 97)OlaparibStandard CT (Capecitabine or Eribulin orVinorelbine)72.2/28.8/0 Vs 63.9/36.1/0146 (71.2) Vs 69 (71.1)60 (29.3) Vs 26 (26.8)7.0 Vs 4.219.3 Vs 17.1EMBRACA431 (287 Vs 144)TalazoparibStandard therapy53.3/44.3/2.1 Vs 58.3/39.6/1.4176(61.4) Vs 90(62.5)46 (16.0) Vs 30 (20.8)8.6 Vs 5.619.3 Vs 19.5BROCADE284 (97 Vs 99)VCPPCP92/5 Vs 93/623(23.7) Vs 37(37.4)NA14.1 Vs 12.328.3 Vs 25.9(94 Vs 99)VTPCP91/3 Vs 93/628(30.6) Vs 37 (37.4)NA7.4 Vs 12.319.1 Vs 25.9BROCADE-3509 (337 Vs 172)VCPPCPNA19%8%14.5 Vs 12.633.5 Vs 28.2SWOG S1416 **321Veliparib + CisplatinPlacebo + Cisplatin69/41Vs 57/4351(32) Vs 49(31)14(9) Vs 18(11)6.2 Vs 6.414.2 Vs 14.6BRAVO-NiraparibPhysician choice CTStudy was prematurely closed after an interim analysis showed too many patients were not completing the necessary assessments in the control arm, and it was no longer suitable as a registration trial.

Table 2: Side effect profile of PARP inh arm vs. CT armNA: Not available**side effect includes all 154 pts in experimental arm and 149 in control armAdverse Events (%)OlympiAD EMBRACABROCADE(VCP & VT Vs PCP)BROCADE-3SWOG S1416**Odds Ratio for Adverse EventsAnemia Grade ≥333 (16.1) Vs 4 (4.4)112 (39.2) Vs 6 (4.8)16 (17.2) &7 (7.5) Vs 17 (17.7)91(27) Vs 29(17)35(23) vs 11(7)3.01 (1.14,7.93) P=0.03Neutropenia Grade ≥319 (9.3) Vs 24 (26.4)60 (20.9) Vs 44 (34.9)52(55.9) &34(36.6) Vs 53 (55.2)175(52) Vs 86 (50)71(46) vs 29(19)0.80 (0.40, 1.62) P=0.53Leukopenia Grade ≥37(3.4) Vs 9 (9.9)19 (6.6) Vs 11(8.7)15(16.1) &11(11.8) Vs 11 (11.5)NA42 (27) Vs 11 (7)1.19 (0.42,3.38) P=0.74Nausea/Vomiting Grade ≥30 Vs 1 (1.1)8 (2.7) Vs 4(3.2)2(2.2) &5(5.4) Vs 3 (3.1)NA28(18) Vs 16(10)1.45 (0.85,2.46) P=0.17Diarrhea Grade ≥31 (0.5) Vs 02 (0.7) Vs 7 (5.6)4(4.3) & 2(2.2) Vs 7(7.3)NANA0.33 (0.13, 0.85) P=0.02Fatigue Grade ≥36 (2.9) vs 1 (1.1)5 (1.7) Vs 4 (3.2)5(5.4) &3(3.2) Vs 8(8.3)NA8(5) Vs 9(6)0.73 (0.40,1.33) P=0.30Treatment discontinuation due to any AE10 (4.9) Vs 7(7.7)17 (5.9) Vs 11 (8.7)NANA0.72 (0.39,1.34) P=0.30

Citation Format: Ranju Kunwor, Daniel P Silver, Saveri Bhattacharya, Rebecca Jaslow, Frederick Fellin, Ana Maria Lopez, Maysa M Abu-Khalaf. PARP inhibitors for treatment of BRCA positive metastatic breast cancer: A systematic review and meta-analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-41.