Abstract P4-13-11: Meta-analyses of visceral versus non-visceral metastases treated by SERM, AI & SERD agents as 1st line endocrine therapy (ET) for HR+ breast cancer (BC)
Authors: Robertson JFR , Paridaens R , Bogaerts J , Lichfield J , Bradbury I , Campbell C 
Published: May 2019

Introduction: There is continuing debate whether efficacy of ET is different in non-visceral metastases (nVM) than VM. Recently fulvestrant 500mg, has been reported to have greater efficacy than an aromatase inhibitor (AI), anastrozole, particularly in nVM – implying efficacy may be both site and agent dependent. Absence of significant overall survival (OS) difference in PALOMA 1 & 3 has increased interest in site of disease, especially given the OS advantage for fulvestrant 500mg monotherapy.

Patients & Methods: Individual patient level data was obtained from 7 randomised controlled trials (RCTs) involving SERM, AI & SERD used as 1st Line ET in known HR+ BC were used in this meta-analysis (MA). Five were Phase 3 double-blind, placebo controlled RCTs. Details of the studies, type of ET and patient numbers are shown in Table. All were rigorously assessed for clinical benefit rate (CBR), progression free survival (PFS), duration of clinical benefit (DoCB) and OS.: Details of the studies, types of ET and patient numbers are shown in the Table. Aa two stage MA IPD meta-analysis was used to analyse these outcomesCBR, PFS, OS & DoCB. Peto method for pooled odds ratios was used to calculate p values and CI for CBR, yYusef pPeto method was used to calculate p-values and CI for PFS, OS, and DoCB. Random effect for trial was included when Tarone's test for heterogeneity was significant, otherwise fixed effect models were generated.

Results:

Outcome data is present for each study and then summarised under SERM, AI, SERD and 'all Ets combined'. Odds Ratios (Ors) & Hazard Ratios (HRs) for VM versus nVM by endocrine agent are shown in the Table

ETStudyNo. of Pats.HR+ Pats.CBRPFSOSDoCBSERM(n)(n)OR (95%CIs)HR (95%CIs)HR (95%CIs)HR (95%CIs)TamEORTC1891781.410.850.770.95Tam00273281441.330.981.051.26Tam00301821622.800.590.440.79Tam00252742091.100.780.730.78subtotal9736931.53** (1.11-2.10)0.79** (0.67-0.94)0.70* (0.52-0.94)0.92 (0.72-1.18)AIExeEORTC1821680.841.110.731.02Ana00273401543.850.550.361.06Ana00301711510.970.881.140.82AnaFALCON2322321.070.980.831.05AnaFIRST1031030.970.540.510.53Subtotal10288081.28 (0.73-2.22)0.80 (0.60-1.06)0.66* (0.45-0.95)0.92 (0.74-1.14)SERDFul 500CONFIRM1621622.940.630.561.15Ful 500FALCON2302302.710.410.450.61Ful 500FIRST1021024.110.580.440.55Subtotal4944943.06*** (2.00-4.06)0.56*** (0.45-0.70)0.50*** (0.39-0.65)0.71* (0.53-0.91)Total249519981.66*** (1.37-2.02)0.73*** (0.62-0.86)0.61*** (0.53-0.71)0.87* (0.75-1.00)CBR-Clinical Benefit Rate (n)= number of patients, pvalues p&lt;0.05*, p&lt;0.01**, p&lt;0.001***

Conclusions: This is the largest reported individual patient MA for nVM versus VM in patients with known HR+ advanced BC and clinical outcomes (CBR, DoCB, PFS & OS) approved to regulatory standards.

1) nVM had significantly better clinical outcomes compared to VM when treated by anti-estrogen receptor blocking agents (SERM & SERD) but not when treated by Ais, which have a fundamentally different mechanism of action.

2) SERD (Fulvestrant 500mg) significantly increased all four clinical outcomes. For nVM compared to VM, fulvestrant put more patients into CB, kept them in remission (DoCB) for longer, resulting in 44% reduction in disease progression and a 50% reduction in death.

3) Site of metastases (ie nVM or VM) is one of the factors to consider when selecting patients for endocrine mono or combination ET (plus CDK4/6i) in the 1st Line setting.

Citation Format: Robertson JFR, Paridaens R, Bogaerts J, Lichfield J, Bradbury I, Campbell C. Meta-analyses of visceral versus non-visceral metastases treated by SERM, AI & SERD agents as 1st line endocrine therapy (ET) for HR+ breast cancer (BC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-11.