Abstract P4-04-09: New oral SERD elacestrant (RAD1901) shows efficacy in breast cancer models harbouring ESR1 mutations and enhances the antiproliferative activity of mTORC1 and CDK4/6 inhibitors
Authors: L-A Martin, S Pancholi, N Simigdala, J Nikitorowicz-Buniak, R Ribas, F Garner, T Bihani, M Dowsett
Journal: Cancer Research (2018)

Abstract Background: Targeting estrogen receptor (ER) signalling is the main therapeutic option for ER+ breast cancer (BC). However, over 30% of patients relapse with endocrine resistance emphasising the need for improved therapeutic strategies. The prevalence of ESR1 mutations in relapsed tumours highlights the sustained reliance on ER signalling, rationalising continued targeting of ER. Unlike other endocrine therapies such as aromatase inhibitors (AI) and tamoxifen, selective ER degraders (SERDs) are competitive ER antagonists, that induce a conformational change in ER resulting in ubiquitination and degradation via the proteasomal pathway. Fulvestrant has shown clinical utility in advanced BC but is limited by its pharmaceutical properties highlighting the need for SERDs with enhanced bioavailability and pharmacokinetic properties. Here, we show that elacestrant (RAD1901) an orally bioavailable SERD, has antitumor activity in endocrine sensitive and resistant models of ER+ BC. Furthermore, elacestrant enhances the efficacy of mTORC1 inhibitor, everolimus and CDK4/6 inhibition, in model systems. Methods: Several ER+ BC lines adapted to long-term E deprivation (LTED) and harbouring wild-type or a naturally occurring ESR1 mutation, were treated with elacestrant or fulvestrant +/- estradiol (E2). Effects on cell proliferation, cell signalling, cell cycle, transcription, ER protein stability and ER genomic binding were assessed. Efficacy in combination with everolimus, palbociclib and abemaciclib was also evaluated. Results: Cell proliferation assays in 2D and spheroids in the presence of 0.01nM E2 showed a concentration-dependent decrease in proliferation in response to elacestrant and fulvestrant. GI50 values for elacestrant in general were 10-fold higher than fulvestrant but equated to doses that are clinically achievable for the drug. Most importantly, elacestrant suppressed proliferation of two LTED models harbouring ESR1 mutations, MCF7 LTEDY537C (GI50 5nM) and SUM44-LTEDY537S (GI50 100nM). GI50 values of elacestrant and fulvestrant showed similar reduction of ER, progesterone receptor (PGR) and cyclinD1 together with decreased phosphorylation of retinoblastoma (RB), concordant with cell cycle arrest. Chromatin immunoprecipitation (ChIP) for ER in response to elacestrant or fulvestrant showed a reduction in recruitment of ER to TFF1, GREB1 and PGR promoters and concomitant reduction in mRNA expression of these genes in the presence of E2. Elacestrant-mediated ER depletion was dependent on the 26S proteasome, as addition of the proteasome inhibitor MG132, fully blocked elacestrant depletion of ER, similar to the effect of MG132 treatment in preventing fulvestrant-mediated ER turnover. The combination of elacestrant with CDK4/6 inhibitors, palbociclib or abemaciclib, demonstrated additivity compared with monotherapy. In addition, elacestrant inhibited growth of palbociclib-resistant MCF7 LTED cells. Conclusion: These findings highlight the potential utility of elacestrant as a 1st or 2nd line drug in the treatment of ER+ BC. The results support the testing of elacestrant versus fulvestrant after relapse on an AI, either alone or in combination with a CDK4/6 inhibitor. Citation Format: Martin L-A, Pancholi S, Simigdala N, Nikitorowicz-Buniak J, Ribas R, Garner F, Bihani T, Dowsett M. New oral SERD elacestrant (RAD1901) shows efficacy in breast cancer models harbouring ESR1 mutations and enhances the antiproliferative activity of mTORC1 and CDK4/6 inhibitors [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 P4-04-09.