Targeting estrogen receptor (ER) signaling is the main therapeutic option for ER-positive breast cancer, but more than 30% of patients relapse due to the development of endocrine resistance.1 However, the prevalence of ESR1 mutations in relapsed tumors highlights the sustained reliance on ER signaling, thereby providing a rationale for continued targeting of ER in developing improved therapeutic strategies. Different from other endocrine therapies, such as aromatase inhibitors and tamoxifen, selective ER degraders (SERDs) are competitive ER antagonists, and fulvestrant has shown clinical utility in advanced breast cancer, but is restricted by its limited bioavailability.2 This highlights the need for SERDs with enhanced bioavailability and improved pharmacokinetic properties.
At SABCS 2017, data were presented showing that elacestrant (RAD1901), an orally bioavailable SERD, has antitumor activity in endocrine-sensitive and resistant models of ER-positive breast cancer, and enhances the efficacy of the mTOR inhibitor, everolimus, and CDK4/6 inhibitors.3 Several ER-positive breast cancer cell lines adapted to long-term estrogen deprivation (LTED) and harboring a wild-type or naturally occurring ESR1 mutation were treated with elacestrant or fulvestrant with or without estradiol (E2). The investigators assessed effects on cell proliferation, cell signaling, cell cycle, transcription, ER protein stability, and ER genomic binding. Efficacy in combination with everolimus, palbociclib, and abemaciclib was also evaluated.
Cell proliferation assays showed a concentration-dependent decrease in proliferation in response to elacestrant and fulvestrant. GI50 values for elacestrant were generally 10-fold higher than fulvestrant but were related to doses that are clinically achievable for the drug. Most important, elacestrant suppressed proliferation of 2 LTED models harboring ESR1 mutations, MCF-7 LTEDY537C (GI50 5 nM) and SUM44-LTEDY537S (GI50 100 nM). GI50 values of elacestrant and fulvestrant showed similar reduction of ER, progesterone receptor, and cyclin D1 together with decreased phosphorylation of retinoblastoma, concordant with cell-cycle arrest. The combination of elacestrant with the CDK4/6 inhibitors, palbociclib or abemaciclib, demonstrated additive effects compared with monotherapy. In addition, elacestrant inhibited growth of palbociclib-resistant MCF-7 LTED cells.
The authors concluded that these findings highlight the potential utility of elacestrant as a first- or second-line drug in the treatment of ER-positive breast cancer. The results support the testing of elacestrant versus fulvestrant after relapse on aromatase inhibitor therapy, either alone or in combination with a CDK4/6 inhibitor.
- Fan W, et al. Future Med Chem. 2015;7:1511-1519.
- Moscetti L, et al. Oncotarget. 2017;8:54528-54536.
- Martin L-A, et al. SABCS 2017. Abstract P4-04-09.